Risk Factors

Latest Research News

We know that traumatic brain injury increases the risk of later developing neurodegenerative disorders such as Alzheimer's disease, but we haven't known why. New mouse studies suggest a reason.

In the research, mice who had a toxic form of tau protein (taken from mice who had suffered TBI) injected into their hippocampus, showed impaired memory and cognition. Moreover, levels of the aggregated tau protein not only increased in the hippocampus, but also in the cerebellum (which is quite some distance away from the hippocampus). This is consistent with other research showing that tau tangles spread from the initial injection site, using mice modeling Alzheimer's disease.

The study followed on from previous research showing that this form of tau protein increases after a traumatic brain injury and may contribute to development of chronic traumatic encephalopathy (a condition experienced by many professional athletes and military personnel).

The findings support the hypothesis that many of the symptoms of TBI may be down to an increase in these tau tangles, and that this may also be responsible for the increased risk for neurodegenerative disease. As an obvious corollary, it also suggests that the tau tangles are an important therapeutic target.


A study involving both mice and human cells adds to evidence that stress is a risk factor for Alzheimer's.

The study found that mice who were subjected to acute stress had more amyloid-beta protein in their brains than a control group. Moreover, they had more of a specific form of the protein, one that has a particularly pernicious role in the development of Alzheimer's disease.

When human neurons were treated with the stress hormone corticotrophin releasing factor (CRF), there was also a significant increase in the amyloid proteins.

It appears that CRF causes the enzyme gamma secretase to increase its activity. This produces more amyloid-beta.

The finding supports the idea that reducing stress is one part of reducing your risk of developing Alzheimer's.

A neurotic personality increases the risk of Alzheimer's disease

An interesting study last year supports this.

The study, involving 800 women who were followed up some 40 years after taking a personality test, found that women who scored highly in "neuroticism" in middle age, have a greater chance of later developing Alzheimer's. People who have a tendency to neuroticism are more readily worried, distressed, and experience mood swings. They often have difficulty in managing stress.

The women, aged 38 to 54, were first tested in 1968, with subsequent examinations in 1974, 1980, 1992, 2000, and 2005. Neuroticism and extraversion were assessed in 1968 using the Eysenck Personality Inventory. The women were asked whether they had experienced long periods of high stress at each follow-up.

Over the 38 years, 153 developed dementia (19%), of whom 104 were diagnosed with Alzheimer's (13% of total; 68% of those with dementia).

A greater degree of neuroticism in midlife was associated with a higher risk of Alzheimer's and long-standing stress. This distress accounted for a lot of the link between neuroticism and Alzheimer's.

Extraversion, while associated with less chronic stress, didn't affect Alzheimer's risk. However, high neuroticism/low extraversion (shy women who are easily worried) was associated with the highest risk of Alzheimer's.

The finding supports the idea that long periods of stress increase the risk of Alzheimer's, and points to people with neurotic tendencies, who are more sensitive to stress, as being particularly vulnerable.



This sounds like pseudoscience, but it appears in Journal of Neuroscience, so … Weirdly, a rat study has found that sleeping on the side (the most common posture for humans and other animals) is the best position for efficiently removing waste from the brain.

Brain waste includes amyloid-beta and tau proteins, whose build-up is a critical factor in the development of Alzheimer's disease.

The study used imaging of the glymphatic pathway, which clears waste products from the brain by filtering cerebrospinal fluid through the brain and exchanging it with interstitial fluid. The process is most efficient during sleep, and its efficiency is affected by the level of consciousness. The researchers compared glymphatic transport during sleep when anesthetized rodents’ brains were in three positions—lateral (side), prone (down), and supine (up).

Of course, these findings need to be confirmed in humans (which might be tricky!), but there is, after all, no harm in changing your sleep position, if you don't already sleep on your side (though I concede it can be a difficult thing to change).

Apart from providing a practical tip for fighting age-related cognitive decline and dementia, the finding also supports the idea that one of the purposes of sleep is to ‘clean up’ the mess that accumulates while we are awake.

The finding is also consistent with increasing evidence that sleep disturbances are a factor in the development and progression of dementia.


[3956] Lee H, Xie L, Yu M, Kang H, Feng T, Deane R, Logan J, Nedergaard M, Benveniste H. The Effect of Body Posture on Brain Glymphatic Transport. The Journal of Neuroscience [Internet]. 2015 ;35(31):11034 - 11044. Available from: http://www.jneurosci.org/content/35/31/11034

A comparison of Alzheimer’s prevalence across the world using 'age-standardized' data (which predict Alzheimer's rates if all countries had the same population birth rate, life expectancy and age structure) has found a strong correlation between national sanitation levels and Alzheimer's, with better hygiene associated with higher rates of Alzheimer’s.

This fits in with the idea that’s been floating around for a while, that over-sanitized environments reduce exposure to a diverse range of microorganisms, perhaps impairing proper development of the immune system. Hence, the rising incidence of allergies and auto-immune diseases in developed countries.

The study compared data from 192 countries. Higher rates of Alzheimer's were seen in countries with higher levels of sanitation, countries with much lower rates of infectious disease, and more urbanized countries. For example, UK and France have 9% higher Alzheimer's rates than Kenya and Cambodia; Switzerland and Iceland have 12% higher rates of Alzheimer's than China and Ghana; UK and Australia have 10% higher rates than Bangladesh and Nepal.

Differences in levels of sanitation, infectious disease and urbanization accounted respectively for 33%, 36% and 28% of the discrepancy in Alzheimer's rates between countries.

Previous research has shown that in the developed world, dementia rates doubled every 5.8 years compared with 6.7 years in low income, developing countries, and that Alzheimer's prevalence in Latin America, China and India are all lower than in Europe, and, within those regions, lower in rural compared with urban settings.

Having said all that, I would query the reliability of Alzheimer’s statistics from less developed countries. A recent study from China, for example, found dramatic under-reporting of Alzheimer’s. While this is certainly a plausible hypothesis, I think the wide variability in diagnosing Alzheimer’s stands in the way of this sort of comparison.



Full text freely available at http://emph.oxfordjournals.org/content/2013/1/173.full

Analysis of post-mortem with and without dementia has found lipopolysaccharide, a component of an oral bacterium (Porphyromonas gingivalis), in four out of 10 Alzheimer’s disease brain samples, but not in any of the 10 brains of people who didn’t have Alzheimer’s.

Gingivitis is extremely common, and about 64% of American seniors (65+) have moderate or severe periodontal disease.

The finding adds to evidence linking gum disease and Alzheimer’s.


A study comparing blood serum levels of the DDT metabolite, DDE, in 86 patients with Alzheimer's disease (average age 74) and 79 controls (average age 70), has found that levels of DDE were 3.8 times higher in 74 of the 86 Alzheimer’s patients (86%). Having the Alzheimer’s gene, APOe4, plus high levels of the pesticide, produced more severe cognitive impairment.

Brain cell studies found that DDE increased production of the amyloid precursor protein (APP).

DDT was banned in the U.S. in 1972, but is still used elsewhere. It also takes a long time to break down in the environment. DDE was found in 75-80% of blood samples collected from the Centers for Disease Control and Prevention for a national health and nutrition survey.



A mouse study has found that mice (genetically engineered for Alzheimer’s) who were sleep deprived for eight weeks, not only showed significant cognitive impairment, but also showed a significant increase in the amount of tau protein that became phosphorylated and formed tangles. The other main characteristic of Alzheimer’s, amyloid-beta plaques, was not affected.

The findings are consistent with growing evidence of a link between sleep disturbance and Alzheimer’s, and suggests that chronic sleep disturbance accelerates Alzheimer’s pathology, and should be treated.

The sleep-deprived mice were given 20 hours of light each day, while the control mice were kept on a schedule of 12 hours of light and 12 hours of darkness.


Data from 1.1 million young Swedish men (conscription information taken at age 18) has shown that those with poorer cardiovascular fitness were 2.5 times more likely to develop early-onset dementia later in life and 3.5 times more likely to develop mild cognitive impairment, while those with a lower IQ had a 4 times greater risk of early dementia and a threefold greater risk of MCI. A combination of both poor cardiovascular fitness and low IQ entailed a more than 7 times greater risk of early-onset dementia, and more than 8 times greater risk of MCI.

The increased risk remained even when controlled for other risk factors, such as heredity, medical history, and social-economic circumstances.

The development of early-onset dementia was taken from national disease registries. During the study period, a total of 660 men were diagnosed with early-onset dementia.

A further study of this database, taken from 488,484 men, of whom 487 developed early-onset dementia (at a median age of 54), found nine risk factors for early-onset dementia that together accounted for 68% of the attributable risk. These factors were alcohol intoxication, stroke, use of antipsychotics, depression, father's dementia, drug intoxication other than alcohol, low cognitive function at age 18, low stature at age 18, and high blood pressure at age 18.




Data from 1,425 cognitively healthy older adults (70-89) has found that a diagnosis of chronic obstructive pulmonary disease (COPD) was associated with an 83% greater risk of developing non-amnestic mild cognitive impairment. The greatest risk was among patients who had COPD for more than five years.

Over the study period, 230 (16%) developed amnestic MCI, 97 (7%) nonamnestic MCI, 27 (2%) MCI of unknown type, and 16 dementia (1%).


A study involving 97 healthy older adults (65-89) has found that those with the “Alzheimer’s gene” (APOe4) who didn’t engage in much physical activity showed a decrease in hippocampal volume (3%) over 18 months. Those with the gene who did exercise showed no change in the size of their hippocampus, nor did those without the gene, regardless of exercise. Physical activity was classified as low if the participant reported two or fewer days per week of low intensity activity, such as no activity, slow walking or light chores. Physical activity was classified as high if the participant reported three or more days/week of moderate to vigorous activity

The finding suggests that those with the risky gene will benefit most from regular exercise — indeed, this is as yet the only known means to counteract hippocampal shrinkage.


[3605] Smith JCarson, Nielson KA, Woodard JL, Seidenberg M, Durgerian S, Hazlett KE, Figueroa CM, Kandah CC, Kay CD, Matthews MA, et al. Physical activity reduces hippocampal atrophy in elders at genetic risk for Alzheimer's disease. Frontiers in Aging Neuroscience [Internet]. 2014 ;6. Available from: http://journal.frontiersin.org/Journal/10.3389/fnagi.2014.00061/full

It’s often argued that telling people that they carry genes increasing their risk of Alzheimer’s will simply upset them to no purpose. A new study challenges that idea.

The study, involving 648 middle-aged adults tested for the “Alzheimer's gene” APOe4, found that 4% were in the highest risk group (carrying two copies of APOe4), while 34% had a single copy, and 62% had none. A year later, APOe4 carriers did not experience more anxiety, depression or distress than non-carriers, and were more active in efforts to reduce their risk of Alzheimer's disease — by exercising, eating a healthy diet and taking recommended vitamins and medications.

However, a more recent study of older adults has found that being told of their genetic status affected their cognitive performance. Specifically, those told they had the Alzheimer's gene judged their memory more harshly, and performed more poorly on a verbal memory test, than those who had the gene but had chosen not to be told. Similarly, those told they did not have the Alzheimer's gene judged their memory more positively, and performed better on the memory test, than those who didn't have the gene but didn't know that.

This is, of course, entirely in keeping with research showing that a person's beliefs about their memory have a significant effect on their cognition.

The study involved 144 cognitively normal older adults (aged 52–89), of whom 74 knew their genetic status (25 had the gene vs 49 without), and 70 did not (25 with vs 45 without).

Taking the findings from both these studies together, it seems likely that providing appropriate advice and support to those informed of their negative genetic status is vital, and that this may be particularly crucial for older adults, who may be more vulnerable to negative results.



Karlawish et al. 2013. What is the experience of being an APOE4 homozygote? Findings from the REVEAL Study. Presented on July 16 at the 2013 Alzheimer's Association International Conference.

Lineweaver  TT;  Bondi  MW;  Galasko  D;  Salmon  DP:  Effect of knowledge of APOE genotype on subjective and objective memory performance in healthy older adults.  Am J Psychiatry 2014; 171:201–208

11 new genetic susceptibility factors for Alzheimer’s identified

The largest international study ever conducted on Alzheimer's disease (I-GAP) has identified 11 new genetic regions that increase the risk of late-onset Alzheimer’s, plus 13 other genes yet to be validated. Genetic data came from 74,076 patients and controls from 15 countries.

Eleven genes for Alzheimer's disease have previously been identified.

Some of the newly associated genes confirm biological pathways already known to be involved, including the amyloid (SORL1, CASS4 ) and tau (CASS4 , FERMT2 ) pathways. The role of the immune response and inflammation (HLA-DRB5/DRB1 , INPP5D , MEF2C ) already implied by previous work (CR1, TREM2) is reinforced, as are the importance of cell migration (PTK2B), lipid transport and endocytosis (SORL1 ). New hypotheses have also emerged related to hippocampal synaptic function (MEF2C , PTK2B), the cytoskeleton and axonal transport (CELF1 , NME8, CASS4) as well as myeloid and microglial cell functions (INPP5D).

All this reinforces the idea that there are several paths to Alzheimer's, and no single treatment approach is likely to be successful.


[3586] Lambert J-C, Ibrahim-Verbaas CA, Harold D, Naj AC, Sims R, Bellenguez C, Jun G, DeStefano AL, Bis JC, Beecham GW, et al. Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer's disease. Nature Genetics [Internet]. 2013 ;45(12):1452 - 1458. Available from: http://www.nature.com/ng/journal/v45/n12/full/ng.2802.html

ADAM10 mutations increase risk of Alzheimer's

Mouse studies have found that two mutations in a gene called ADAM10 (which codes for an enzyme involved in processing the amyloid precursor protein) impaired the folding of the gene, resulting in an increase in toxic amyloid-beta, and reduced neurogenesis in the hippocampus. Previous research had found that either of these mutations was associated with an increased risk of Alzheimer’s in seven families with the late-onset form of the disease.

The finding suggests that increasing ADAM10 activity might be a potential therapeutic approach.


[3610] Suh J, Choi SH, Romano DM, Gannon MA, Lesinski AN, Kim DY, Tanzi RE. ADAM10 Missense Mutations Potentiate β-Amyloid Accumulation by Impairing Prodomain Chaperone Function. Neuron [Internet]. 2013 ;80(2):385 - 401. Available from: http://www.cell.com/article/S0896627313007940/abstract

TREM2 gene variant has dramatic effect on brain atrophy

Back in January 2013, a study (initially involving 2261 Icelanders, but then repeated on data from the U.S., Norway, the Netherlands, and Germany) reported on a rare genetic variant (TREM2) that nearly trebled Alzheimer’s risk. The variant was found in 0.46% of controls aged 85+. Carriers (aged 85-100) without Alzheimer’s also had poorer cognitive function than non-carriers.

TREM2 is thought to have an anti-inflammatory role, and so it’s thought that this rare mutation reduces its effectiveness.

In a more recent study, brain scans of 478 older adults (average age 76), of whom 100 had Alzheimer's, 221 had MCI and 157 were healthy controls, found that those carrying the TREM2 mutation lost 1.4-3.3% more of their brain tissue than non-carriers, and twice as fast. The loss appeared to be concentrated in the temporal lobe and hippocampus. Those carrying the TREM2 mutation may develop the disease three years earlier than expected.


[3581] Jonsson T, Stefansson H, Steinberg S, Jonsdottir I, Jonsson PV, Snaedal J, Bjornsson S, Huttenlocher J, Levey AI, Lah JJ, et al. Variant of TREM2 Associated with the Risk of Alzheimer's Disease. New England Journal of Medicine [Internet]. 2013 ;368(2):107 - 116. Available from: http://www.nejm.org/doi/full/10.1056/NEJMoa1211103

Rajagopalan, P., Hibar, D.P., & Thompson, P.M. (2013). TREM2 and neurodegenerative disease. The New England Journal of Medicine, 369(16), 1564-1567. Published online Oct. 16, 2013; doi:10.1056/NEJMc1306509

Understanding a protein's role in familial Alzheimer's disease

Genetic engineering of human induced pluripotent stem cells has revealed very specifically how a key mutated protein is involved in familial Alzheimer's. Familial Alzheimer’s is a subset of early-onset Alzheimer's disease that is caused by inherited gene mutations.

The study looked at presenilin 1 (PS1), a protein that catalyzes gamma-secretase, an enzyme that splits amyloid precursor protein (APP), creating amyloid-beta. About 20% of the time, these cuts result in potentially harmful amyloid-beta fragments. What this study has found is that mutations in PS1 double the frequency of these bad cuts. Such PS1 mutations are the most common cause of familial Alzheimer’s disease.


[3620] Woodruff G, Young JE, Martinez FJ, Buen F, Gore A, Kinaga J, Li Z, Yuan SH, Zhang K, Goldstein LSB. The Presenilin-1 ΔE9 Mutation Results in Reduced γ-Secretase Activity, but Not Total Loss of PS1 Function, in Isogenic Human Stem Cells. Cell Reports [Internet]. 2013 ;5(4):974 - 985. Available from: http://www.cell.com/article/S2211124713006025/abstract

Rare genomic mutations linked to familial Alzheimer's

Mutations in three genes – amyloid precursor protein (APP) and presenilins 1 and 2 – account for around half of all cases of early-onset familial Alzheimer's. A new study has now implicated 10 copy-number variants (duplications or deletions creating a change in the number of copies of a gene), which were found in affected members of 10 families with early-onset Alzheimer's. Notably, different genomic changes were identified in each family.

Genetic data from 261 families with at least one member who developed Alzheimer's before the age of 65 found that two families had CNVs that included the well-established APP gene, but 10 others had CNVs not previously associated with Alzheimer's (although two, CHMP2B and MAPT, have been associated with frontotemporal dementia).

CNVs are now thought to have a greater impact on genomic diversity than do single-nucleotide changes (single-nucleotide polymorphisms, SNPs, are the most common type of genetic variation, involving a change in a single nucleotide: A, G, T, C).


[3577] Hooli BV, Kovacs-Vajna ZM, Mullin K, Blumenthal MA, Mattheisen M, Zhang C, Lange C, Mohapatra G, Bertram L, Tanzi RE. Rare autosomal copy number variations in early-onset familial Alzheimer’s disease. Molecular Psychiatry [Internet]. 2014 ;19(6):676 - 681. Available from: http://www.nature.com/mp/journal/v19/n6/full/mp201377a.html

A brain imaging study of 162 healthy babies (2-25 months) has found that those who carried the ApoE4 gene (60 of the 162) tended to have increased brain growth in areas in the frontal lobe, and decreased growth in several areas in the middle and rear of the brain (precuneus, posterior/middle cingulate, lateral temporal, and medial occipitotemporal regions) — areas that tend to be affected in Alzheimer’s disease.

While this does not mean that those children are destined to develop Alzheimer’s, the findings do suggest brains of ApoE4 carriers tend to develop differently from those of non-carriers, and perhaps these early changes provide a “foothold” for the development of Alzheimer’s pathologies.


[3567] Dean DC, Jerskey BA, Chen K, et al. Brain differences in infants at differential genetic risk for late-onset alzheimer disease: A cross-sectional imaging study. JAMA Neurology [Internet]. 2014 ;71(1):11 - 22. Available from: http://dx.doi.org/10.1001/jamaneurol.2013.4544

A gene linked to Alzheimer's has been linked to brain changes in childhood. This gene, SORL1, has two connections to Alzheimer’s: it carries the code for the sortilin-like receptor, which is involved in recycling some molecules before they develop into amyloid-beta; it is also involved in lipid metabolism, putting it at the heart of the vascular risk pathway.

Brain imaging of 186 healthy individuals (aged 8-86) found that, even among the youngest, those with a specific variant of SORL1 showed a reduction in white matter connections. Post-mortem brain tissue from 269 individuals (aged 0-92) without Alzheimer's disease, found that the same SORL1 variant was linked to a disruption in the process by which the gene translated its code to become the sortilin-like receptor, and this was most prominent during childhood and adolescence. Another set of post-mortem brains from 710 individuals (aged 66-108), of whom the majority had mild cognitive impairment or Alzheimer's, found that the SORL1 risk gene was linked with the presence of amyloid-beta.

It may be that, for those carrying this gene variant, lifestyle interventions may be of greatest value early in life.


[3570] Felsky D, Szeszko P, Yu L, Honer WG, De Jager PL, Schneider JA, Malhotra AK, Lencz T, Ikuta T, Pipitone J, et al. The SORL1 gene and convergent neural risk for Alzheimer’s disease across the human lifespan. Molecular Psychiatry [Internet]. 2013 . Available from: http://www.nature.com/mp/journal/vaop/ncurrent/full/mp2013142a.html

Analysis of data from 237 patients with mild cognitive impairment (mean age 79.9) has found that, compared to those carrying the ‘normal’ ApoE3 gene (the most common variant of the ApoE gene), the ApoE4 carriers showed markedly greater rates of shrinkage in 13 of 15 brain regions thought to be key components of the brain networks disrupted in Alzheimer’s.


[3578] Hostage CA, Choudhury KR, Doraiswamy MP, Petrella JR. Mapping the Effect of the Apolipoprotein E Genotype on 4-Year Atrophy Rates in an Alzheimer Disease–related Brain Network. Radiology [Internet]. 2013 ;271(1):211 - 219. Available from: http://pubs.rsna.org/doi/abs/10.1148/radiol.13131041

Two studies indicate that young people carrying the “Alzheimer’s gene” (ApoE4) do not have the pathological changes found later in life. The first study, involving 1412 adolescents, found no differences in hippocampal volume or asymmetry as a function of gene status. The second study, involving 173 young adults (average age, 28 ± 7.6 years), found no difference in plasma concentrations of amyloid-beta peptides.


[3583] Khan W, Giampietro V, Ginestet C, Dell'Acqua F, Bouls D, Newhouse S, Dobson R, Banaschewski T, Barker GJ, Bokde ALW, et al. No Differences in Hippocampal Volume between Carriers and Non-Carriers of the ApoE ε4 and ε2 Alleles in Young Healthy Adolescents. Journal of Alzheimer's Disease [Internet]. 2014 ;40(1):37 - 43. Available from: http://dx.doi.org/10.3233/JAD-131841

[3627] Zimmermann R, Huber E, Schamber C, Lelental N, Mroczko B, Brandner S, Maler JM, Oberstein T, Szmitkowski M, Rauh M, et al. Plasma Concentrations of the Amyloid-β Peptides in Young Volunteers: The Influence of the APOE Genotype. Journal of Alzheimer's Disease [Internet]. 2014 ;40(4):1055 - 1060. Available from: http://dx.doi.org/10.3233/JAD-132687

Analysis of data from more than 8,000 people, most of them older than 60, has revealed that, among the 5,000 people initially tested cognitively normal, carrying one copy of the “Alzheimer’s gene” (ApoE4) only slightly increased men’s risk of developing MCI or Alzheimer’s — but nearly doubled women’s risk (healthy men with APOE4 were 27% more likely to develop MCI or Alzheimer’s compared to those without the gene, while female carriers had an 81% greater risk).

Among the 2,200 who were initially diagnosed with mild cognitive impairment, women were more likely to progress to Alzheimer’s (116% greater risk vs 64% for men), but the difference wasn’t significant. However, it was significant when only comparing carriers of 2 copies of the common ApoE3 variant with carriers of one ApoE3 copy and one ApoE4 copy (there are three variants of the ApoE gene: E3 is the most common; E4 is the ‘bad’ one; E2 is actually protective). Analysis of imaging and biomarker data from 1,000 patients confirmed the gender difference.

A gender difference was first suggested in a 1997 paper, but the research had never been followed up until recently. The current study was preceded by a 2012 imaging study, that found that female ApoE4 carriers had brain connectivity significantly different from normal, while male carriers’ brains were little different than normal.

While it’s not known why there should be such differences, biomarkers suggested that the increased female risk has something to do with tau pathology. Previous research has also indicated that ApoE4 interacts with estrogen.

The finding suggests why Alzheimer’s is so much more common in women — not just because they tend to live longer, but because they are, indeed, more at risk. It also tells us that research referencing the ApoE gene should separate by gender.



[3549] Altmann A, Tian L, Henderson VW, Greicius MD, Alzheimer's Disease Neuroimaging Initiative (ADNI). Sex modifies the APOE-related risk of developing Alzheimer disease. Annals of Neurology [Internet]. 2014 ;75(4):563 - 573. Available from: http://onlinelibrary.wiley.com/doi/10.1002/ana.24135/abstract

Analysis of 700 subjects from the Alzheimer's Disease Neuroimaging Initiative has revealed a genetic mutation (rs4728029) that’s associated with people who develop Alzheimer’s pathology but don’t show clinical symptoms in their lifetime. The gene appears to be related to an inflammatory response in the presence of phosphorylated tau. In other words, some people’s brains react to phosphorylated tau with a ‘bad’ inflammatory response, while others don’t.


[3576] Hohman TJ, Koran MEI, Thornton-Wells TA, Alzheimer's Disease Neuroimaging Initiative (ADNI). Genetic modification of the relationship between phosphorylated tau and neurodegeneration. Alzheimer's & Dementia: The Journal of the Alzheimer's Association [Internet]. 2014 . Available from: http://www.alzheimersanddementia.com/article/S1552-5260(14)00013-2/abstract

Studies linking head trauma with increased risk and earlier age of onset for Alzheimer's disease have yielded contradictory results. Now a population-based study involving 448 healthy older adults (70+) and 141 seniors with mild cognitive impairment has found that a history of head trauma was associated with higher levels of amyloid-beta plaques (a marker for Alzheimer’s) in those with MCI, but not in the cognitively normal. Similar rates of self-reported head trauma were found in the two groups (17% and 18%, respectively).


[3591] Mielke MM, Savica R, Wiste HJ, Weigand SD, Vemuri P, Knopman DS, Lowe VJ, Roberts RO, Machulda MM, Geda YE, et al. Head trauma and in vivo measures of amyloid and neurodegeneration in a population-based study. Neurology [Internet]. 2014 ;82(1):70 - 76. Available from: http://www.neurology.org/content/82/1/70

Analysis of 5715 cases from the National Alzheimer's Coordinating Center (NACC) database has found that nearly 80% of more than 4600 Alzheimer's disease patients showed some degree of vascular pathology, compared with 67% of the controls, and 66% in the Parkinson's group. The link was especially strong for younger patients with Alzheimer’s.

The findings support the view that early management of vascular risk factors, such as high blood pressure and cholesterol, and adopting a 'heart healthy' diet as well as exercise and other lifestyles in midlife, may delay or prevent the onset of dementia due to Alzheimer's.


[3612] Toledo JB, Arnold SE, Raible K, Brettschneider J, Xie SX, Grossman M, Monsell SE, Kukull WA, Trojanowski JQ. Contribution of cerebrovascular disease in autopsy confirmed neurodegenerative disease cases in the National Alzheimer’s Coordinating Centre. Brain [Internet]. 2013 ;136(9):2697 - 2706. Available from: http://brain.oxfordjournals.org/content/136/9/2697

Following on from the evidence that Alzheimer’s brains show higher levels of metals such as iron, copper, and zinc, a mouse study has found that amyloid plaques in Alzheimer’s-like brains with significant neurodegeneration have about 25% more copper than those with little neurodegeneration. This is consistent with a human study showing very high levels of copper in Alzheimer’s plaques.

Iron, though doubled in Alzheimer’s brains compared to controls, was not significantly different as a function of neurodegeneration, and zinc showed very little difference.

The findings suggest that the cellular control of copper is altered in some way in Alzheimer’s brains, while the increase in oxidized iron suggests it might be useful as a biomarker for the early diagnosis of Alzheimer’s.


[3555] Bourassa MW, Leskovjan AC, Tappero RV, Farquhar ER, Colton CA, Van Nostrand WE, Miller LM. Elevated copper in the amyloid plaques and iron in the cortex are observed in mouse models of Alzheimer's disease that exhibit neurodegeneration. Biomedical Spectroscopy and Imaging [Internet]. 2013 ;2(2):129 - 139. Available from: http://dx.doi.org/10.3233/BSI-130041

An Italian study has found that a significant percentage of Alzheimer’s patients suffer from Obstructive Sleep Apnea Syndrome. This respiratory disorder, which causes people to temporarily stop breathing during their sleep, affects cerebral blood flow, promoting cognitive decline. The finding adds to evidence that detecting and treating OSA early is important for preventing cognitive decline and dementia.


Buratti, L. et al. 2013. Vascular Impairment in Alzheimer’s Disease: The Role of Obstructive Sleep Apnea. Journal of Alzheimer's Disease, 38 (2), 445-53.

Data from 70 older adults (average age 76) in the Baltimore Longitudinal Study of Aging has found that those who reported poorer sleep (shorter sleep duration and lower sleep quality) showed a greater buildup of amyloid-beta plaques.


[3606] Spira AP, Gamaldo AA, An Y, et al. Self-reported sleep and β-amyloid deposition in community-dwelling older adults. JAMA Neurology [Internet]. 2013 ;70(12):1537 - 1543. Available from: http://dx.doi.org/10.1001/jamaneurol.2013.4258

A new discovery helps explain why the “Alzheimer’s gene” ApoE4 is such a risk factor. It appears that ApoE4 causes a dramatic reduction in SirT1, an "anti-aging protein" that is targeted by resveratrol (present in red wine). This reduction in SirT1 was associated with a change in the way the amyloid precursor protein (APP) was processed. Moreover, there was evidence that ‘bad’ tau and amyloid-beta could be prevented by increasing SirT1.


[3611] Theendakara V, Patent A, Libeu CPA, Philpot B, Flores S, Descamps O, Poksay KS, Zhang Q, Cailing G, Hart M, et al. Neuroprotective Sirtuin ratio reversed by ApoE4. Proceedings of the National Academy of Sciences [Internet]. 2013 ;110(45):18303 - 18308. Available from: http://www.pnas.org/content/110/45/18303

A study involving genetically engineered fruit flies adds to our understanding of why sleep and bioclock disruptions are common in those with Alzheimer's disease. People with Alzheimer's often have poor biological rhythms — periods of sleep become shorter and more fragmented, resulting in periods of wakefulness at night and snoozing during the day. It has been thought that Alzheimer’s destroys the biological clock, but this new study indicates that the clock is still working — however, it’s being ignored by other parts of the brain.


[3560] Chen K-F, Possidente B, Lomas DA, Crowther DC. The central molecular clock is robust in the face of behavioural arrhythmia in a Drosophila model of Alzheimer’s disease. Disease Models & Mechanisms [Internet]. 2014 ;7(4):445 - 458. Available from: http://dmm.biologists.org/content/7/4/445

Brain scans of 10 persons with Down syndrome but no dementia, 10 persons with Down syndrome and dementia, and 10 healthy controls, have revealed a linear correlation between cognitive ability and compromised white matter connections in the frontal lobes among those with Down syndrome. Those with higher cognitive ability and motor skill coordination had healthier white matter integrity, and those with additional dementia showed the most deterioration.

Adults with Down Syndrome are known to be at high risk of developing Alzheimer’s after age 40.


[3600] Powell D, Caban-Holt A, Jicha G, Robertson W, Davis R, Gold BT, Schmitt FA, Head E. Frontal white matter integrity in adults with Down syndrome with and without dementia. Neurobiology of Aging [Internet]. 2014 ;35(7):1562 - 1569. Available from: http://www.sciencedirect.com/science/article/pii/S0197458014001596

A study involving 74 older adults (70+), of whom 3 had mild dementia, 33 were cognitively normal and 38 had mild cognitive impairment, has found that high levels of "good" cholesterol and low levels of "bad" cholesterol correlated with lower levels of the amyloid-beta plaques in the brain (a hallmark of Alzheimer's disease).


Previous research has indicated that about a quarter of older adults who become mildly depressed will go on to become seriously depressed within a year or two. A study comparing problem-solving therapy for primary care — a seven-step approach delivered by non-mental-health professionals to help patients resolve difficulties and thus improve coping skills and confidence — with a program of dietary coaching (same number of sessions and hours), has found that elderly adults with mild symptoms of depression responded equally well to both treatments.

The study involved 244 participants, of whom 90 were African-American. Only 9% of people in each intervention went on to experience an episode of major depression, and they all had a similar reduction in depressive symptoms over the two-year study period. Both approaches were equally successful among black and white participants.

The benefit of both programs is assumed to lie in the way they give people greater perceived control over their lives.


A study involving 614 patients with type 2 diabetes (mean age 62) has found that longer duration of diabetes was associated with more brain volume loss, particularly in the gray matter. Roughly, for every 10 years of diabetes, the brain was similar to that of a non-diabetic person who was two years older.

However, the study did not confirm any association of diabetes characteristics with small vessel ischemic disease.


A large study, involving 3,690 older adults, has found that drugs with strong anticholinergic effects cause memory and cognitive impairment when taken continuously for a mere two months. Moreover, taking multiple drugs with weaker anticholinergic effects, such as many common over-the-counter digestive aids, affected cognition after 90 days’ continuous use. In both these cases, the risk of cognitive impairment doubled (approximately).

More positively, risk of Alzheimer’s did not seem to be affected (however, I do have to wonder how much weight we can put on that, given the apparent length of the study — although this is not a journal to which I have access, so I can’t be sure of that).

Although somewhat unexpected, previous research linking anticholinergics and cognitive impairment is consistent with this new finding.

Anticholinergic drugs block the neurotransmitter acetylcholine. Older adults commonly use over-the-counter drugs with anticholinergic effects as sleep aids and to relieve bladder leakage. Drugs with anticholinergic effects are also frequently prescribed for many chronic diseases including hypertension, cardiovascular disease and chronic obstructive pulmonary disease.

You can download a list detailing the ‘anticholinergic burden’ of medications at: http://www.indydiscoverynetwork.org/AnticholinergicCognitiveBurdenScale.html


[3449] Cai X, Campbell N, Khan B, Callahan C, Boustani M. Long-term anticholinergic use and the aging brain. Alzheimer's & Dementia: The Journal of the Alzheimer's Association [Internet]. 2013 ;9(4):377 - 385. Available from: http://www.alzheimersanddementia.com/article/S1552-5260(12)00081-7/abstract

A new study adds to growing evidence of a link between sleep problems and Alzheimer’s. The interesting thing is that this association – between sleep apnea and Alzheimer’s biomarkers — wasn’t revealed until the data was separated out according to BMI.

Those with sleep apnea and a BMI under 25 showed several Alzheimer’s biomarkers (increased levels of tau in the cerebrospinal fluid, greater atrophy of the hippocampus, glucose hypometabolism in regions vulnerable to Alzheimer’s). This (with the exception of glucose hypometabolism in the mediotemporal lobe only) was not found in those with sleep apnea and a higher BMI.

The study involved 68 healthy older adults (average age 71), of whom 18 had normal breathing, 33 mild sleep apnea, and 17 moderate-severe apnea. Those in the latter group tended to have higher BMIs.

Some 10-20% of middle-aged adults in the U.S. have sleep apnea, and this jumps dramatically in those over 65 (30-60%), where the link to obesity is much smaller. The researchers suggest that early preclinical Alzheimer’s damage might be a reason, and plan follow-up research to assess what impact CPAP therapy for sleep apnea has on the Alzheimer’s biomarkers.

Those interested in the relationship between poor sleep and later development of Alzheimer’s might also like to read a Guardian article on the subject.


Osorio, R.S. et al. 2013. Sleep-Disordered Breathing, Aging And Risk For Alzheimer's Disease In Cognitively Normal Subjects. Abstract 38456. Presented at the ATS 2013 International Conference.

Because long-term cognitive decline can occur in some older adults after undergoing surgery, there has been some concern that exposure to anesthesia may be associated with increased dementia risk. It is therefore pleasing to report that data from the very large, long-running Mayo Clinic Study, the Rochester Epidemiology Project, has found that receiving general anesthesia for procedures after age 45 is not a risk factor for developing dementia.


[3409] Sprung J, Jankowski CJ, Roberts RO, Weingarten TN, Aguilar AL, Runkle KJ, Tucker AK, McLaren KC, Schroeder DR, Hanson AC, et al. Anesthesia and Incident Dementia: A Population-Based, Nested, Case-Control Study. Mayo Clinic Proceedings [Internet]. Submitted . Available from: http://www.mayoclinicproceedings.org/article/S0025-6196(13)00124-9/abstract

I’ve talked before about the evidence linking diabetes to an increased risk of Alzheimer’s disease, but now a new study suggests that elevated blood sugar levels increase Alzheimer’s risk even in those without diabetes, even in those without ‘pre-diabetes’.

The study used data from 124 cognitively normal, non-diabetic adults (aged 47-68) with a family history of Alzheimer’s disease. Higher faster serum glucose levels were associated with lower rates of metabolism in brain regions associated with reduced metabolism in Alzheimer’s. This link was not affected by the presence or otherwise of the so-called ‘Alzheimer’s gene’ (ApoE4).

The finding raises additional questions about the role of the metabolic process in the development of Alzheimer’s.


[3403] Burns CM, Chen K, Kaszniak AW, Lee W, Alexander GE, Bandy D, Fleisher AS, Caselli RJ, Reiman EM. Higher serum glucose levels are associated with cerebral hypometabolism in Alzheimer regions. Neurology [Internet]. 2013 ;80(17):1557 - 1564. Available from: http://www.neurology.org/content/80/17/1557

A study involving nearly 6,000 African American older adults has found those with a specific gene variant have almost double the risk of developing late-onset Alzheimer’s disease compared with African Americans who lack the variant. The size of the effect is comparable to that of the ‘Alzheimer’s gene’, APOE-e4.

The gene (ABCA7) is involved in the production of cholesterol and lipids. It also affects the transport of several important proteins, including amyloid precursor protein, which is involved in the production of amyloid-beta.

The finding suggests that lipid metabolism may be a more important pathway in Alzheimer’s disease in African Americans than in whites. Cholesterol and lipid imbalances are more common in African Americans.

The gene does not seem to be a significant risk factor for whites, adding more weight to the idea that there are multiple pathways to the disease, and showing that the genetic underpinnings may vary among different populations (although it should be noted that other genes linked to Alzheimer’s risk in white populations were also significant for this group).


[3364] Reitz C JG. VAriants in the atp-binding cassette transporter (abca7), apolipoprotein e ϵ4,and the risk of late-onset alzheimer disease in african americans. JAMA [Internet]. 2013 ;309(14):1483 - 1492. Available from: http://dx.doi.org/10.1001/jama.2013.2973

Analysis of data from 418 older adults (70+) has found that carriers of the ‘Alzheimer’s gene’, APOEe4, were 58% more likely to develop mild cognitive impairment compared to non-carriers. However, ε4 carriers with MCI developed Alzheimer’s at the same rate as non-carriers. The finding turns prevailing thinking on its head: rather than the gene increasing the risk of developing Alzheimer’s, it appears that it increases the risk of MCI — and people with MCI are the main source of new Alzheimer’s diagnoses.

In this regard, it’s worth noting that the cognitive effects of this gene variant have been demonstrated in adults as young as the mid-20s.

The finding points to the benefit of genetic testing for assessing your likelihood of cognitive impairment rather than dementia — and using this knowledge to build habits that fight cognitive impairment.


[3370] Brainerd CJ, Reyna VF, Petersen RC, Smith GE, Kenney AE, Gross CJ, Taub ES, Plassman BL, Fisher GG. The apolipoprotein E genotype predicts longitudinal transitions to mild cognitive impairment but not to Alzheimer's dementia: Findings from a nationally representative study. Neuropsychology. 2013 ;27(1):86 - 94.

Previous research has pointed to an association between not having teeth and a higher risk of cognitive decline and dementia. One reason might have to do with inflammation — inflammation is a well-established risk factor, and at least one study has linked gum disease to a higher dementia risk. Or it might have to do with the simple mechanical act of chewing, reducing blood flow to the brain. A new study has directly investigated chewing ability in older adults.

The Swedish study, involving 557 older adults (77+), found that those with multiple tooth loss, and those who had difficulty chewing hard food such as apples, had a significantly higher risk of developing cognitive impairments (cognitive status was measured using the MMSE). However, when adjusted for sex, age, and education, tooth loss was no longer significant, but chewing difficulties remained significant.

In other words, what had caused the tooth loss didn’t matter. The important thing was to maintain chewing ability, whether with your own natural teeth or dentures.

This idea that the physical act of chewing might affect your cognitive function (on a regular basis; I don’t think anyone is suggesting that you’re brighter when you chew!) is an intriguing and unexpected one. It does, however, give even more emphasis to the importance of physical exercise, which is a much better way of increasing blood flow to the brain.

The finding also reminds us that there are many things going on in the brain that may deteriorate with age and thus lead to cognitive decline and even dementia.

Problems with myelin — demyelination (seen most dramatically in MS, but also in other forms of neurodegeneration, including normal aging and depression); failure to develop sufficient myelin (in children and adolescents) — are increasingly being implicated in a wide range of disorders. A new animal study adds to that evidence by showing that social isolation brings about both depression and loss of myelin.

In the study, adult mice were isolated for eight weeks (which is of course longer for a mouse than it is to us) to induce a depressive-like state. They were then introduced to a mouse they hadn’t seen before. Although typically very social animals, those who had been socially isolated didn’t show any interest in interacting with the new mouse — a common pattern in human behavior as well.

Analysis of their brains revealed significantly lower levels of gene transcription for oligodendrocyte cells (the components of myelin) in the prefrontal cortex. This appeared to be caused by a lower production of heterochromatin (tightly packed DNA) in the cell nuclei, producing less mature oligodendrocytes.

Interestingly, even short periods of isolation were sufficient to produce changes in chromatin and myelin, although behavior wasn’t affected.

Happily, however, regardless of length of isolation, myelin production went back to normal after a period of social integration.

The findings add to the evidence that environmental factors can have significant effects on brain development and function, and support the idea that socializing is good for the brain.

It’s been unclear whether hormone therapy helps older women reduce their risk of Alzheimer’s or in fact increases the risk. To date, the research has been inconsistent, with observational studies showing a reduced risk, and a large randomized controlled trial showed an increased risk. As mentioned before, the answer to the inconsistency may lie in the timing of the therapy. A new study supports this view.

The 11-year study (part of the Cache County Study) involved 1,768 older women (65+), of whom 1,105 women had used hormone therapy (either estrogen alone or in combination with a progestin). During the study, 176 women developed Alzheimer's disease. This included 87 (7.9%) of the 1,105 women who had taken hormone therapy, and 89 (13.4%) of the 663 others.

Women who began hormone therapy, of any kind, within five years of menopause had a 30% lower risk of developing Alzheimer's within the study period (especially if they continued the therapy for 10 or more years). Those who began treatment more than five years after menopause, had a ‘normal’ risk (i.e., not reduced or increased). However, those who had started a combined therapy of estrogen and progestin when they were at least 65 years old had a significantly higher risk of developing Alzheimer’s.

The findings support the idea that the timing of hormone therapy, and the type, are critical factors, although the researchers cautiously note that more research is needed before they can make new clinical recommendations.

In a large Mayo Clinic study, self-reported diet was found to be significantly associated with the risk of seniors developing mild cognitive impairment or dementia over a four-year period.

The study involved 1,230 older adults (70-89) who completed a 128-item food-frequency questionnaire about their diet during the previous year. Of these, around three-quarters (937) showed no signs of cognitive impairment at the beginning of the study period, and were asked to return for follow-up cognitive assessments. These assessments took place every 15 months. After about four years, 200 (21%) had developed mild cognitive impairment (MCI) or dementia.

The likelihood of cognitive deterioration was significantly affected by the type of diet. Those with the highest carbohydrate intake were nearly twice as likely to develop cognitive impairment compared to those with the lowest carbohydrate consumption, and when total fat and protein intake were taken into account, they were 3.6 times likelier to develop impairment.

Those with the highest sugar intake were 1.5 times more likely to develop cognitive impairment.

But — a finding that will no doubt surprise many — those with the highest fat consumption were 42% less likely to develop cognitive impairment, compared to those with the lowest level of fats.

Less surprisingly, those with highest intake of protein had a reduced risk of 21%.

In other words, the worst diet you can have, if you want to keep your brain healthy, is one that receives most of its calories from carbohydrates and sugar, and relatively little from fats and protein.

The findings about carbs, sugar, and protein are consistent with other research. The finding regarding fats is somewhat more surprising. The inconsistency may lie in the type of fat. Research implicating high-fat diets as a risk factor in Alzheimer’s have used saturated fats. Diets high in olive oil, on the other hand, have been found to be beneficial.

It seems likely that the danger of carbs and too much sugar lies in the effects on glucose and insulin metabolism. Saturated fats also interfere with glucose metabolism. Alzheimer’s has sometimes been called Type 3 diabetes, because of its association with insulin problems.

Roberts RO, Roberts LA, Geda YE, Cha RH, Pankratz VS, O'Connor HM, Knopman DS, Petersen RC. 2012. Relative intake of macronutrients impacts risk of mild cognitive impairment or dementia. Journal of Alzheimers Disease, 32(2), 329-39.

I reported a few months ago on some evidence of a link between disturbed sleep and the development of Alzheimer’s. Now a mouse study adds to this evidence.

The mouse study follows on from an earlier study showing that brain levels of amyloid beta naturally rise when healthy young mice are awake and drop after they go to sleep, and that sleep deprivation disrupted this cycle and accelerated the development of amyloid plaques. This natural rhythm was confirmed in humans.

In the new study, it was found that this circadian rhythm showed the first signs of disruption as soon as Alzheimer’s plaques began forming in the mice’s brains. When the genetically engineered mice were given a vaccine against amyloid beta, the mice didn’t develop plaques in old age, the natural fluctuations in amyloid beta levels continued, and sleep patterns remained normal.

Research with humans in now underway to see whether patients with early markers of Alzheimer’s show sleep problems, and what the nature of these problems is.

Just to make it clear: the point is not so much that Alzheimer’s patients are more likely to have sleep problems, but that the sleep problems may in fact be part of the cause of Alzheimer’s disease development. The big question, of course, is whether you can prevent its development by attacking the dysfunction in circadian rhythm. (See more on this debate at Biomed)

I’ve reported before on the growing evidence that metabolic syndrome in middle and old age is linked to greater risk of cognitive impairment in old age and faster decline. A new study shows at least part of the reason.

The study involved 71 middle-aged people recruited from the Wisconsin Registry for Alzheimer's Prevention (WRAP), of whom 29 met the criteria for metabolic syndrome (multiple cardiovascular and diabetes risk factors including abdominal obesity, high blood pressure, high blood sugar and high cholesterol).

Those with metabolic syndrome averaged 15% less blood flow to the brain than those without the syndrome.

One tried and true method of increasing blood flow to the brain is of course through exercise.

The study was presented at the Alzheimer's Association International Conference in Vancouver, Canada by Barbara Bendlin.

The latest finding from the large, long-running Health, Aging, and Body Composition (Health ABC) Study adds to the evidence that preventing or controlling diabetes helps prevent age-related cognitive decline.

The study involves 3,069 older adults (70+), of whom 717 (23%) had diabetes at the beginning of the study in 1997. Over the course of the study, a further 159 developed diabetes. Those with diabetes at the beginning had lower cognitive scores, and showed faster decline. Those who developed diabetes showed a rate of decline that was between that faster rate and the slower rate of those who never developed diabetes.

Among those with diabetes, those who had higher levels of a blood marker called glycosylated hemoglobin had greater cognitive impairment. Higher levels of this blood marker reflect poorer control of blood sugar.

In other words, both duration and severity of diabetes are important factors in determining rate of cognitive decline in old age.

While the ‘Alzheimer’s gene’ is relatively common — the ApoE4 mutation is present in around 15% of the population — having two copies of the mutation is, thankfully, much rarer, at around 2%. Having two copies is of course a major risk factor for developing Alzheimer’s, and it has been thought that having a single copy is also a significant (though lesser) risk factor. Certainly there is quite a lot of evidence linking ApoE4 carriers to various markers of cognitive impairment.

And yet, the evidence has not been entirely consistent. I have been puzzled by this myself, and now a new finding suggests a reason. It appears there are gender differences in responses to this gene variant.

The study involved 131 healthy older adults (median age 70), whose brains were scanned. The scans revealed that in older women with the E4 variant, brain activity showed the loss of synchronization that is typically seen in Alzheimer’s patients, with the precuneus (a major hub in the default mode network) out of sync with other brain regions. This was not observed in male carriers.

The finding was confirmed by a separate set of data, taken from the Alzheimer's Disease Neuroimaging Initiative database. Cerebrospinal fluid from 91 older adults (average age 75) revealed that female carriers had substantially higher levels of tau protein (a key Alzheimer’s biomarker) than male carriers or non-carriers.

It’s worth emphasizing that the participants in the first study were all cognitively normal — the loss of synchronization was starting to happen before visible Alzheimer’s symptoms appeared.

The findings suggest that men have less to worry about than women, as far as the presence of this gene is concerned. The study may also explain why more women than men get the disease (3 women to 2 men); it is not (although of course this is a factor) simply a consequence of women tending to live longer.

Whether or not these gender differences extend to carriers of two copies of the gene is another story.

A study involving those with a strong genetic risk of developing Alzheimer’s has found that the first signs of the disease can be detected 25 years before symptoms are evident. Whether this is also true of those who develop the disease without having such a strong genetic predisposition is not yet known.

The study involved 128 individuals with a 50% chance of inheriting one of three mutations that are certain to cause Alzheimer’s, often at an unusually young age. On the basis of participants’ parents’ medical history, an estimate of age of onset was calculated.

The first observable brain marker was a drop in cerebrospinal fluid levels of amyloid-beta proteins, and this could be detected 25 years before the anticipated age of onset. Amyloid plaques in the precuneus became visible on brain scans 15-20 years before memory problems become apparent; elevated cerebrospinal fluid levels of the tau protein 10-15 years, and brain atrophy in the hippocampus 15 years. Ten years before symptoms, the precuneus showed reduced use of glucose, and slight impairments in episodic memory (as measured in the delayed-recall part of the Wechsler’s Logical Memory subtest) were detectable. Global cognitive impairment (measured by the MMSE and the Clinical Dementia Rating scale) was detected 5 years before expected symptom onset, and patients met diagnostic criteria for dementia at an average of 3 years after expected symptom onset.

Family members without the risky genes showed none of these changes.

The risky genes are PSEN1 (present in 70 participants), PSEN2 (11), and APP (7) — note that together these account for 30-50% of early-onset familial Alzheimer’s, although only 0.5% of Alzheimer’s in general. The ‘Alzheimer’s gene’ APOe4 (which is a risk factor for sporadic, not familial, Alzheimer’s), was no more likely to be present in these carriers (25%) than noncarriers (22%), and there were no gender differences. The average parental age of symptom onset was 46 (note that this pushes back the first biomarker to 21! Can we speculate a connection to noncarriers having significantly more education than carriers — 15 years vs 13.9?).

The results paint a clear picture of how Alzheimer’s progresses, at least in this particular pathway. First come increases in the amyloid-beta protein, followed by amyloid pathology, tau pathology, brain atrophy, and decreased glucose metabolism. Following this biological cascade, cognitive impairment ensues.

The degree to which these findings apply to the far more common sporadic Alzheimer’s is not known, but evidence from other research is consistent with this progression.

It must be noted, however, that the findings are based on cross-sectional data — that is, pieced together from individuals at different ages and stages. A longitudinal study is needed to confirm.

The findings do suggest the importance of targeting the first step in the cascade — the over-production of amyloid-beta — at a very early stage.

Researchers encourage people with a family history of multiple generations of Alzheimer’s diagnosed before age 55 to register at http://www.DIANXR.org/, if they would like to be considered for inclusion in any research.

[2997] Bateman RJ, Xiong C, Benzinger TLS, Fagan AM, Goate A, Fox NC, Marcus DS, Cairns NJ, Xie X, Blazey TM, et al. Clinical and Biomarker Changes in Dominantly Inherited Alzheimer's Disease. New England Journal of Medicine [Internet]. 2012 :120723122607004 - 120723122607004. Available from: http://www.nejm.org/doi/full/10.1056/NEJMoa1202753

A number of studies have come out in recent years linking age-related cognitive decline and dementia risk to inflammation and infection (put inflammation into the “Search this site” box at the top of the page and you’ll see what I mean). New research suggests one important mechanism.

In a mouse study, mice engineered to be deficient in receptors for the CCR2 gene — a crucial element in removing beta-amyloid and also important for neurogenesis — developed Alzheimer’s-like pathology more quickly. When these mice had CCR2 expression boosted, accumulation of beta-amyloid decreased and the mice’s memory improved.

In the human study, the expression levels of thousands of genes from 691 older adults (average age 73) in Italy (part of the long-running InCHIANTI study) were analyzed. Both cognitive performance and cognitive decline over 9 years (according to MMSE scores) were significantly associated with the expression of this same gene. That is, greater CCR2 activity was associated with lower cognitive scores and greater decline.

Expression of the CCR2 gene was also positively associated with the Alzheimer’s gene — meaning that those who carry the APOE4 variant are more likely to have higher CCR2 activity.

The finding adds yet more weight to the importance of preventing / treating inflammation and infection.

[2960] Harries LW, Bradley-Smith RM, Llewellyn DJ, Pilling LC, Fellows A, Henley W, Hernandez D, Guralnik JM, Bandinelli S, Singleton A, et al. Leukocyte CCR2 Expression Is Associated with Mini-Mental State Examination Score in Older Adults. Rejuvenation Research [Internet]. 2012 :120518094735004 - 120518094735004. Available from: http://online.liebertpub.com/doi/abs/10.1089/rej.2011.1302

Naert, G. & Rivest S. 2012. Hematopoietic CC-chemokine receptor 2-(CCR2) competent cells are protective for the cognitive impairments and amyloid pathology in a transgenic mouse model of Alzheimer's disease. Molecular Medicine, 18(1), 297-313.

El Khoury J, et al. 2007. Ccr2 deficiency impairs microglial accumulation and accelerates progression of Alzheimer-like disease. Nature Medicine, 13, 432–8.

I’ve reported before on the evidence suggesting that carriers of the ‘Alzheimer’s gene’, APOE4, tend to have smaller brain volumes and perform worse on cognitive tests, despite being cognitively ‘normal’. However, the research hasn’t been consistent, and now a new study suggests the reason.

The e4 variant of the apolipoprotein (APOE) gene not only increases the risk of dementia, but also of cardiovascular disease. These effects are not unrelated. Apoliproprotein is involved in the transportation of cholesterol. In older adults, it has been shown that other vascular risk factors (such as elevated cholesterol, hypertension or diabetes) worsen the cognitive effects of having this gene variant.

This new study extends the finding, by looking at 72 healthy adults from a wide age range (19-77).

Participants were tested on various cognitive abilities known to be sensitive to aging and the effects of the e4 allele. Those abilities include speed of information processing, working memory and episodic memory. Blood pressure, brain scans, and of course genetic tests, were also performed.

There are a number of interesting findings:

  • The relationship between age and hippocampal volume was stronger for those carrying the e4 allele (shrinkage of this brain region occurs with age, and is significantly greater in those with MCI or dementia).
  • Higher systolic blood pressure was significantly associated with greater atrophy (i.e., smaller volumes), slower processing speed, and reduced working memory capacity — but only for those with the e4 variant.
  • Among those with the better and more common e3 variant, working memory was associated with lateral prefrontal cortex volume and with processing speed. Greater age was associated with higher systolic blood pressure, smaller volumes of the prefrontal cortex and prefrontal white matter, and slower processing. However, blood pressure was not itself associated with either brain atrophy or slower cognition.
  • For those with the Alzheimer’s variant (e4), older adults with higher blood pressure had smaller volumes of prefrontal white matter, and this in turn was associated with slower speed, which in turn linked to reduced working memory.

In other words, for those with the Alzheimer’s gene, age differences in working memory (which underpin so much of age-related cognitive impairment) were produced by higher blood pressure, reduced prefrontal white matter, and slower processing. For those without the gene, age differences in working memory were produced by reduced prefrontal cortex and prefrontal white matter.

Most importantly, these increases in blood pressure that we are talking about are well within the normal range (although at the higher end).

The researchers make an interesting point: that these findings are in line with “growing evidence that ‘normal’ should be viewed in the context of individual’s genetic predisposition”.

What it comes down to is this: those with the Alzheimer’s gene variant (and no doubt other genetic variants) have a greater vulnerability to some of the risk factors that commonly increase as we age. Those with a family history of dementia or serious cognitive impairment should therefore pay particular attention to controlling vascular risk factors, such as hypertension and diabetes.

This doesn’t mean that those without such a family history can safely ignore such conditions! When they get to the point of being clinically diagnosed as problems, then they are assuredly problems for your brain regardless of your genetics. What this study tells us is that these vascular issues appear to be problematic for Alzheimer’s gene carriers before they get to that point of clinical diagnosis.

Data from the Women's Health Study, involving 6,183 older women (65+), has found that it isn’t the amount of fat but the type of fat that is associated with cognitive decline. The women were given three cognitive function tests at two-yearly intervals, and filled out very detailed food frequency surveys at the beginning of the study.

Women who consumed the highest amounts of saturated fat (such as that from animals) had significantly poorer cognitive function compared to those who consumed the lowest amounts. Women who instead had a high intake of monounsaturated fats (such as olive oil) had better cognitive scores over time. Total fat, polyunsaturated fat, and trans fat, were not associated with cognitive performance.

The findings are consistent with research associating the Mediterranean diet (high in olive oil) with lower Alzheimer’s risk, and studies linking diets high in saturated fats with greater cognitive decline.

Damage to the retina (retinopathy) doesn’t produce noticeable symptoms in the early stages, but a new study indicates it may be a symptom of more widespread damage. In the ten-year study, involving 511 older women (average age 69), 7.6% (39) were found to have retinopathy. These women tended to have lower cognitive performance, and brain scans revealed that they had more areas of small vascular damage within the brain — 47% more overall, and 68% more in the parietal lobe specifically. They also had more white matter damage. They did not have any more brain atrophy.

These correlations remained after high blood pressure and diabetes (the two major risk factors for retinopathy) were taken into account. It’s estimated that 40-45% of those with diabetes have retinopathy.

Those with retinopathy performed similarly to those without on a visual acuity test. However, testing for retinopathy is a simple test that should routinely be carried out by an optometrist in older adults, or those with diabetes or hypertension.

The findings suggest that eye screening could identify developing vascular damage in the brain, enabling lifestyle or drug interventions to begin earlier, when they could do most good. The findings also add to the reasons why you shouldn’t ignore pre-hypertensive and pre-diabetic conditions.

Older adults who sleep poorly react to stress with increased inflammation

A study involving 83 older adults (average age 61) has found that poor sleepers reacted to a stressful situation with a significantly greater inflammatory response than good sleepers. High levels of inflammation increase the risk of several disorders, including cardiovascular disease and diabetes, and have been implicated in Alzheimer’s.

Each participant completed a self-report of sleep quality, perceived stress, loneliness and medication use. Around 27% were categorized as poor sleepers. Participants were given a series of tests of verbal and working memory designed to increase stress, with blood being taken before and after testing, as well as three more times over the next hour. The blood was tested for levels of a protein marker for inflammation (interleukin-6).

Poor sleepers reported more depressive symptoms, more loneliness and more perceived stress compared to good sleepers. Before cognitive testing, levels of IL-6 were the same for poor and good sleepers. However, while both groups showed increases in IL-6 after testing, poor sleepers showed a significantly larger increase — as much as four times larger and at a level found to increase risk for illness and death in older adults.

After accounting for loneliness, depression or perceived stress, this association remained. Surprisingly, there was no evidence that poor sleep led to worse cognitive performance, thus causing more stress. Poor sleepers did just as well on the tests as the good sleepers (although I note that we cannot rule out that poor sleepers were having to put in more effort to achieve the same results). Although there was a tendency for poor sleepers to be in a worse mood after testing (perhaps because they had to put in more effort? My own speculation), this mood change didn’t predict the increased inflammatory response.

The findings add to evidence that poor sleep (unfortunately common as people age) is an independent risk factor for cognitive and physical health, and suggest we should put more effort into dealing with it, rather than just accepting it as a corollary of age.

REM sleep disorder doubles risk of MCI, Parkinson's

A recent Mayo Clinic study has also found that people with rapid eye movement sleep behavior disorder (RBD) have twice the risk of developing mild cognitive impairment or Parkinson’s disease. Some 34% of those diagnosed with probable RBD developed MCI or Parkinson's disease within four years of entering the study, a rate 2.2 times greater than those with normal REM sleep.

Earlier research has found that 45% of those with RBD developed MCI or Parkinson's disease within five years of diagnosis, but these findings were based on clinical patients. The present study involved cognitively healthy older adults (70-89) participating in a population-based study of aging, who were diagnosed for probable RBD on the basis of the Mayo Sleep Questionnaire.

Genetic analysis of 9,232 older adults (average age 67; range 56-84) has implicated four genes in how fast your hippocampus shrinks with age (rs7294919 at 12q24, rs17178006 at 12q14, rs6741949 at 2q24, rs7852872 at 9p33). The first of these (implicated in cell death) showed a particularly strong link to a reduced hippocampus volume — with average consequence being a hippocampus of the same size as that of a person 4-5 years older.

Faster atrophy in this crucial brain region would increase people’s risk of Alzheimer’s and cognitive decline, by reducing their cognitive reserve. Reduced hippocampal volume is also associated with schizophrenia, major depression, and some forms of epilepsy.

In addition to cell death, the genes linked to this faster atrophy are involved in oxidative stress, ubiquitination, diabetes, embryonic development and neuronal migration.

A younger cohort, of 7,794 normal and cognitively compromised people with an average age of 40, showed that these suspect gene variants were also linked to smaller hippocampus volume in this age group. A third cohort, comprised of 1,563 primarily older people, showed a significant association between the ASTN2 variant (linked to neuronal migration) and faster memory loss.

In another analysis, researchers looked at intracranial volume and brain volume in 8,175 elderly. While they found no genetic associations for brain volume (although there was one suggestive association), they did discover that intracranial volume (the space occupied by the fully developed brain within the skull — this remains unchanged with age, reflecting brain size at full maturity) was significantly associated with two gene variants (at loci rs4273712, on chromosome 6q22, and rs9915547, on 17q21). These associations were replicated in a different sample of 1,752 older adults. One of these genes is already known to play a unique evolutionary role in human development.

A meta-analysis of seven genome-wide association studies, involving 10,768 infants (average age 14.5 months), found two loci robustly associated with head circumference in infancy (rs7980687 on chromosome 12q24 and rs1042725 on chromosome 12q15). These loci have previously been associated with adult height, but these effects on infant head circumference were largely independent of height. A third variant (rs11655470 on chromosome 17q21 — note that this is the same chromosome implicated in the study of older adults) showed suggestive evidence of association with head circumference; this chromosome has also been implicated in Parkinson's disease and other neurodegenerative diseases.

Previous research has found an association between head size in infancy and later development of Alzheimer’s. It has been thought that this may have to do with cognitive reserve.

Interestingly, the analyses also revealed that a variant in a gene called HMGA2 (rs10784502 on 12q14.3) affected intelligence as well as brain size.

Why ‘Alzheimer’s gene’ increases Alzheimer’s risk

Investigation into the so-called ‘Alzheimer’s gene’ ApoE4 (those who carry two copies of this variant have roughly eight to 10 times the risk of getting Alzheimer’s disease) has found that ApoE4 causes an increase in cyclophilin A, which in turn causes a breakdown of the cells lining the blood vessels. Blood vessels become leaky, making it more likely that toxic substances will leak into the brain.

The study found that mice carrying the ApoE4 gene had five times as much cyclophilin A as normal, in cells crucial to maintaining the integrity of the blood-brain barrier. Blocking the action of cyclophilin A brought blood flow back to normal and reduced the leakage of toxic substances by 80%.

The finding is in keeping with the idea that vascular problems are at the heart of Alzheimer’s disease — although it should not be assumed from that, that other problems (such as amyloid-beta plaques and tau tangles) are not also important. However, one thing that does seem clear now is that there is not one single pathway to Alzheimer’s. This research suggests a possible treatment approach for those carrying this risky gene variant.

Note also that this gene variant is not only associated with Alzheimer’s risk, but also Down’s syndrome dementia, poor outcome following TBI, and age-related cognitive decline.

On which note, I’d like to point out recent findings from the long-running Nurses' Health Study, involving 16,514 older women (70-81), that suggest that effects of postmenopausal hormone therapy for cognition may depend on apolipoprotein E (APOE) status, with the fastest rate of decline being observed among HT users who carried the APOe4 variant (in general HT was associated with poorer cognitive performance).

It’s also interesting to note another recent finding: that intracranial volume modifies the effect of apoE4 and white matter lesions on dementia risk. The study, involving 104 demented and 135 nondemented 85-year-olds, found that smaller intracranial volume increased the risk of dementia, Alzheimer's disease, and vascular dementia in participants with white matter lesions. However, white matter lesions were not associated with increased dementia risk in those with the largest intracranial volume. But intracranial volume did not modify dementia risk in those with the apoE4 gene.

More genes involved in Alzheimer’s

More genome-wide association studies of Alzheimer's disease have now identified variants in BIN1, CLU, CR1 and PICALM genes that increase Alzheimer’s risk, although it is not yet known how these gene variants affect risk (the present study ruled out effects on the two biomarkers, amyloid-beta 42 and phosphorylated tau).

Same genes linked to early- and late-onset Alzheimer's

Traditionally, we’ve made a distinction between early-onset Alzheimer's disease, which is thought to be inherited, and the more common late-onset Alzheimer’s. New findings, however, suggest we should re-think that distinction. While the genetic case for early-onset might seem to be stronger, sporadic (non-familial) cases do occur, and familial cases occur with late-onset.

New DNA sequencing techniques applied to the APP (amyloid precursor protein) gene, and the PSEN1 and PSEN2 (presenilin) genes (the three genes linked to early-onset Alzheimer's) has found that rare variants in these genes are more common in families where four or more members were affected with late-onset Alzheimer’s, compared to normal individuals. Additionally, mutations in the MAPT (microtubule associated protein tau) gene and GRN (progranulin) gene (both linked to frontotemporal dementia) were also found in some Alzheimer's patients, suggesting they had been incorrectly diagnosed as having Alzheimer's disease when they instead had frontotemporal dementia.

Of the 439 patients in which at least four individuals per family had been diagnosed with Alzheimer's disease, rare variants in the 3 Alzheimer's-related genes were found in 60 (13.7%) of them. While not all of these variants are known to be pathogenic, the frequency of mutations in these genes is significantly higher than it is in the general population.

The researchers estimate that about 5% of those with late-onset Alzheimer's disease have changes in these genes. They suggest that, at least in some cases, the same causes may underlie both early- and late-onset disease. The difference being that those that develop it later have more protective factors.

Another gene identified in early-onset Alzheimer's

A study of the genes from 130 families suffering from early-onset Alzheimer's disease has found that 116 had mutations on genes already known to be involved (APP, PSEN1, PSEN2 — see below for some older reports on these genes), while five of the other 14 families all showed mutations on a new gene: SORL1.

I say ‘new gene’ because it hasn’t been implicated in early-onset Alzheimer’s before. However, it has been implicated in the more common late-onset Alzheimer’s, and last year a study reported that the gene was associated with differences in hippocampal volume in young, healthy adults.

The finding, then, provides more support for the idea that some cases of early-onset and late-onset Alzheimer’s have the same causes.

The SORL1 gene codes for a protein involved in the production of the beta-amyloid peptide, and the mutations seen in this study appear to cause an under-expression of SORL1, resulting in an increase in the production of the beta-amyloid peptide. Such mutations were not found in the 1500 ethnicity-matched controls.


Older news reports on these other early-onset genes (brought over from the old website):

New genetic cause of Alzheimer's disease

Amyloid protein originates when it is cut by enzymes from a larger precursor protein. In very rare cases, mutations appear in the amyloid precursor protein (APP), causing it to change shape and be cut differently. The amyloid protein that is formed now has different characteristics, causing it to begin to stick together and precipitate as amyloid plaques. A genetic study of Alzheimer's patients younger than 70 has found genetic variations in the promoter that increases the gene expression and thus the formation of the amyloid precursor protein. The higher the expression (up to 150% as in Down syndrome), the younger the patient (starting between 50 and 60 years of age). Thus, the amount of amyloid precursor protein is a genetic risk factor for Alzheimer's disease.

Theuns, J. et al. 2006. Promoter Mutations That Increase Amyloid Precursor-Protein Expression Are Associated with Alzheimer Disease. American Journal of Human Genetics, 78, 936-946.


Evidence that Alzheimer's protein switches on genes

Amyloid b-protein precursor (APP) is snipped apart by enzymes to produce three protein fragments. Two fragments remain outside the cell and one stays inside. When APP is produced in excessive quantities, one of the cleaved segments that remains outside the cell, called the amyloid b-peptides, clumps together to form amyloid plaques that kill brain cells and may lead to the development of Alzheimer’s disease. New research indicates that the short "tail" segment of APP that is trapped inside the cell might also contribute to Alzheimer’s disease, through a process called transcriptional activation - switching on genes within the cell. Researchers speculate that creation of amyloid plaque is a byproduct of a misregulation in normal APP processing.

[2866] Cao X, Südhof TC. A Transcriptively Active Complex of APP with Fe65 and Histone Acetyltransferase Tip60. Science [Internet]. 2001 ;293(5527):115 - 120. Available from: http://www.sciencemag.org/content/293/5527/115


Inactivation of Alzheimer's genes in mice causes dementia and brain degeneration

Mutations in two related genes known as presenilins are the major cause of early onset, inherited forms of Alzheimer's disease, but how these mutations cause the disease has not been clear. Since presenilins are involved in the production of amyloid peptides (the major components of amyloid plaques), it was thought that such mutations might cause Alzheimer’s by increasing brain levels of amyloid peptides. Accordingly, much effort has gone into identifying compounds that could block presenilin function. Now, however, genetic engineering in mice has revealed that deletion of these genes causes memory loss and gradual death of nerve cells in the mouse brain, demonstrating that the protein products of these genes are essential for normal learning, memory and nerve cell survival.

Saura, C.A., Choi, S-Y., Beglopoulos, V., Malkani, S., Zhang, D., Shankaranarayana Rao, B.S., Chattarji, S., Kelleher, R.J.III, Kandel, E.R., Duff, K., Kirkwood, A. & Shen, J. 2004. Loss of Presenilin Function Causes Impairments of Memory and Synaptic Plasticity Followed by Age-Dependent Neurodegeneration. Neuron, 42 (1), 23-36.


[2858] Consortium ENIGM-A (ENIGMA), Cohorts Heart Aging Research Genomic Epidemiology (charge). Common variants at 12q14 and 12q24 are associated with hippocampal volume. Nature Genetics [Internet]. 2012 ;44(5):545 - 551. Available from: http://www.nature.com/ng/journal/v44/n5/full/ng.2237.html

[2909] Taal RH, Pourcain BS, Thiering E, Das S, Mook-Kanamori DO, Warrington NM, Kaakinen M, Kreiner-Møller E, Bradfield JP, Freathy RM, et al. Common variants at 12q15 and 12q24 are associated with infant head circumference. Nature Genetics [Internet]. 2012 ;44(5):532 - 538. Available from: http://www.nature.com/ng/journal/v44/n5/abs/ng.2238.html

[2859] Cohorts Heart Aging Research Genomic Epidemiology (charge), Consortium EGG (EGG). Common variants at 6q22 and 17q21 are associated with intracranial volume. Nature Genetics [Internet]. 2012 ;44(5):539 - 544. Available from: http://www.nature.com/ng/journal/v44/n5/full/ng.2245.html

[2907] Stein JL, Medland SE, Vasquez AA, Hibar DP, Senstad RE, Winkler AM, Toro R, Appel K, Bartecek R, Bergmann Ø, et al. Identification of common variants associated with human hippocampal and intracranial volumes. Nature Genetics [Internet]. 2012 ;44(5):552 - 561. Available from: http://www.nature.com/ng/journal/v44/n5/abs/ng.2250.html

[2925] Bell RD, Winkler EA, Singh I, Sagare AP, Deane R, Wu Z, Holtzman DM, Betsholtz C, Armulik A, Sallstrom J, et al. Apolipoprotein E controls cerebrovascular integrity via cyclophilin A. Nature [Internet]. 2012 . Available from: http://www.nature.com/nature/journal/vaop/ncurrent/full/nature11087.html?WT.ec_id=NATURE-20120517

Kang, J. H., & Grodstein F. (2012).  Postmenopausal hormone therapy, timing of initiation, APOE and cognitive decline. Neurobiology of Aging. 33(7), 1129 - 1137.

Skoog, I., Olesen P. J., Blennow K., Palmertz B., Johnson S. C., & Bigler E. D. (2012).  Head size may modify the impact of white matter lesions on dementia. Neurobiology of Aging. 33(7), 1186 - 1193.

[2728] Cruchaga C, Chakraverty S, Mayo K, Vallania FLM, Mitra RD, Faber K, Williamson J, Bird T, Diaz-Arrastia R, Foroud TM, et al. Rare Variants in APP, PSEN1 and PSEN2 Increase Risk for AD in Late-Onset Alzheimer's Disease Families. PLoS ONE [Internet]. 2012 ;7(2):e31039 - e31039. Available from: UR - http://dx.doi.org/10.1371/journal.pone.0031039,http://dx.doi.org/10.1371/journal.pone.0031039

Full text available at http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0031039

[2897] Pottier C, Hannequin D, Coutant S, Rovelet-Lecrux A, Wallon D, Rousseau S, Legallic S, Paquet C, Bombois S, Pariente J, et al. High frequency of potentially pathogenic SORL1 mutations in autosomal dominant early-onset Alzheimer disease. Molecular Psychiatry [Internet]. 2012 . Available from: http://www.nature.com/mp/journal/vaop/ncurrent/full/mp201215a.html

McCarthy, J. J., Saith S., Linnertz C., Burke J. R., Hulette C. M., Welsh-Bohmer K. A., et al. (2012).  The Alzheimer's associated 5′ region of the SORL1 gene cis regulates SORL1 transcripts expression. Neurobiology of Aging. 33(7), 1485.e1-1485.e8 - 1485.e1-1485.e8

A study involving 1,575 older adults (aged 58-76) has found that those with DHA levels in the bottom 25% had smaller brain volume (equivalent to about 2 years of aging) and greater amounts of white matter lesions. Those with levels of all omega-3 fatty acids in the bottom quarter also scored lower on tests of visual memory, executive function, and abstract thinking.

The finding adds to the evidence that higher levels of omega-3 fatty acids reduce dementia risk.

For more about omega-3 oils and cognition

Another study adds to the evidence that changes in the brain that may lead eventually to Alzheimer’s begin many years before Alzheimer’s is diagnosed. The findings also add to the evidence that what we regard as “normal” age-related cognitive decline is really one end of a continuum of which the other end is dementia.

In the study, brain scans were taken of 137 highly educated people aged 30-89 (participants in the Dallas Lifespan Brain Study). The amount of amyloid-beta (characteristic of Alzheimer’s) was found to increase with age, and around a fifth of those over 60 had significantly elevated levels of the protein. These higher amounts were linked with worse performance on tests of working memory, reasoning and processing speed.

More specifically, across the whole sample, amyloid-beta levels affected processing speed and fluid intelligence (in a dose-dependent relationship — that is, as levels increased, these functions became more impaired), but not working memory, episodic memory, or crystallized intelligence. Among the elevated-levels group, increased amyloid-beta was significantly associated with poorer performance for processing speed, working memory, and fluid intelligence, but not episodic memory or crystallized intelligence. Among the group without elevated levels of the protein, increasing amyloid-beta only affected fluid intelligence.

These task differences aren’t surprising: processing speed, working memory, and fluid intelligence are the domains that show the most decline in normal aging.

Those with the Alzheimer’s gene APOE4 were significantly more likely to have elevated levels of amyloid-beta. While 38% of the group with high levels of the protein had the risky gene variant, only 15% of those who didn’t have high levels carried the gene.

Note that, while the prevalence of carriers of the gene variant matched population estimates (24%), the proportion was higher among those in the younger age group — 33% of those under 60, compared to 19.5% of those aged 60 or older. It seems likely that many older carriers have already developed MCI or Alzheimer’s, and thus been ineligible for the study.

The average age of the participants was 64, and the average years of education 16.4.

Amyloid deposits varied as a function of age and region: the precuneus, temporal cortex, anterior cingulate and posterior cingulate showed the greatest increase with age, while the dorsolateral prefrontal cortex, orbitofrontal cortex, parietal and occipital cortices showed smaller increases with age. However, when only those aged 60+ were analyzed, the effect of age was no longer significant. This is consistent with previous research, and adds to evidence that age-related cognitive impairment, including Alzheimer’s, has its roots in damage occurring earlier in life.

In another study, brain scans of 408 participants in the Mayo Clinic Study of Aging also found that higher levels of amyloid-beta were associated with poorer cognitive performance — but that this interacted with APOE status. Specifically, carriers of the Alzheimer’s gene variant were significantly more affected by having higher levels of the protein.

This may explain the inconsistent findings of previous research concerning whether or not amyloid-beta has significant effects on cognition in normal adults.

As the researchers of the first study point out, what’s needed is information on the long-term course of these brain changes, and they are planning to follow these participants.

In the meantime, all in all, the findings do provide more strength to the argument that your lifestyle in mid-life (and perhaps even younger) may have long-term consequences for your brain in old age — particularly for those with a genetic susceptibility to Alzheimer’s.

A small study of the sleep patterns of 100 people aged 45-80 has found a link between sleep disruption and level of amyloid plaques (characteristic of Alzheimer’s disease). The participants were recruited from the Adult Children Study, of whom half have a family history of Alzheimer’s disease.

Sleep was monitored for two weeks. Those who woke frequently (more than five times an hour!) and those who spent less than 85% of their time in bed actually asleep, were more likely to have amyloid plaques. A quarter of the participants had evidence of amyloid plaques.

The study doesn’t tell us whether disrupted sleep leads to the production of amyloid plaques, or whether brain changes in early Alzheimer's disease lead to changes in sleep, but evidence from other studies do, I think, give some weight to the first idea. At the least, this adds yet another reason for making an effort to improve your sleep!

The abstract for this not-yet-given conference presentation, or the press release, don’t mention any differences between those with a family history of Alzheimer’s and those without, suggesting there was none — but since the researchers made no mention either way, I wouldn’t take that for granted. Hopefully we’ll one day see a journal paper providing more information.

The main findings are supported by another recent study. A Polish study involving 150 older adults found that those diagnosed with Alzheimer’s after a seven-year observation period were more likely to have experienced sleep disturbances more often and with greater intensity, compared to those who did not develop Alzheimer’s.

Ju, Y., Duntley, S., Fagan, A., Morris, J. & Holtzman, D. 2012. Sleep Disruption and Risk of Preclinical Alzheimer Disease. To be presented April 23 at the American Academy of Neurology's 64th Annual Meeting in New Orleans.

Bidzan L, Grabowski J, Dutczak B, Bidzan M. 2011. [Sleep disorders in the preclinical period of the Alzheimer's disease]. Psychiatria Polska, 45(6), 851-60. http://www.ncbi.nlm.nih.gov/pubmed/22335128

Following on from research showing an association between lower walking speed and increased risk of dementia, and weaker hand grip strength and increased dementia risk, a large study has explored whether this association extends to middle-aged and younger-old adults.

Part of the long-running Framingham study, the study involved 2,410 men and women with an average age of 62, who underwent brain scans and tests for walking speed, hand grip strength and cognitive function. During the follow-up period of up to 11 years, 34 people (1.4%) developed dementia (28 Alzheimer’s) and 79 people (3.3%) had a stroke.

Those who had a slower walking speed at the start of the study were one-and-a-half times more likely to develop dementia compared to people with faster walking speed, while stronger hand grip strength was associated with a 42% lower risk of stroke or transient ischemic attack in people over age 65.

Slower walking speed and weaker hand grip strength were also associated with lower brain volume and poorer cognitive performance. Specifically, those with slower walking speed scored significantly worse on tests of visual reproduction, paired associate learning, executive function, visual organization, and language (Boston Naming test). Higher hand grip strength was associated with higher scores on tests of visual reproduction, executive function, visual organization, language and abstraction (similarities test).

While the nature of the association is not yet understood, the findings do seem to support the benefits of physical fitness. At the least, these physical attributes can serve as pointers to the need for more investigation of an older person’s brain health. But they might also serve as a warning to improve physical fitness.

Camargo, E.C., Beiser, A., Tan, Z.S., Au, R., DeCarli, C., Pikula, A., Kelly-Hayes, M., Kase, C., Wolf, P. & Seshadri, S. 2012. Walking Speed, Handgrip Strength and Risk of Dementia and Stroke: The Framingham Offspring Study. To be presented April 25 at the American Academy of Neurology's 64th Annual Meeting in New Orleans.

More data from the long-running Mayo Clinic Study of Aging has revealed that, in this one part of the U.S. at least, MCI develops at an overall rate of 6.4% a year among older adults (70+), with a higher rate for men and the less-educated.

The study involved 1,450 older adults (aged 70-89), who underwent memory testing every 15 months for an average of three years. By the end of the study period, 296 people had developed MCI, a rate of 6.4% per year. For men, the rate was 7.2% compared to 5.7% for women.

It should be noted that these rates apply to a relatively homogeneous group of people. Participants come from one county in Minnesota, an overwhelmingly white part of the U.S.

MCI comes in two types: amnestic (involving memory loss) and non-amnestic. Amnestic MCI was more than twice as common as non-amnestic MCI. The incidence rate of aMCI was also higher for men (4.4%) than women (3.3%), as was the risk of naMCI (2% vs 1.1%).

Those who had less education also had higher rates of MCI. For aMCI, the rate for those with 12 years or less of education was 4.3%, compared to 3.25% for those with more education. Similarly, for naMCI, the rates were 2% and 1%, respectively.

While the great majority of people diagnosed with MCI continued to have the disorder or progressed to dementia, some 12% were later re-diagnosed as not having it. This, I would presume, probably reflects temporary ‘dips’ in cognitive performance as a consequence of physical or emotional problems.

The differences between aMCI and naMCI, and between genders, suggest that risk factors for these should be considered separately.

The study involved 104 healthy older adults (average age 87) participating in the Oregon Brain Aging Study. Analysis of the nutrient biomarkers in their blood revealed that those with diets high in omega 3 fatty acids and in vitamins C, D, E and the B vitamins had higher scores on cognitive tests than people with diets low in those nutrients, while those with diets high in trans fats were more likely to score more poorly on cognitive tests.

These were dose-dependent, with each standard deviation increase in the vitamin BCDE score ssociated with a 0.28 SD increase in global cognitive score, and each SD increase in the trans fat score associated with a 0.30 SD decrease in global cognitive score.

Trans fats are primarily found in packaged, fast, fried and frozen food, baked goods and margarine spreads.

Brain scans of 42 of the participants found that those with diets high in vitamins BCDE and omega 3 fatty acids were also less likely to have the brain shrinkage associated with Alzheimer's, while those with high trans fats were more likely to show such brain atrophy.

Those with higher omega-3 scores also had fewer white matter hyperintensities. However, this association became weaker once depression and hypertension were taken into account.

Overall, the participants had good nutritional status, but 7% were deficient in vitamin B12 (I’m surprised it’s so low, but bear in mind that these are already a select group, being healthy at such an advanced age) and 25% were deficient in vitamin D.

The nutrient biomarkers accounted for 17% of the variation in cognitive performance, while age, education, APOE genotype (presence or absence of the ‘Alzheimer’s gene’), depression and high blood pressure together accounted for 46%. Diet was more important for brain atrophy: here, the nutrient biomarkers accounted for 37% of the variation, while the other factors accounted for 40% (meaning that diet was nearly as important as all these other factors combined!).

The findings add to the growing evidence that diet has a significant role in determining whether or not, and when, you develop Alzheimer’s disease.

A certain level of mental decline in the senior years is regarded as normal, but some fortunate few don’t suffer from any decline at all. The Northwestern University Super Aging Project has found seniors aged 80+ who match or better the average episodic memory performance of people in their fifties. Comparison of the brains of 12 super-agers, 10 cognitively-normal seniors of similar age, and 14 middle-aged adults (average age 58) now reveals that the brains of super-agers also look like those of the middle-aged. In contrast, brain scans of cognitively average octogenarians show significant thinning of the cortex.

The difference between the brains of super-agers and the others was particularly marked in the anterior cingulate cortex. Indeed, the super agers appeared to have a much thicker left anterior cingulate cortex than the middle-aged group as well. Moreover, the brain of a super-ager who died revealed that, although there were some plaques and tangles (characteristic, in much greater quantities, of Alzheimer’s) in the mediotemporal lobe, there were almost none in the anterior cingulate. (But note an earlier report from the researchers)

Why this region should be of special importance is somewhat mysterious, but the anterior cingulate is part of the attention network, and perhaps it is this role that underlies the superior abilities of these seniors. The anterior cingulate also plays a role error detection and motivation; it will be interesting to see if these attributes are also important.

While the precise reason for the anterior cingulate to be critical to retaining cognitive abilities might be mysterious, the lack of cortical atrophy, and the suggestion that super-agers’ brains have much reduced levels of the sort of pathological damage seen in most older brains, adds weight to the growing evidence that cognitive aging reflects clinical problems, which unfortunately are all too common.

Sadly, there are no obvious lifestyle factors involved here. The super agers don’t have a lifestyle any different from their ‘cognitively average’ counterparts. However, while genetics might be behind these people’s good fortune, that doesn’t mean that lifestyle choices don’t make a big difference to those of us not so genetically fortunate. It seems increasingly clear that for most of us, without ‘super-protective genes’, health problems largely resulting from lifestyle choices are behind much of the damage done to our brains.

It should be emphasized that these unpublished results are preliminary only. This conference presentation reported on data from only 12 of 48 subjects studied.

Harrison, T., Geula, C., Shi, J., Samimi, M., Weintraub, S., Mesulam, M. & Rogalski, E. 2011. Neuroanatomic and pathologic features of cognitive SuperAging. Presented at a poster session at the 2011 Society for Neuroscience conference.

In the last five years, three studies have linked lower neighborhood socioeconomic status to lower cognitive function in older adults. Neighborhood has also been linked to self-rated health, cardiovascular disease, and mortality. Such links between health and neighborhood may come about through exposure to pollutants or other environmental stressors, access to alcohol and cigarettes, barriers to physical activity, reduced social support, and reduced access to good health and social services.

Data from the large Women’s Health Initiative Memory Study has now been analyzed to assess whether the relationship between neighborhood socioeconomic status can be explained by various risk and protective factors for poor cognitive function.

Results confirmed that higher neighborhood socioeconomic status was associated with higher cognitive function, even after individual factors such as age, ethnicity, income, education, and marital status have been taken into account. A good deal of this was explained by vascular factors (coronary heart disease, diabetes, stroke, hypertension), health behaviors (amount of alcohol consumed, smoking, physical activity), and psychosocial factors (depression, social support). Nevertheless, the association was still (barely) significant after these factors were taken account of, suggesting some other factors may also be involved. Potential factors include cognitive activity, diet, and access to health services.

In contradiction of earlier research, the association appeared to be stronger among younger women. Consistent with other research, the association was stronger for non-White women.

Data from 7,479 older women (65-81) was included in the analysis. Cognitive function was assessed by the Modified MMSE (3MSE). Neighborhood socioeconomic status was assessed on the basis of: percentage of adults over 25 with less than a high school education, percentage of male unemployment, percentage of households below the poverty line, percentage of households receiving public assistance, percentage of female-headed households with children, and median household income. Around 87% of participants were White, 7% Black, 3% Hispanic, and 3% other. Some 92% had graduated high school, and around 70% had at least some college.

[2523] Shih RA, Ghosh-Dastidar B, Margolis KL, Slaughter ME, Jewell A, Bird CE, Eibner C, Denburg NL, Ockene J, Messina CR, et al. Neighborhood Socioeconomic Status and Cognitive Function in Women. Am J Public Health [Internet]. 2011 ;101(9):1721 - 1728. Available from: http://ajph.aphapublications.org/cgi/content/abstract/101/9/1721


Lang IA, Llewellyn DJ, Langa KM, Wallace RB, Huppert FA, Melzer D. 2008. Neighborhood deprivation, individual socioeconomic status, and cognitive function in older people: analyses from the English Longitudinal Study of Ageing. J Am Geriatr Soc., 56(2), 191-198.

Sheffield KM, Peek MK. 2009. Neighborhood context and cognitive decline in older Mexican Americans: results from the Hispanic Established Populations for Epidemiologic Studies of the Elderly. Am J Epidemiol., 169(9), 1092-1101.

Wight RG, Aneshensel CS, Miller-Martinez D, et al. 2006. Urban neighborhood context, educational attainment, and cognitive function among older adults. Am J Epidemiol., 163(12), 1071-1078.

A ten-year study involving 7,239 older adults (65+) has found that each common health complaint increased dementia risk by an average of about 3%, and that these individual risks compounded. Thus, while a healthy older adult had about an 18% chance of developing dementia after 10 years, those with a dozen of these health complaints had, on average, closer to a 40% chance.

It’s important to note that these complaints were not for serious disorders that have been implicated in Alzheimer’s. The researchers constructed a ‘frailty’ index, involving 19 different health and wellbeing factors: overall health, eyesight, hearing, denture fit, arthritis/rheumatism, eye trouble, ear trouble, stomach trouble, kidney trouble, bladder control, bowel control, feet/ankle trouble, stuffy nose/sneezing, bone fractures, chest problems, cough, skin problems, dental problems, other problems.

Not all complaints are created equal. The most common complaint — arthritis/rheumatism —was only slightly higher among those with dementia. Two of the largest differences were poor eyesight (3% of the non-demented group vs 9% of those with dementia) and poor hearing (3% and 6%).

At the end of the study, 4,324 (60%) were still alive, and of these, 416 (9.6%) had Alzheimer's disease, 191 (4.4%) had another sort of dementia and 677 (15.7%) had other cognitive problems (but note that 1,023 were of uncertain cognitive ability).

While these results need to be confirmed in other research — the study used data from broader health surveys that weren’t specifically designed for this purpose, and many of those who died during the study will have probably had dementia — they do suggest the importance of maintaining good general health.

Common irregular heartbeat raises risk of dementia

In another study, which ran from 1994 to 2008 and followed 3,045 older adults (mean age 74 at study start), those with atrial fibrillation were found to have a significantly greater risk of developing Alzheimer’s.

At the beginning of the study, 4.3% of the participants had atrial fibrillation (the most common kind of chronically irregular heartbeat); a further 12.2% developed it during the study. Participants were followed for an average of seven years. Over this time, those with atrial fibrillation had a 40-50% higher risk of developing dementia of any type, including probable Alzheimer's disease. Overall, 18.8% of the participants developed some type of dementia during the course of the study.

While atrial fibrillation is associated with other cardiovascular risk factors and disease, this study shows that atrial fibrillation increases dementia risk more than just through this association. Possible mechanisms for this increased risk include:

  • weakening the heart's pumping ability, leading to less oxygen going to the brain;
  • increasing the chance of tiny blood clots going to the brain, causing small, clinically undetected strokes;
  • a combination of these plus other factors that contribute to dementia such as inflammation.

The next step is to see whether any treatments for atrial fibrillation reduce the risk of developing dementia.

Stress may increase risk for Alzheimer's disease

And a rat study has shown that increased release of stress hormones leads to cognitive impairment and that characteristic of Alzheimer’s disease, tau tangles. The rats were subjected to stress for an hour every day for a month, by such means as overcrowding or being placed on a vibrating platform. These rats developed increased hyperphosphorylation of tau protein in the hippocampus and prefrontal cortex, and these changes were associated with memory deficits and impaired behavioral flexibility.

Previous research has shown that stress leads to that other characteristic of Alzheimer’s disease: the formation of beta-amyloid.

In the first mouse study, when young and old mice were conjoined, allowing blood to flow between the two, the young mice showed a decrease in neurogenesis while the old mice showed an increase. When blood plasma was then taken from old mice and injected into young mice, there was a similar decrease in neurogenesis, and impairments in memory and learning.

Analysis of the concentrations of blood proteins in the conjoined animals revealed the chemokine (a type of cytokine) whose level in the blood showed the biggest change — CCL11, or eotaxin. When this was injected into young mice, they indeed showed a decrease in neurogenesis, and this was reversed once an antibody for the chemokine was injected. Blood levels of CCL11 were found to increase with age in both mice and humans.

The chemokine was a surprise, because to date the only known role of CCL11 is that of attracting immune cells involved in allergy and asthma. It is thought that most likely it doesn’t have a direct effect on neurogenesis, but has its effect through, perhaps, triggering immune cells to produce inflammation.

Exercise is known to at least partially reverse loss of neurogenesis. Exercise has also been shown to produce chemicals that prevent inflammation. Following research showing that exercise after brain injury can help the brain repair itself, another mouse study has found that mice who exercised regularly produced interleukin-6 (a cytokine involved in immune response) in the hippocampus. When the mice were then exposed to a chemical that destroys the hippocampus, the interleukin-6 dampened the harmful inflammatory response, and prevented the loss of function that is usually observed.

One of the actions of interleukin-6 that brings about a reduction in inflammation is to inhibit tumor necrosis factor. Interestingly, I previously reported on a finding that inhibiting tumor necrosis factor in mice decreased cognitive decline that often follows surgery.

This suggests not only that exercise helps protect the brain from the damage caused by inflammation, but also that it might help protect against other damage, such as that caused by environmental toxins, injury, or post-surgical cognitive decline. The curry spice cucurmin, and green tea, are also thought to inhibit tumor necrosis factor.

Sleep apnea linked to later dementia

A study involving 298 older women with sleep problems found that those who had disordered breathing (such as sleep apnea) were significantly more likely to develop dementia or mild cognitive impairment.

Around a third of the women (average age 82) had disordered breathing (slowing down or stopping breathing during sleep and often having to gasp to catch up). None showed signs of cognitive impairment at the time of the sleep testing. When re-tested some five years later, 45% of those who had disordered breathing had developed dementia or MCI, compared with 31% of those with no breathing irregularities.

Those whose sleep irregularities had been particularly severe (15 or more breathing stoppages per hour and more than 7% of sleep time not breathing) during the earlier part of the study were nearly twice as likely as those without breathing problems to develop dementia or MCI. Other measures of sleep quality — waking after sleep onset, sleep fragmentation, sleep duration — were not associated with cognitive impairment.

The finding adds to the evidence for the importance of treating sleep apnea. Previous research has found that CPAP treatment effectively counteracts cognitive impairment caused by sleep apnea.

Brain injury raises dementia risk

Analysis of medical records on 281,540 U.S. military veterans aged at least 55 at the beginning of the study has found that over the next seven years those who had at one time suffered a traumatic brain injury were more than twice as likely to develop dementia than those who had not suffered such an injury. Around 1.7% (4,902) had incurred a traumatic brain injury, in many cases during the Vietnam War, and over 15% of these developed dementia. In contradiction of the prevailing belief that only moderate or severe brain injuries predispose people to dementia, severity of the injury made no difference.

Injuries due to strokes were weeded out of the study.

In another study, following up on nearly 4,000 retired National Football League players surveyed in 2001, 35% appeared to have significant cognitive problems (as assessed by questionnaire). When 41 of them were tested, they were found to have mild cognitive impairment that resembled a comparison group of much older patients from the general population.

The findings are a reminder of the importance of treating even mild head injuries, and of following a regime designed to mitigate damage: exercising, eating a healthy diet, reducing stress, and so on.

[2444] Yaffe K, Laffan AM, Harrison SL, Redline S, Spira AP, Ensrud KE, Ancoli-Israel S, Stone KL. Sleep-Disordered Breathing, Hypoxia, and Risk of Mild Cognitive Impairment and Dementia in Older Women. JAMA: The Journal of the American Medical Association [Internet]. 2011 ;306(6):613 - 619. Available from: http://jama.ama-assn.org/content/306/6/613.abstract

The brain injury studies were reported in July at the Alzheimer's Association International Conference in France. http://www.alz.org/aaic/

The brain tends to shrink with age, with different regions being more affected than others. Atrophy of the hippocampus, so vital for memory and learning, is associated with increased risk of developing Alzheimer’s, and has also been linked to depression.

In a study involving 268 older adults (58+), the hippocampus of those reporting a life-changing religious experience was found to be shrinking significantly more compared to those not reporting such an experience. Significantly greater hippocampal atrophy was also found among born-again Protestants, Catholics, and those with no religious affiliation, compared with Protestants not identifying as born-again.

The participants are not a general sample — they were originally recruited for the NeuroCognitive Outcomes of Depression in the Elderly. However, some of the participants were from the control group, who had no history of depression. Brain scans were taken at the beginning of the study, and then every two years. The length of time between the baseline scan and the final scan ranged from 2 to 8 years (average was 4).

Questions about religious experiences were asked in an annual survey, so could change over time. Two-thirds of the group was female, and 87% were white. The average age was 68. At baseline, 42% of the group was non-born-again Protestant, 36% born-again Protestant; 8% Catholic; 6% other religion. Only 7% reported themselves as having no religion. By the end of the study, 44% (119 participants) reported themselves born-again, and 13% (36) reported having had life-changing religious experiences.

These associations persisted after depression status, acute stress, and social support were taken into account. Nor did other religious factors (such as prayer, meditation, or Bible study) account for the changes.

It is still possible that long-term stress might play a part in this association — the study measured acute rather than cumulative stress. The researchers suggest that life-changing religious experiences can be stressful, if they don’t fit in with your existing beliefs or those of your family and friends, or if they lead to new social systems that add to your stress.

Of course, the present results can be interpreted in several ways — is it the life-changing religious experience itself that is the crucial factor? Or the factors leading up to that experience? Or the consequences of that experience? Still, it’s certainly an intriguing finding, and it will be interesting to see more research expanding and confirming (or not!) this result.

More generally, the findings may help clarify the conflicting research about the effects of religion on well-being, by pointing to the fact that religion can’t be considered a single factor, but one subject to different variables, some of which may be positive and others not.

I commonly refer to ApoE4 as the ‘Alzheimer’s gene’, because it is the main genetic risk factor, tripling the risk for getting Alzheimer's. But it is not the only risky gene.

A mammoth genetic study has identified four new genes linked to late-onset Alzheimer's disease. The new genes are involved in inflammatory processes, lipid metabolism, and the movement of molecules within cells, pointing to three new pathways that are critically related to the disease.

Genetic analysis of more than 11,000 people with Alzheimer's and a nearly equal number of healthy older adults, plus additional data from another 32,000, has identified MS4A, CD2AP, CD33, and EPHA1 genes linked to Alzheimer’s risk, and confirmed two other genes, BIN1 and ABCA7.

A second meta-analysis of genetic data has also found another location within the MS4A gene cluster which is associated with Alzheimer's disease. Several of the 16 genes within the cluster are implicated in the activities of the immune system and are probably involved in allergies and autoimmune disease. The finding adds to evidence for a role of the immune system in the development of Alzheimer's.

Another study adds to our understanding of how one of the earlier-known gene factors works. A variant of the clusterin gene is known to increase the risk of Alzheimer’s by 16%. But unlike the ApoE4 gene, we didn’t know how, because we didn’t know what the CLU gene did. A new study has now found that the most common form of the gene, the C-allele, impairs the development of myelin.

The study involved 398 healthy adults in their twenties. Those carrying the CLU-C gene had poorer white-matter integrity in multiple brain regions. The finding is consistent with increasing evidence that degeneration of myelin in white-matter tracts is a key component of Alzheimer’s and another possible pathway to the disease. But this gene is damaging your brain (in ways only detectible on a brain scan) a good 50 years before any clinical symptoms are evident.

Moreover, this allele is present in 88% of Caucasians. So you could say it’s not so much that this gene variant is increasing your risk, as that having the other allele (T) is protective.

[2257] Naj AC, Jun G, Beecham GW, Wang L-S, Vardarajan BN, Buros J, Gallins PJ, Buxbaum JD, Jarvik GP, Crane PK, et al. Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer's disease. Nat Genet [Internet]. 2011 ;43(5):436 - 441. Available from: http://dx.doi.org/10.1038/ng.801

Antunez, C. et al. 2011. The membrane-spanning 4-domains, subfamily A (MS4A) gene cluster contains a common variant associated with Alzheimer's disease. Genome Medicine,  3:33 doi:10.1186/gm249
Full text available at http://genomemedicine.com/content/3/5/33/abstract

[2254] Braskie MN, Jahanshad N, Stein JL, Barysheva M, McMahon KL, de Zubicaray GI, Martin NG, Wright MJ, Ringman JM, Toga AW, et al. Common Alzheimer's Disease Risk Variant Within the CLU Gene Affects White Matter Microstructure in Young Adults. The Journal of Neuroscience [Internet]. 2011 ;31(18):6764 - 6770. Available from: http://www.jneurosci.org/content/31/18/6764.abstract

Growing evidence has pointed to the benefits of social and mental stimulation in preventing dementia, but until now no one has looked at the role of physical environment.

A study involving 1294 healthy older adults found that those whose life-space narrowed to their immediate home were almost twice as likely to develop the condition as those with the largest life-space (out-of-town). The homebound also had an increased risk of MCI and a faster rate of global cognitive decline.

By the end of the eight-year study (average follow-up of 4.4 years), 180 people (13.9%) had developed Alzheimer’s. The association remained after physical function, disability, depressive symptoms, social network size, vascular disease burden, and vascular risk factors, were taken into account.

It may be that life-space is an indicator of how engaged we are with the world, with the associated cognitive stimulation that offers.

Supporting earlier research, a study involving 8,534 older adults (65+; mean age 74.4) has found those who were obese in middle age had almost four times (300%) more risk of developing dementia. Those who were overweight in middle age had a 1.8 times (80%) higher risk of developing dementia.

Participants were drawn from the Swedish Twin Registry. Height and weight had been measured at a mean age of 43.3, and 29.8% were defined as overweight or obese. Dementia was diagnosed in 350 participants (4.1%), with a further 114 (1.33%) diagnosed as questionable.

Apart from the clear links between excess weight and risk factors such as cholesterol, diabetes, hypertension, inflammation, there are also correlational factors. Higher education (which helps protect against brain damage) was also associated with about 10% reduced risk of overweight and obesity.

A study in which mice were exposed to polluted air for three 5-hour sessions a week for 10 weeks, has revealed that such exposure damaged neurons in the hippocampus and caused inflammation in the brain. The polluted air was laden with particles collected from an urban freeway.

Another recent study found that, of 215 children, those whose cord blood showed high levels of combustion-related pollutants such as polycyclic aromatic hydrocarbons (PAH), had more attention (and anxiety) problems at ages 5 and 7. The children were born to nonsmoking African-American and Dominican women residing in New York City.

A study involved 117 older adults (mean age 78) found those at greater risk of coronary artery disease had substantially greater risk for decline in verbal fluency and the ability to ignore irrelevant information. Verbal memory was not affected.

The findings add to a growing body of research linking cardiovascular risk factors and age-related cognitive decline, leading to the mantra: What’s good for the heart is good for the brain.

The study also found that the common classification into high and low risk groups was less useful in predicting cognitive decline than treating risk as a continuous factor. This is consistent with a growing view that no cognitive decline is ‘normal’, but is always underpinned by some preventable damage.

Risk for coronary artery disease was measured with the Framingham Coronary Risk Score, which uses age, cholesterol levels, blood pressure, presence of diabetes, and smoking status to generate a person's risk of stroke within 10 years. 37 (31%) had high scores. Age, education, gender, and stroke history were controlled for in the analysis.

Gooblar, J., Mack, W.J., Chui, H.C., DeCarli, C., Mungas, D., Reed, B.R. & Kramer, J.H. 2011. Framingham Coronary Risk Profile Predicts Poorer Executive Functioning in Older Nondemented Adults. Presented at the American Academy of Neurology annual meeting on Tuesday, April 12, 2011.

A two-year study involving 53 older adults (60+) has found that those with a mother who had Alzheimer's disease had significantly more brain atrophy than those with a father or no parent with Alzheimer's disease. More specifically, they had twice as much gray matter shrinkage, and about one and a half times more whole brain shrinkage per year.

This atrophy was particularly concentrated in the precuneus and parahippocampal gyrus. Those with the APOE4 gene also had more atrophy in the frontal cortex than those who didn’t carry the ‘Alzheimer’s gene’.

This adds to evidence indicating that maternal history is a far greater risk factor for Alzheimer’s than paternal history. Eleven participants reported having a mother with Alzheimer's disease, 10 had a father with Alzheimer's disease and 32 had no family history of the disease. It has been estimated that people who have first-degree relatives with Alzheimer's disease are four to 10 times more likely to develop the disease.

Data from the Baltimore Longitudinal Study on Aging, begun in 1958, has revealed that seniors with hearing loss are significantly more likely to develop dementia than those who retain their hearing. The study involved 639 people whose hearing and cognitive abilities were tested between 1990 and 1994, then re-tested every one to two years. By 2008, 58 (9%) of them had developed dementia (37 of which were Alzheimer’s).

Those with hearing loss at the beginning of the study were significantly more likely to have developed dementia. The degree of hearing loss also correlated with greater risk: those with mild, moderate, and severe hearing loss had twofold, threefold, and fivefold, respectively, the risk of developing dementia over time. The association was maintained after other risk factors, (high blood pressure, smoking, education, age, sex, race) were taken into account.

The reason for the association is not yet known. It’s possible that a common pathology may underlie both, or that the strain of decoding sounds over the years may make the brain more vulnerable to dementia, or that hearing loss makes people more socially isolated (a known risk factor for dementia).

The findings do suggest that hearing loss should be regarded more seriously, and not simply accepted as a natural part of growing old.

The new label of ‘metabolic syndrome’ applies to those having three or more of the following risk factors: high blood pressure, excess belly fat, higher than normal triglycerides, high blood sugar and low high-density lipoprotein (HDL) cholesterol (the "good" cholesterol). Metabolic syndrome has been linked to increased risk of heart attack.

A new French study, involving over 7,000 older adults (65+) has found that those with metabolic syndrome were 20% more likely to show cognitive decline on a memory test (MMSE) over a two or four year interval. They were also 13% more likely to show cognitive decline on a visual working memory test. Specifically, higher triglycerides and low HDL cholesterol were linked to poorer memory scores; diabetes (but not higher fasting blood sugar) was linked to poorer visual working memory and word fluency scores.

The findings point to the importance of managing the symptoms of metabolic syndrome.

High cholesterol and blood pressure in middle age tied to early memory problems

Another study, involving some 4800 middle-aged adults (average age 55), has found that those with higher cardiovascular risk were more likely to have lower cognitive function and a faster rate of cognitive decline over a 10-year period. A 10% higher cardiovascular risk was associated not only with increased rate of overall mental decline, but also poorer cognitive test scores in all areas except reasoning for men and fluency for women.

The cardiovascular risk score is based on age, sex, HDL cholesterol, total cholesterol, systolic blood pressure and whether participants smoked or had diabetes.

Memory problems may be sign of stroke risk

A very large study (part of the REGARDS study) tested people age 45 and older (average age 67) who had never had a stroke. Some 14,842 people took a verbal fluency test, and 17,851 people took a word recall memory test. In the next 4.5 years, 123 participants who had taken the verbal fluency test and 129 participants who had taken the memory test experienced a stroke.

Those who had scored in the bottom 20% for verbal fluency were 3.6 times more likely to develop a stroke than those who scored in the top 20%. For the memory test, those who scored in the bottom 20% were 3.5 times more likely to have a stroke than those in the top quintile.

The effect was greatest at the younger ages. At age 50, those who scored in the bottom quintile of the memory test were 9.4 times more likely to later have a stroke than those in the top quintile.


Together, these studies, which are consistent with many previous studies, confirm that cardiovascular problems and diabetes add to the risk of greater cognitive decline (and possible dementia) in old age. And point to the importance of treating these problems as soon as they appear.

[2147] Raffaitin C, Féart C, Le Goff M, Amieva H, Helmer C, Akbaraly TN, Tzourio C, Gin H, Barberger-Gateau P. Metabolic syndrome and cognitive decline in French elders. Neurology [Internet]. 2011 ;76(6):518 - 525. Available from: http://www.neurology.org/content/76/6/518.abstract

The findings of the second and third studies are to be presented at the American Academy of Neurology's 63rd Annual Meeting in Honolulu April 9 to April 16, 2011

Lesions of the brain microvessels include white-matter hyperintensities and the much less common silent infarcts leading to loss of white-matter tissue. White-matter hyperintensities are common in the elderly, and are generally regarded as ‘normal’ (although a recent study suggested we should be less blasé about them — that ‘normal’ age-related cognitive decline reflects the presence of these small lesions). However, the degree of white-matter lesions is related to the severity of decline (including increasing the risk of Alzheimer’s), and those with hypertension or diabetes are more likely to have a high number of them.

A new study has investigated the theory that migraines might also lead to a higher number of white-matter hyperintensities. The ten-year French population study involved 780 older adults (65+; mean age 69). A fifth of the participants (21%) reported a history of severe headaches, of which 71% had migraines.

Those with severe headaches were twice as likely to have a high quantity of white-matter hyperintensities as those without headaches. However, there was no difference in cognitive performance between the groups. Those who suffered from migraines with aura (2% of the total), also showed an increased number of silent cerebral infarcts — a finding consistent with other research showing that people suffering from migraine with aura have an increased risk of cerebral infarction (or strokes). But again, no cognitive decline was observed.

The researchers make much of their failure to find cognitive impairment, but I would note that, nevertheless, the increased number of brain lesions does suggest that, further down the track, there is likely to be an effect on cognitive performance. Still, headache sufferers can take comfort in the findings, which indicate the effect is not so great that it shows up in this decade-long study.

Research into the link, if any, between cholesterol and dementia, has been somewhat contradictory. A very long-running Swedish study may explain why. The study, involving 1,462 women aged 38-60 in 1968, has found that cholesterol measured in middle or old age showed no link to dementia, but there was a connection between dementia and the rate of decline in cholesterol level. Those women whose cholesterol levels decreased the most from middle to older age were more than twice as likely to develop dementia as those whose cholesterol levels increased or stayed the same (17.5% compared to 8.9%).After 32 years, 161 women had developed dementia.

Later in life, women with slightly higher body mass index, higher levels of cholesterol and higher blood pressure tend to be healthier overall than those whose weight, cholesterol and blood pressure are too low. But it is unclear whether "too low" cholesterol, BMI and blood pressure are risk factors for dementia or simply signs that dementia is developing, for reasons we do not yet understand.

On the other hand, a recent rat study has found that consuming a high cholesterol diet for five months caused memory impairment, cholinergic dysfunction, inflammation, enhanced cortical beta-amyloid and tau and induced microbleedings — all of which is strikingly similar to Alzheimer's pathology. And this finding is consistent with a number of other studies. So it does seem clear that the story of how exactly cholesterol impacts Alzheimer’s is a complex one that we are just beginning to unravel.

In light of other research indicating that the response of men and women to various substances (eg caffeine) may be different, we should also bear in mind that the results of the Swedish study may apply only to women.

In a study in which 78 healthy elders were given 5 different tests and then tested for cognitive performance 18 months later, two tests combined to correctly predict nearly 80% of those who developed significant cognitive decline. These tests were a blood test to identify presence of the ‘Alzheimer’s gene’ (APOE4), and a 5-minute fMRI imaging scan showing brain activity during mental tasks.

The gene test in itself correctly classified 61.5% of participants (aged 65-88; mean age 73), showing what a strong risk factor this is, but when taken with activity on the fMRI test, the two together correctly classified 78.9% of participants. Age, years of education, gender and family history of dementia were not accurate predictors of future cognitive decline. A smaller hippocampus was also associated with a greater risk of cognitive decline.

These two tests are readily available and not time-consuming, and may be useful in identifying those at risk of MCI and dementia.

Woodard, J.L.  et al. 2010. Prediction of Cognitive Decline in Healthy Older Adults using fMRI. Journal of Alzheimer’s Disease, 21 (3), 871-885.

A study involving 68 healthy older adults (65-85) has compared brain activity among four groups, determined whether or not they carry the Alzheimer’s gene ApoE4 and whether their physical activity is reported to be high or low. The participants performed a task involving the discrimination of famous people, which engages 15 different functional regions of the brain. Among those carrying the gene, those with higher physical activity showed greater activation in many regions than those who were sedentary. Moreover, physically active people with the gene had greater brain activity than physically active people without the gene.

And adding to the evidence supporting the potential for exercise to lower the risk of dementia, another recent study has found that after ten years exercise (in terms of the number of different types of exercises performed and number of exercise sessions lasting at least 20 minutes) was inversely associated with the onset of cognitive impairment. The study used data from the National Long Term Care Survey.

Carriers of the so-called ‘Alzheimer’s gene’ (apoE4) comprise 65% of all Alzheimer's cases. A new study helps us understand why that’s true. Genetically engineered mice reveal that apoE4 is associated with the loss of GABAergic interneurons in the hippocampus. This is consistent with low levels of GABA (produced by these neurons) typically found in Alzheimer’s brains. This loss was associated with cognitive impairment in the absence of amyloid beta accumulation, demonstrating it is an independent factor in the development of this disease.

The relationship with the other major characteristic of the Alzheimer’s brain, tau tangles, was not independent. When the mice’s tau protein was genetically eliminated, the mice stopped losing GABAergic interneurons, and did not develop cognitive deficits. Previous research has shown that suppressing tau protein can also prevent amyloid beta from causing memory deficits.

Excitingly, daily injections of pentobarbital, a compound that enhances GABA action, restored cognitive function in the mice.

The findings suggest that increasing GABA signaling and reducing tau are potential strategies to treat or prevent apoE4-related Alzheimer's disease.

A Chinese study involving 153 older men (55+; average age 72), of whom 47 had mild cognitive impairment, has found that 10 of those in the MCI group developed probable Alzheimer's disease within a year. These men also had low testosterone, high blood pressure, and elevated levels of the ApoE4 protein.

The findings support earlier indications that low testosterone is associated with increased risk of Alzheimer's in men, but it’s interesting to note the combination with high blood pressure and having the ApoE4 gene. I look forward to a larger study.

Chu, L-W. et al. 2010. Bioavailable Testosterone Predicts a Lower Risk of Alzheimer’s Disease in Older Men. Journal of Alzheimer's Disease, 21 (4), 1335-45.

A seven-year study involving 271 Finns aged 65-79 has revealed that increases in the level of homocysteine in the blood were associated with increasing risk of developing Alzheimer’s (each micromolar increase in the concentration of homocysteine increased the risk of Alzheimer's by 16%), while increases in the level of vitamin B12 decreased the risk (each picomolar increase in concentration of B12 reduced risk by 2%). A larger study is needed to confirm this. 17 people (6%) developed Alzheimer’s over the course of the study.

Still, these results are consistent with a number of other studies showing greater risk with higher homocysteine and lower B12. High levels of vitamin B12 are known to lower homocysteine. However, studies directly assessing the effects of B12 supplements have had mixed results. Low levels of B12 are common in the elderly.

Data from 21,123 people, surveyed between 1978 and 1985 when in their 50s and tracked for dementia from 1994 to 2008, has revealed that those who smoked more than two packs per day in middle age had more than twice the risk of developing dementia, both Alzheimer's and vascular dementia, compared to non-smokers.

A quarter of the participants (25.4%) were diagnosed with dementia during the 23 years follow-up, of whom a little over 20% were diagnosed with Alzheimer's disease and nearly 8% with vascular dementia.

Former smokers, or those who smoked less than half a pack per day, did not appear to be at increased risk. Associations between smoking and dementia did not vary by race or sex.

Smoking is a well-established risk factor for stroke, and is also known to contribute to oxidative stress and inflammation.

Previous research has indicated that obesity in middle-age is linked to higher risk of cognitive decline and dementia in old age. Now a study of 32 middle-aged adults (40-60) has revealed that although obese, overweight and normal-weight participants all performed equally well on a difficult cognitive task (a working memory task called the 2-Back task), obese individuals displayed significantly lower activation in the right inferior parietal cortex. They also had lower insulin sensitivity than their normal weight and overweight peers (poor insulin sensitivity may ultimately lead to diabetes). Analysis pointed to the impaired insulin sensitivity mediating the relationship between task-related activation in that region and BMI.

This suggests that it is insulin sensitivity that is responsible for the higher risk of cognitive impairment later in life. The good news is that insulin sensitivity is able to be modified through exercise and diet.

A follow-up study to determine if a 12-week exercise intervention can reverse the differences is planned.

Type 2 diabetes is known to increase the risk of cognitive impairment in old age. Now analysis of data from 41 older diabetics (aged 55-81) and 458 matched controls in the Victoria Longitudinal Study has revealed that several other factors make it more likely that an older diabetic will develop cognitive impairment. These factors are: having higher (though still normal) blood pressure, having gait and balance problems, and/or reporting yourself to be in bad health regardless of actual problems.

Diabetes and hypertension often go together, and both are separately associated with greater cognitive impairment and dementia risk, so it is not surprising that higher blood pressure is one of the significant factors that increases risk. The other factors are less expected, although gait and balance problems have been linked to cognitive impairment in a recent study, and they may be connected to diabetes through diabetes’ effect on nerves. Negativity about one’s health may reflect emotional factors such as anxiety, stress, or depression, although depression and well-being measures were not themselves found to be mediating effects for cognitive impairment in diabetics (Do note that this study is not investigating which factors, in general, are associated with age-related cognitive impairment; it is trying to establish which factors are specifically sensitive to cognitive impairment in older diabetics).

In the U.S., type 2 diabetes occurs in over 23% of those over 60; in Canada (where this study took place) the rate is 19%. It should be noted that the participants in this study are not representative of the general population, in that they were fairly well-educated older Canadians, most of whom have benefited from a national health care system. Moreover, the study did not have longitudinal data on these various factors, meaning that we don’t know the order of events (which health problems come first? How long between the development of the different problems?). Nevertheless, the findings provide useful markers to alert diabetics and health providers.

Following on from indications that gum disease might be a risk factor for dementia, analysis of data from 152 subjects in the Danish Glostrop Aging Study has revealed that periodontal inflammation at age 70 was strongly associated with lower cognitive scores (on the Digit Symbol Test). Those with periodontal inflammation were nine times more likely to test in the lower range compared to those with little or no periodontal inflammation. A larger follow-up study, among a more ethnically diverse range of subjects, is planned. I hope they also plan to extend the cognitive testing.

The findings were presented by Dr. Angela Kamer at the 2010 annual meeting of the International Association for Dental Research July 16, in Barcelona, Spain.

Data from a 35-year study of women from Gothenburg in Sweden has revealed that the risk of dementia was about 65% higher in women who reported repeated periods of stress in middle age than in those who did not. The risk increased with number of periods of stress, with women who reported stress on all three occasions they were asked (1968, 1974 and 1980) having more than double the risk of dementia. Stress was defined as a sense of irritation, tension, nervousness, anxiety, fear or sleeping problems lasting a month or more due to work, health, family or other problems. Of the 1462 women in the sample used, 11% developed dementia, 65% of which was Alzheimer’s and 25% vascular dementia.

I have often spoken of the mantra: What’s good for your heart is good for your brain. The links between cardiovascular risk factors and cognitive decline gets more confirmation in this latest finding that people whose hearts pumped less blood had smaller brains than those whose hearts pumped more blood. The study involved 1,504 participants of the decades-long Framingham Offspring Cohort who did not have a history of stroke, transient ischemic attack or dementia. Participants were 34 to 84 years old.

Worryingly, it wasn’t simply those with the least amount of blood pumping from the heart who had significantly more brain atrophy (equivalent to almost two years more brain aging) than the people with the highest cardiac index. Those with levels at the bottom end of normal showed similar levels of brain atrophy. Moreover, although only 7% of the participants had heart disease, 30% had a low cardiac index.

A study involving over 180,000 older veterans (average age 68.8 at study start), of whom 29% had PTSD, has revealed that those with PTSD had a significantly greater risk of developing dementia. Over the seven years of the study, 10.6% of the veterans with PTSD developed dementia compared to 6.6% of those without PTSD. When age was used as the time scale, the risk for those with PTSD was more than double. Results were similar when those with a history of head injury, substance abuse, or clinical depression, were excluded.

One possibility for the link is that the stress induced by PTSD contributes to the development of dementia.

Anticholinergics are widely used for a variety of common medical conditions including insomnia, allergies, or incontinence, and many are sold over the counter. Now a large six-year study of older African-Americans has found that taking one anticholinergic significantly increased an individual's risk of developing mild cognitive impairment and taking two of these drugs doubled this risk. The risk was greater for those who didn’t have the ‘Alzheimer’s gene’, APOE-e4.

This class of drugs includes Benadryl®, Dramamine®, Excedrin PM®, Nytol®, Sominex®, Tylenol PM®, Unisom®, Paxil®, Detrol®, Demerol® and Elavil® (for a more complete list of medications with anticholinergic effects, go to http://www.indydiscoverynetwork.org/AnticholienrgicCognitiveBurdenScale....).

Another study has come out showing that older adults with low levels of vitamin D are more likely to have cognitive problems. The six-year study followed 858 adults who were age 65 or older at the beginning of the study. Those who were severely deficient in vitamin D were 60% more likely to have substantial cognitive decline, and 31% more likely to have specific declines in executive function, although there was no association with attention. Vitamin D deficiency is common in older adults in the United States and Europe (levels estimated from 40% to 100%!), and has been implicated in a wide variety of physical disease.

A brain scanning study using Pittsburgh Compound B, involving 42 healthy individuals (aged 50-80), of whom 14 had mothers who developed Alzheimer's, 14 had fathers with Alzheimer's, and 14 had no family history of the disease, has found that those with a maternal history had 15% more amyloid-beta plaques than those with a paternal history, and 20% more than those with no family history. The findings add to evidence that having a mother with Alzheimer’s is a greater risk factor than having a father with Alzheimer’s. The groups did not differ in age, gender, education, or apolipoprotein E (ApoE) status.

Data from over 900 community-dwelling older adults participating in the Rush Memory and Aging Project has found that greater purpose in life was associated with a substantially reduced risk of developing Alzheimer's disease, as well as a reduced risk of mild cognitive impairment and a slower rate of cognitive decline. Specifically, those scoring in the top 10% of a purpose in life measure (4.2 out of 5) were approximately 2.4 times more likely to remain free of Alzheimer's disease than individuals in the bottom 10% (score of 3.0). The association was independent of sociodemographic status, depression, neuroticism, social network size, and number of chronic health conditions.

Another gene has been identified that appears to increase risk of Alzheimer’s. The gene, MTHFD1L, is located on chromosome six. Comparison of the genomes of 2,269 people with late-onset Alzheimer's disease and 3,107 people without the disease found those with a particular variation in this gene were almost twice as likely to develop Alzheimer's disease as those people without the variation. The gene is involved in influencing the body's levels of homocysteine (high levels are known to be a strong risk factor), and have also been implicated in coronary artery disease.

The results were presented at the American Academy of Neurology's 62nd Annual Meeting in Toronto, April 10–17, 2010.

A study involving 733 participants from the Framingham Heart Study Offspring Cohort (average age 60) provides more evidence that excess abdominal fat places otherwise healthy, middle-aged people at greater risk for dementia later in life. The study also confirms that a higher BMI (body mass index) is associated with lower brain volumes in both older and middle-aged adults. However the association between visceral fat and total brain volume was independent of BMI. Visceral fat differs from subcutaneous fat in that it is buried deeper, beneath the muscles, around the organs. While it can only be seen by CT imaging, a pot belly or thick waist suggests its presence. For women (who become particularly vulnerable to this after menopause), a waistline above 88 cm is regarded as signaling a dangerous amount of visceral fat. Regular vigorous exercise, and consumption of polyunsaturated fats rather than saturated fats, is recommended.

A 12-year study involving 1,221 married couples ages 65 or older (part of the Cache County (Utah) Memory Study) has revealed that husbands or wives who care for spouses with dementia are six times more likely to develop Alzheimer’s themselves than those whose spouses don't have it. The increased risk is of comparable size to having the ‘Alzheimer's gene’. The researchers speculate that the great stress of caregiving might be responsible for the increased dementia risk, emphasizing the need for greater caregiver support.

A comprehensive study reveals how the ‘Alzheimer's gene’ (APOE ε4) affects the nature of the disease. It is not simply that those with the gene variant tend to be more impaired (in terms of both memory loss and brain damage) than those without. Different parts of the brain (and thus different functions) tend to be differentially affected, depending on whether the individual is a carrier of the gene or not. Carriers displayed significantly greater impairment on tests of memory retention, while noncarriers were more impaired on tests of working memory, executive control, and lexical access. Consistent with this, carriers showed greater atrophy in the mediotemporal lobe, and noncarriers greater atrophy in the frontoparietal area. The findings have implications both for diagnosis and treatment.

Older news items (pre-2010) brought over from the old website

High protein diet shrinks brain in Alzheimer’s mice

A study using genetically engineered mice has tested the effects of four diets for their effects on Alzheimer’s pathology: a regular diet, a high fat/low carbohydrate custom diet, a high protein/low carb version, or a high carbohydrate/low fat option. Unexpectedly, mice fed the high protein/low carbohydrate diet had brains 5% lighter that all the others, and regions of their hippocampus were less developed. Mice on the high fat diet had higher levels of amyloid-beta protein, although no effect on plaque burden was detected.

Franciosi, S., Gama Sosa, M., English, D., Oler, E., Oung, T., Janssen, W., et al. (2009). Novel cerebrovascular pathology in mice fed a high cholesterol diet. Molecular Neurodegeneration, 4(1), 42. doi: 10.1186/1750-1326-4-42. Full text available at http://www.molecularneurodegeneration.com/content/4/1/40


Infections may lead to faster memory loss in Alzheimer's disease

A 6-month study involving 222 people with Alzheimer's disease (average age 83) has found that people who had infections or even bumps and bruises from a fall were more likely to have high blood levels of tumor necrosis factor-α, a protein involved in the inflammatory process, and were also more likely to experience memory loss or cognitive decline than people who did not have infections and who had low levels of the protein. Nearly half the participants experienced an infection or injury that led to inflammation during the study, and they experienced memory loss that was at twice the rate of those who did not have infections or injuries. Those with high levels of the protein in their blood at the beginning of the study had memory loss at four times the rate of those with low levels of the protein at the start of the study, and those with high levels who also experienced acute infections during the study had memory loss at 10 times the rate of those who started with low levels and had no infections over the six-month period.

Holmes, C. et al. 2009. Systemic inflammation and disease progression in Alzheimer disease. Neurology, 73, 768-774.


Poor sleep linked to later development of Alzheimer's

A mouse study has found that amyloid-beta significantly increases during periods of sleep deprivation. The discovery follows observation that peptide levels in both mice and humans increase significantly during the day and drop at night. When mice were only allowed to sleep four hours a day for 21 days, they had higher amyloid-beta plaque build-up in their brain than similar-aged mice with regular sleeping habits. The circadian fluctuation was found to reflect the activity of orexin, a hormone that regulates wakefulness. The findings suggest insomnia, late-night habits, and irregular sleep schedules during mid-life may be linked to the later development of Alzheimer's disease.

Kang, J-E. et al. 2009. Amyloid- Dynamics Are Regulated by Orexin and the Sleep-Wake Cycle. Science, Published Online September 24

Alzheimers linked to lack of Zzzzs

Greater dementia risk in former N.F.L. players

A study commissioned by the National Football League reports that Alzheimer’s disease or similar memory-related diseases appear to have been diagnosed in the league’s former players vastly more often than in the national population: five times the national average among those 50 and older (6.1%)and 19 times for those aged 30 through 49. The findings are consistent with several recent studies regarding N.F.L. players and the effects of their occupational head injuries. The study involved a phone survey of 1,063 retired players (from an original random list of 1,625), who were asked questions derived from the standard National Health Interview Survey. Some health issues were reported at higher than the population rate (sleep apnea and elevated cholesterol — both risk factors for cognitive problems).


Oxygen treatment hastens memory loss in Alzheimer's mice

A study using genetically engineered mice has found that young adult Alzheimer's mice exposed to 100% oxygen during several 3-hour sessions demonstrated substantial memory loss, while those exposed to normal air had no measurable memory loss, and neither did normal mice without any genetic predisposition for Alzheimer's disease. The results suggest that people genetically predisposed to Alzheimer's disease or with excessive amounts of beta amyloid in their brains are at increased risk of developing the disease earlier if they receive high concentrations of oxygen, for example during or after surgery. The findings may help explain why some elderly patients develop memory loss after major surgery.

Arendash, G.W. et al. 2009. Oxygen treatment triggers cognitive impairment in Alzheimer's transgenic mice. NeuroReport, 20 (12), 1087-1092.


Delirium rapidly accelerates memory decline in Alzheimer's patients

A new analysis of data spanning 15 years and involving 408 Alzheimer’s patients, has revealed that among those 72 patients who developed delirium at some point, the average decline on cognitive tests was 2.5 points per year before the episode of delirium, and 4.9 points per year after. Across groups, the rate of decline was about three times faster in those who had delirium compared to those who did not. Delirium often develops in elderly patients following a medical disturbance, surgery or infection, but it is preventable in up to 40% of cases.

Fong, T.G. et al. 2009. Delirium accelerates cognitive decline in Alzheimer disease. Neurology, 72, 1570-1575.


Connection between heart disorder and Alzheimer's

A very large study, involving over 37,000 patients, has found that those with atrial fibrillation, regardless of age, were 44% more likely to develop dementia, and those younger than 70 were 130% more likely to develop Alzheimer's. Previous studies have shown a connection between atrial fibrillation and vascular dementia. Atrial fibrillation is the most common heart rhythm problem, and has a strong genetic link. It is also a risk factor for stroke.

The findings were presented Friday, May 15, at "Heart Rhythm 2009," the annual scientific sessions of the Heart Rhythm Society in Boston.


Inflammatory response to infection and injury may worsen dementia

Systemic inflammation – inflammation in the body as a whole – is known to have direct effects on brain function, but there has been little research into the impact of systemic inflammation on the progress of dementia and neurodegenerative diseases. Now, in a study to mimic the effect of bacterial infection in people with dementia, a mouse study has revealed that that the inflammatory response to infection in mice with prior neurodegenerative disease leads to exaggerated symptoms of the infection, causes changes in memory and learning and leads to accelerated progression of dementia.

Cunningham, C. et al. In press. Systemic Inflammation Induces Acute Behavioral and Cognitive Changes and Accelerates Neurodegenerative Disease. Biological Psychiatry


Physical frailty may be linked to Alzheimer's disease

Autopsies of the brains of 165 people who had been participants in a larger community study of chronic diseases of aging has revealed that Alzheimer's disease pathology (plaques and tangles) was associated with physical frailty in older persons regardless of whether they had dementia. The level of frailty was approximately twice as high in a person with a high level of Alzheimer’s pathology, and this was true regardless of medical history or level of physical activity. These findings raise the possibility that Alzheimer's disease may contribute to frailty or that frailty and Alzheimer's disease share a common cause. Studies show that about 7% of people over age 65 are considered frail; 45% after age 85.

Buchman, A.S., Schneider, J.A., Leurgans, S. & Bennett, D.A. 2008. Physical frailty in older persons is associated with Alzheimer disease pathology. Neurology, 71, 499-504.


Thyrotropin levels associated with Alzheimer's risk in women

A clinically detectable over- or under-active thyroid has long been recognized as a potentially reversible cause of cognitive impairment. Now a large long-running study of thyrotropin (a hormone secreted by the pituitary gland that helps regulate thyroid gland function) levels has found that women with the lowest and highest levels of thyrotropin had more than double the risk of developing Alzheimer's disease. No relationship was observed between thyrotropin levels and Alzheimer's disease risk in men.

Tan, Z.S. et al. 2008. Thyroid Function and the Risk of Alzheimer Disease: The Framingham Study. Archives of Internal Medicine, 168(14), 1514-1520.


Short arms and legs linked to risk of dementia

Several studies have shown that early life environment plays an important role in susceptibility to chronic disease later in life. Data from the Cardiovascular Health Cognition Study (involving 2,798 people for an average of five years) has now found that women with the shortest arm spans were 1.5 times more likely to develop dementia and Alzheimer’s disease than women with longer arm spans. For every inch longer a woman’s leg, the risk of dementia and Alzheimer’s disease was reduced by 16%. In men, only arm span was associated with a lower risk of dementia. With every increased inch in arm span, men had a 6% decrease in risk of dementia. The association between short limbs and dementia risk may be due to poor nutrition in early life, which can affect limb growth (which implies that there should be no such connection if your short limbs are due to genetics).

Szekely, C.A. et al. 2008. No advantage of Aβ42-lowering NSAIDs for prevention of Alzheimer dementia in six pooled cohort studies. Neurology, 70, 2291-2298.


Inhaled anesthetics might increase the risk of Alzheimer's

A study using a new imaging technique has been able to see why anesthetics might cause amyloid β peptides to clump together, and whether one method of anesthesia was better than another. Previous studies have found that the inhaled anesthetics halothane and isoflurane and the intravenous anesthetic propofol encouraged the growth and clumping of Aβ in a test tube experiment. The new study found that the inhaled anesthetics caused the highest levels of Aβ aggregation, while the injected anesthetic propofol only interacted and caused aggregation at high concentrations, and thiopental did not cause the clustering of Aβ peptides even at high concentrations.

Mandal, P.K., Williams, J.P. & Mandal, R. 2007. Molecular Understanding of Aβ Peptide Interaction with Isoflurane, Propofol, and Thiopental: NMR Spectroscopic Study. Biochemistry, 46 (3), 762 –771.


Anesthetics a risk factor for Alzheimer’s?

The link between surgery and cognitive problems has long been noted, but it’s never been clear whether postoperative cognitive dysfunction was the result of the surgery itself or the anaesthetics. Now animal studies and test tube experiments are beginning to show that certain anaesthetics reduce the rate at which brain cells are born and develop. The latest study reveals that the inhaled anaesthetics halothane and isoflurane encourage clumping of beta amyloid protein, as does the commonly used intravenous anaesthetic propofol, at least at higher concentrations — suggesting that giving elderly patients certain general anaesthetics could increase their risk of developing Alzheimer's disease. The intravenous anaesthetic thiopental appears to have no effect on the proteins.

The study was presented at the annual Society for Neuroscience Meeting held in Atlanta, Georgia, October 14-18.


Brain activity, drugs could affect Alzheimer's progression

Mouse studies have revealed that the activity of connections among brain cells significantly affects levels of the toxic protein beta-amyloid, suggesting that the kind of mental activity people practice or drugs they might take fo affect their risk of Alzheimer’s or the disease progression. The researchers suggest that enriched environments may increase overall synaptic activity in some brain regions and decrease it in others. Increased activity in some brain regions might result in increased susceptibility to beta-amyloid deposition if the activated neural circuits contain high levels of human APP expression. Drugs used to treat neuropsychiatric disorders directly influence neurotransmitters, and their receptors, thereby altering synaptic activity.

Cirrito, J.R. et al. 2005. Synaptic Activity Regulates Interstitial Fluid Amyloid-b Levels In Vivo. Neuron, 48, 913–922.


New research suggests heart bypass surgery increases risk of Alzheimer's disease

Patients who have either coronary artery bypass graft surgery or coronary angioplasty are at an increased risk of developing Alzheimer's disease, according to a study involving 5,216 people who underwent coronary artery bypass graft surgery (CABG) and 3,954 people who had a percutaneous transluminal coronary angioplasty (PTCA) in 1996 and 1997. The researchers suggest the trauma to the brain during surgery is the principle cause.

Lee, T.A., Wolozin, B., Weiss, K.B. & Bednar, M.M. 2005. Assessment of the Emergence of Alzheimer's Disease Following Coronary Artery Bypass Graft Surgery or Percutaneous Transluminal Coronary Angioplasty. Journal of Alzheimer's Disease, 7 (4), 319-324.


Testosterone loss may lead to Alzheimer's

A new study suggests that, like estrogen loss in older women, decreased levels of testosterone may put aging men at risk for Alzheimer's disease. The research suggests that testosterone both protects neurons from injury, and reduces levels of beta-amyloid.

Rosario, E.R., Chang, L., Stanczyk, F.Z. & Pike, C.J. 2004. Age-Related Testosterone Depletion and the Development of Alzheimer Disease. JAMA, 292, 1431-1432.


Coronary artery bypass surgery not a risk factor for dementia

A comparison of dementia patients with controls has found that dementia patients are no more likely than those without dementia to have had coronary artery bypass surgery.


Minorities hardest hit by Alzheimer's disease

A study of 119 Latinos and 55 non-Latino white Alzheimer patients suggests that Latinos in the U.S. develop Alzheimer's symptoms much earlier than their white, non-Latino peers. There are several known factors which may be responsible for this apparent vulnerability in Latinos: high rates of vascular disease, leave school earlier, and less likely to use medical services or have health insurance than other Americans.

South Carolina, as the only U.S. state that keeps a comprehensive database of people with a diagnosis of Alzheimer's disease, has found that African Americans aged 55 to 64 years were more than three times as likely to have Alzheimer's as their European American counterparts. At ages 65 to 84, African Americans were more than twice as likely to have Alzheimer's. South Carolina has greater rates of obesity, diabetes, and related health problems than the rest of the country, especially amongst African Americans.

Another study has found that, in order to avoid overestimating the number of African Americans who may have early signs of Alzheimer's disease, screening tests must be adapted to cultural differences. The study involved 635 people over the age of 60. Researchers found that, using current scoring methods, African Americans scored lower on various neuropsychological tests. Even when education was taken into account, 35% of African Americans scored low enough to warrant a diagnosis of MCI, compared to only 15% of European Americans. However, when the researchers applied new, racially sensitive scoring methods they've developed, the difference in MCI rates disappeared.

Reported at The 9th International Conference on Alzheimer's Disease and Related Disorders (ICAD), July 17-22, at the Pennsylvania Convention Center in Philadelphia, Pennsylvania:

Christopher Clark – Latino Patients with AD Have An Earlier Age of Symptoms Onset Compared to Anglos (P1-041)

James Laditka – Epidemiology of Alzheimer's Disease: Race Effects, Area Variation, and Clustering (P3-132)

Marjorie Marenberg – Racial Differences in Screening of MCI in a Primary Care Population (O4-01-02)


Alzheimer's Association offers information about providing culturally sensitive care at http://www.alz.org//Resources/Diversity/

Low free testosterone levels linked to Alzheimer's disease in older men

A study evaluating the testosterone levels of 574 men, ages 32 to 87, who participated in the Baltimore Longitudinal Study of Aging (BLSA), found that older men with lower levels of free, or unbound, testosterone circulating in their bloodstreams were apparently at higher risk of developing Alzheimer's than their peers. This is believed to be the first study to associate low circulating blood levels of free testosterone with Alzheimer’s years before diagnosis. Previously, the same researchers had found that older men with high levels of circulating free testosterone have better visual and verbal memory and perform spatial tasks more adeptly than their peers.

Moffat, S.D., Zonderman, A.B., Metter, E.J., Kawas, C., Blackman, M.R., Harman, S.M. & Resnick, S.M. 2004. Free testosterone and risk for Alzheimer disease in older men. Neurology, 62, 188-193.