Alzheimer's Genes

I've spoken before about how the presence or absence of the “Alzheimer's gene” may affect which lifestyle changes are beneficial for you. A new study has added to that idea with a finding that seafood consumption was associated with fewer signs of Alzheimer's-related pathology, but only among those with the APOEe4 gene.

Seafood consumption was also associated with increased mercury levels in the brain, with levels rising the more seafood was consumed. However, higher levels of mercury were not correlated with any neuropathologies.

Fish oil supplementation was not associated with any differences in neuropathology. However, higher levels of alpha-linolenic acid (an omega-3 fatty acid found in flaxseed, chia seeds, walnuts, etc) were associated with a reduced chance of cerebral infarctions.

The study involved 554 deceased participants (average age 89.9 years) from the long-running Memory and Aging Project (MAP) conducted by Rush University Medical Center. The participants had completed annual dietary questionnaires over a number of years. The brains of 286 participants were autopsied, to assess neuropathologies and mercury levels.

The average educational attainment of the participants was 14.6 years; 67% were women.

The finding tempers the evidence from many studies that eating fish reduces Alzheimer's risk. However, it is consistent with what I believe is becoming apparent: that there are different paths to Alzheimer's, and thus different factors involved in preventing it, depending on your own particular gene-environment attributes.

A small study involving 50 children and teens living in Mexico City (aged 13.4 ± 4.8 years) has found that those with the 'Alzheimer's gene' APOEε4 (22 of the 50) were more vulnerable to the effects of air pollution on cognition. Those with the gene variant had a reduced NAA/Cr ratio in the right frontal white matter (as those with Alzheimer's do), poorer attention and short-term memory, and below-average scores in Verbal and Full Scale IQ (>10 points), compared to those with the 'normal' ε3 variant. They also had problems with odor detection, also typical of those developing Alzheimer's.

The study is small and lacks a proper control group, but while other studies have found some signs of early brain differences in those carrying the ε4 variant, they have not been nearly as marked as this. The finding certainly warrants concern and further study.

Calderón-Garcidueñas, L. et al. 2015. Decreases in Short Term Memory, IQ, and Altered Brain Metabolic Ratios in Urban Apolipoprotein ε4 Children Exposed to Air Pollution. Journal of Alzheimer's Disease, 45(3)

Alzheimer's the evolutionary cost of better brains?

A recent genetics paper reports on evidence that changes in six genes involved in human brain development occurred around 50,000 to 200,000 years ago. These mutations may have helped increase the connectivity of our neurons, making us smarter. But these same genes are also implicated in Alzheimer's. Researchers speculate that the disorder is thus connected to our increased intelligence — the price we pay for having better brains. This is not inconsistent with a previous suggestion that the myelin ("white matter") sheathing our brain wiring was the key evolutionary change in making us unique, and that this myelin sheathing may also be the cause of our unique vulnerability to neurological disorders.

The study examined the genomes of 90 people with African, Asian, or European ancestry.

Genetics overlap found between Alzheimer's disease and cardiovascular risk factors

Data from genome-wide association studies of more than 200,000 individuals has revealed a genetic overlap between Alzheimer's disease and two significant cardiovascular disease risk factors: high levels of inflammatory C-reactive protein (CRP) and plasma lipids. The two identified genes (HS3ST1 and ECHDC3, on chromosomes 4 and 10) were not previously associated with Alzheimer's risk. However, the association of high plasma lipid levels and inflammation with Alzheimer's risk is supported by previous research.

The findings support the idea that inflammation and high blood lipids play a role in dementia risk, and may offer therapeutic targets.

How genetic changes lead to familial Alzheimer's disease

Variants in the presenilin-1 gene are the most common cause of inherited, early-onset Alzheimer's. Because presenilin is a component of gamma secretase, which cuts up amyloid precursor protein into Abeta40 and Abeta42 (the protein found in plaques), it's been thought that these presenilin-1 variants increase the activity of gamma secretase. However, attempts to stop Alzheimer's by using drugs to block gamma-secretase have so far been fruitless (indeed, counter-productive). Now a new mouse study has explained why: it appears that the presenilin-1 variants may in fact decrease, rather than increase, the activity of gamma-secretase. This suggests that the presenilin-1 variants are acting on other causes of Alzheimer's, and also suggests the possibility that restoring gamma-secretase, rather than blocking it, may be a more effective therapeutic strategy.

Mice genetically engineered for Alzheimer's are usually given dispositions for excessive amyloid plaques. However, it's becoming clear that Alzheimer's is more complex than a single cause. This may explain the signal failure of mouse models to provide treatments that work on humans. This research provides a different mouse model, which may help in the development of treatments.

Mining big data yields new Alzheimer's gene

Analysis of brain scans from the ENIGMA Consortium and genetic information from The Mouse Brain Library has revealed a new gene for Alzheimer's risk. The gene MGST3 regulates the size of the hippocampus.

The finding confirms the importance of hippocampal volume for maintaining memory and cognition, and supports the idea that “cognitive reserve” helps prevent age-related cognitive decline and dementia.

Gene involved in waste removal increases risk of Alzheimer's & other neurodegenerative disorders

Previous research has pointed to the gene TREM2 as a genetic risk factor for Alzheimer's disease. A recent study explains why variants in this gene might be associated with neurodegenerative disorders such as Alzheimer's, Parkinson's, ALS, and frontotemporal dementia.

It appears that the gene is involved in the microglia — the “cleaners” of the brain. Variants in the gene affect the recognition of waste products left behind by dead cells, reducing the amount of debris that the microglia can cope with.

The finding may point to a way of slowing the progression of these neurodegenerative diseases even when the disease is well established.

[3923] Zhou H, Hu S, Matveev R, Yu Q, Li J, Khaitovich P, Jin L, Lachmann M, Stoneking M, Fu Q, et al. A Chronological Atlas of Natural Selection in the Human Genome during the Past Half-million Years. bioRxiv [Internet]. 2015 . Available from:

[3918] Desikan RS, Schork AJ, Wang Y, Thompson WK, Dehghan A, Ridker PM, Chasman DI, McEvoy LK, Holland D, Chen C-H, et al. Polygenic Overlap Between C-Reactive Protein, Plasma Lipids and Alzheimer's Disease. Circulation [Internet]. 2015 . Available from:

[3922] Xia D, Watanabe H, Wu B, Lee SHun, Li Y, Tsvetkov E, Bolshakov VY, Shen J, Kelleher RJ. Presenilin-1 Knockin Mice Reveal Loss-of-Function Mechanism for Familial Alzheimer’s Disease. Neuron [Internet]. 2015 ;85(5):967 - 981. Available from:

[3916] Ashbrook DG, Williams RW, Lu L, Stein JL, Hibar DP, Nichols TE, Medland SE, Thompson PM, Hager R. Joint genetic analysis of hippocampal size in mouse and human identifies a novel gene linked to neurodegenerative disease. BMC Genomics [Internet]. 2014 ;15(1). Available from:

[3920] Kleinberger G, Yamanishi Y, Suárez-Calvet M, Czirr E, Lohmann E, Cuyvers E, Struyfs H, Pettkus N, Wenninger-Weinzierl A, Mazaheri F, et al. TREM2 mutations implicated in neurodegeneration impair cell surface transport and phagocytosis. Science Translational Medicine [Internet]. 2014 ;6(243):243ra86 - 243ra86. Available from:

A small study involving 52 people aged 32-72 has found that those whose parents both had Alzheimer's disease showed more severe abnormalities in brain volume and metabolism and 5-10% more amyloid plaques in certain brain regions, compared to those with either a father or mother, or neither parent, with the disease. There were 13 in each group.

Consistent with previous research, those whose mother had Alzheimer's disease showed a greater level of the Alzheimer's disease biomarkers than those whose father had the disease.

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:

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:

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:

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:

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:

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:

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:

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:

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:

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:

[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:

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:

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:

Data from 848 adults of all ages has found that brain volume in the default mode network declined in both healthy and pathological aging, but the greatest decline occurred in Alzheimer’s patients and in those who progressed from mild cognitive impairment to Alzheimer’s disease. Reduced brain volumes in these regions were associated with declines in cognitive ability, the presence of Alzheimer’s biomarkers in the cerebrospinal fluid, and with carrying the “Alzheimer’s gene”, the APOE4 allele.

The findings support the idea that neurodegeneration spreads through networks of connected brain regions, in a disease specific manner.

[3607] Spreng RNathan, Turner GR. Structural Covariance of the Default Network in Healthy and Pathological Aging. The Journal of Neuroscience [Internet]. 2013 ;33(38):15226 - 15234. Available from:

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:

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:

We know that the E4 variant of the APOE gene greatly increases the risk of developing Alzheimer’s disease, but the reason is a little more mysterious. It has been thought that it makes it easier for amyloid plaques to form because it produces a protein that binds to amyloid beta. However, a new study shows that APOE and amyloid beta don’t bind together in cerebrospinal fluid and in fluids present outside cells grown in dishes, making it unlikely that they are binding together in the brain.

Mouse and cell culture experiments suggest instead that the APOE protein may be blocking a pathway that normally helps degrade amyloid beta — both APOE and amyloid beta seem to compete to bind to an astrocyte receptor. Previous work has shown that astrocytes can degrade amyloid beta.

The findings suggest that therapeutic strategies that target APOE need to be redirected.

[3410] Verghese PB, Castellano JM, Garai K, Wang Y, Jiang H, Shah A, Bu G, Frieden C, Holtzman DM. ApoE influences amyloid-β (Aβ) clearance despite minimal apoE/Aβ association in physiological conditions. Proceedings of the National Academy of Sciences [Internet]. 2013 ;110(19):E1807 - E1816. Available from:

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:

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.

Two studies have come out in favor of a diet rich in foods containing vitamin E to help protect against Alzheimer's disease. One study involved 815 Chicago residents age 65 and older with no initial symptoms of mental decline, who were questioned about their eating habits and followed for an average of about four years. When factors like age and education were taken into account, those eating the most vitamin E-rich foods had a lower risk of developing Alzheimer’s, provided they did not have the ApoE e4 allele. This was not true when vitamin E was taken as a supplement. Intake of vitamin C and beta carotene appeared protective, but not at a statistically significant level. The other study involved 5,395 people in the Netherlands age 55 and older who were followed for an average of six years. Those with high intakes of vitamins E and C were less likely to become afflicted with Alzheimer's, regardless of whether they had the gene variation. This association was most pronounced for current smokers, for whom beta carotene also seemed to be protective. A number of clinical trials are underway to further investigate these links.

Engelhart, M.J., Geerlings, M.I., Ruitenberg, A., van Swieten, J.C., Hofman, A., Witteman, J.C.M. & Breteler, M.M.B. 2002. Dietary Intake of Antioxidants and Risk of Alzheimer Disease. JAMA, 287, 3223-3229. Morris, M.C., Evans, D.A., Bienias, J.L., Tangney, C.C., Bennett, D.A., Aggarwal, N., Wilson, R.S. & Scherr, P.A. 2002. Dietary Intake of Antioxidant Nutrients and the Risk of Incident Alzheimer Disease in a Biracial Community Study. JAMA, 287, 3230-3237.

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

Impact of Alzheimer's gene on healthy brains

And another new imaging analysis technique has cast light on the impact of the Alzheimer’s gene ApoE4 in healthy brains. Healthy older adults with the gene were found to have reduced cognitive performance, decreased brain volume in the hippocampus and amygdala, and decreased white matter integrity in the left parahippocampal gyrus.

Honea, Robyn A., Eric Vidoni, Amith Harsha and Jeffrey M. Burns. Impact of APOE on the Healthy Aging Brain: A Voxel-Based MRI and DTI Study. J Alzheimers Dis 18:3, 553-564.

Three new genes associated with Alzheimer's found

Only one gene, ApoE4, has been associated with the non-familial (common) form of Alzheimer’s. Now the largest ever Alzheimer's genome-wide association study involving 16,000 individuals, has found three more. CLU or ApoJ (which produces a protective protein called clusterin or apolipoprotein J), PICALM (important at synapses and involved in transporting molecules within and into nerve cells), and CR1. Both CLU and CR1 have previously been implicated in the clearance of amyloid beta peptide. CLU is encoded on chromosome 8, CR1 on chromosome 1, and PICALM on chromosome 11.

Harold, D. et al. 2009. Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease. Nature Genetics, 41, 1088–1093. Lambert, J-C et al. 2009. Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer's disease. Nature Genetics, 41, 1094-1099.

Carriers of Alzheimer's gene show different brain activity as young adults

Possession of the ApoE4 gene variant associated with Alzheimer’s risk is found in about a quarter of the population, and has been shown to be associated with differences in the hippocampus in middle-aged and elderly healthy carriers. Now a new study of 36 younger adults (20-35) has revealed that differences in brain activity patterns between carriers and non-carriers are also evident at this stage, not only when performing a memory task, but even when the brain was at rest. Carriers of the gene had more brain activity in the hippocampus during the memory task, and more activity in the default mode network during rest. The findings support a theory that the brain's memory function may gradually wear itself out in those who go on to develop Alzheimer's.

Filippini, N. et al. 2009. Distinct patterns of brain activity in young carriers of the APOE-ε4 allele. Proceedings of the National Academy of Sciences, 106, 7209-7214.

Having a parent with dementia may affect memory in midlife

A study of 715 participants from the second generation of the Framingham Heart Study (average age 59) has found that, among those with the ApoE ε4 gene, those who had parents with dementia scored significantly worse on tests of verbal memory and visual memory than persons who did not have parents with dementia. The impairment was strongest in those whose parents had Alzheimer’s (rather than other forms of dementia), and in them was equivalent to around 15 years of brain aging. The effect of parental dementia was not found in those who didn’t have the ApoE ε4 gene.

Debette, S. et al. 2009. Parental Dementia and Alzheimer Disease Are Associated with Poorer Memory in Middle-Aged Adults: The Framingham Offspring Study. Presented April 29 at the American Academy of Neurology's 61st Annual Meeting in Seattle, Washington.

Memory gene linked to late-onset Alzheimer's

Following the finding that carriers of one variant (the T-allele) of the KIBRA gene performed better on memory tests compared to those carrying the C-allele, researchers have now found that carriers of the T-allele have a 25% lower risk of developing Alzheimer's disease. The conclusion is supported by three studies. A study of 702 deceased persons diagnosed with Alzheimer's, and 1,026 living and deceased persons with and without Alzheimer's, found that non-carriers of the KIBRA T-allele had increased risk of late-onset Alzheimer¹s. A study of brain tissue from 47 deceased individuals found that KIBRA, and a subset of other molecules directly interacting with it, were significantly altered in regions of the brain involved in Alzheimer's disease pathology, but not in a region of the brain typically unaffected -- the primary visual cortex. PET scans of 136 individuals aged 47 to 68, with close relatives diagnosed with Alzheimer's, of whom half carried the T-allele, found that non-carriers exhibited, on average, less metabolic activity in key brain regions known to be altered in the earliest stages of the disease. Similar findings have been found when looking at the epsilon 4 allele of apolipoprotein E (the ‘Alzheimer’s gene’). In the current study, the effects of this allele were controlled for.

Corneveaux, J.J. et al. In press. Evidence for an association between KIBRA and late-onset Alzheimer's disease. Neurobiology of Aging

Healthy children of Alzheimer patients show early brain changes

A study of 28 neurologically-normal subjects, between ages 45 and 65, of whom 12 carried the ‘Alzheimer’s gene’ APOE-4, has found that although there was no significant difference in educational level or neuropsychological performances, those who didn’t carry the gene had significantly better functional connectivity between the hippocampus and the posterior cingulated cortex.

The findings were presented at the Alzheimer's Association International Conference on Alzheimer's disease in Chicago, July 29.

Women more likely to have memory problems in very old age

Dementia risk for both men and women increases from age 65 to 85, but a study of about 900 people age 90 and older has found that women were nearly twice as likely to have dementia in their 90s compared to men. The results also showed that the likelihood of having dementia doubled every five years in women but not in men. Women with a higher education appeared to be as much as 45% less likely to have dementia compared to women with less education.

Corrada, M.M. et al. 2008. Prevalence of dementia after age 90: Results from The 90+ Study. Neurology, 71 (5), 337-343.

Gene variation linked to earlier onset of Alzheimer's symptoms

Another genetic variation has been found for Alzheimer’s disease. Unlike the ‘Alzheimer’s gene’ APOe4, which is linked to the rare early-onset form, this gene variant is linked to early presentation in people afflicted with the more common, late-onset form. Rather than increasing the risk of Alzheimer’s, the gene increases the vulnerability of carriers to the effects of amyloid plaques, so that symptoms become evident earlier. The gene codes for the tau protein found in neurofibrillary tangles. Previous studies have had inconsistent results, but the new study has dealt with previous difficulties.

Kauwe, J.S.K. et al. 2008. Variation in MAPT is associated with cerebrospinal fluid tau levels in the presence of amyloid-beta deposition. Proceedings of the National Academy of Sciences, 105 (23), 8050-8054.

Maternal inheritance more importance than paternal for Alzheimer's risk?

In an intriguing preliminary study comparing brain metabolism among cognitively normal people who have a father, a mother, or no relatives with Alzheimer’s disease, researchers have found that only those with an affected mother have reduced brain metabolism in the same brain regions as Alzheimer’s patients.

Mosconi, L. et al. 2007. Maternal family history of Alzheimer's disease predisposes to reduced brain glucose metabolism. PNAS, 104, 19067-19072.

Familial link between Parkinson's and dementia

A study of relatives of patients with Parkinson’s disease provides evidence that relatives of patients with Parkinson’s disease (primarily younger age at onset Parkinson’s) have an increased risk of cognitive impairment or dementia.

Rocca, W.A. et al. 2007. Risk of Cognitive Impairment or Dementia in Relatives of Patients With Parkinson Disease. Archives of Neurology, 64(10),1458-1464.

High stress and genetic risk factor lead to increased memory decline

A study involving 91 older, healthy subjects (mean age 78.8 years) has found that those low on stress (low levels in cortisol) or without the APOE-ε4 gene performed better on memory measures than those with high stress or those with the APOE-ε4 gene. Those who had the gene and had high stress levels showed the greatest memory impairment.

Peavy, G.M. et al. 2007. The Effects of Prolonged Stress and APOE Genotype on Memory and Cortisol in Older Adults. Biological Psychiatry, 62 (5), 472-478.

New Alzheimer's gene

A study comparing more genetic markers in the DNA of people with and without Alzheimer’s disease than ever before has revealed a new gene that may increase a person’s risk for developing Alzheimer’s disease. The gene — GAB2 — appears to modify an individual’s risk when associated with other genes, including APOE4. It’s suggested that the healthy form of the GAB2 gene protects brain cells from developing tangles. If confirmed, this discovery could provide a target for future therapeutic drugs.

Reiman, E.M. et al. 2007. GAB2 Alleles Modify Alzheimer's Risk in APOE e4 Carriers. Neuron, 54, 713-720.

Study examines genetic risk factors for Alzheimer's disease

A Welsh study that tested more than 17,000 gene variants in 4,000 volunteers has found evidence for several genes contributing to Alzheimer’s disease, the most interesting one being GALP, thought to affect the development of tangles within brain cells.

The findings will be published in a future issue of Human Molecular Genetics.

Two-fold role of Alzheimer’s genes?

The genes responsible for an inherited form of Alzheimer's disease — two genes known as presenilins — are primarily known for their role as an enzyme that cleaves amyloid precursor protein (APP) to form amyloid ß-peptide, which function has a direct connection to Alzheimer’s, and consequently has been the focus of attention. However, new research indicates that these genes also may control the balance of calcium within cells by acting as a calcium channel, and that the mutated forms of these genes lose this ability. Given the role that calcium signaling plays in cognitive function, it may be that this other role of presenilins is also important in the development of Alzheimer’s. If so, drugs that restore normal calcium levels might be useful for treating Alzheimer's disease.

Tu, H. et al. 2006. Presenilin Forms ER Ca2+ Leak Channels, a Function Disrupted by Familial Alzheimer's Disease-Linked Mutations. Cell, 126, 981–993.

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.

Alzheimer's has higher genetic risk than thought

In a study far larger than any undertaken before, results suggest the highest estimates of the genetic risk of developing Alzheimer’s are in fact correct. The study involved all participants in the Swedish Twin Registry aged 65 or older in 1998 (nearly 12,000 of them) and found 392 pairs with evidence of Alzheimer's in at least one twin. In the model that best fit the data, genetic influence accounted for 79% of Alzheimer's risk, with 95% probability of being within the range 67 to 88%. The other 21% of Alzheimer's risk was due to non- shared environmental causes. Risk from shared environments was statistically negligible. Genetic risk for Alzheimer's was the same for men and women after controlling for age. The study raises doubts about the widely held view that Alzheimer's has two forms: the "familial," with genetic roots, and the "sporadic," with environmental causes. This doesn’t mean, however, that environment is unimportant.

Gatz, M. et al. 2006. Role of Genes and Environments for Explaining Alzheimer Disease. Archives of General Psychiatry, 63, 168-174.

Key genetic risk for Alzheimer's linked to myelin breakdown

Myelin, the fatty insulation coating the brain's internal wiring, builds up in childhood, and breaks down as we age. Myelin is critical for speedy communication between neurons. A new study supports a growing body of evidence that myelin breakdown is a key contributor to the onset of Alzheimer disease later in life. Moreover, it has also revealed that the severity and rate of myelin breakdown in healthy older individuals is associated with ApoE status. Thus both age, the most important risk factor for Alzheimer disease, and ApoE status, the second-most important risk factor, seem to act through the process of myelin breakdown.

Bartzokis, G., Lu, P.H., Geschwind, D.H., Edwards, N., Mintz, J. & Cummings, J.L. 2006. Apolipoprotein E Genotype and Age-Related Myelin Breakdown in Healthy Individuals: Implications for Cognitive Decline and Dementia. Archives of General Psychiatry, 63, 63-72.

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.

Genes influence memory in families with Alzheimer's disease

A study of 1,036 people from 266 families, most of whom had more than one person living with Alzheimer's in the extended family, found that about half of the variation in memory performance among individuals was due to genetics. The influence of genetics was not as strong in the areas of attention, abstract reasoning, language and visual-spatial ability. The genetic influence seemed to have little to do with the gene apolipoprotein E, known to increase the risk of developing Alzheimer's. It should be noted, however, that participants in the study had an average of only six years of education.

Lee, J.H., Flaquer, A., Stern, Y., Tycko, B. & Mayeux, R. 2004. Genetic influences on memory performance in familial Alzheimer disease. Neurology, 62, 414-421.

Genes identified for age of onset of Alzheimer's

Genes responsible for controlling the age of onset of Alzheimer's or Parkinson's diseases in those individuals genetically predisposed to developing these diseases have been identified. It appears that chromosome 10, already thought to contain a risk gene for Alzheimer's disease, could also contain an age at onset gene that affects both Alzheimer's and Parkinson's diseases.

Li, Y. et al. 2002. Age at Onset in Two Common Neurodegenerative Diseases Is Genetically Controlled. American Journal of Human Genetics, 70, 985-993.

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:

New genetic risk factor for susceptibility to Alzheimer's disease

In a decade-long research study following more than 300 first-degree relatives of 189 Alzheimer's patients, researchers at the University of Pittsburgh have identified a small area of chromosome 10 that, when combined with the previously identified APOE E4 gene, significantly increase a person's risk of developing the disease. This combination of genes produced a 16-fold increase in the risk of AD among first-degree relatives. By comparison, this effect is greater than the increased risk of lung cancer caused by smoking. These new results are supported by independent studies of AD patients and controls from Pittsburgh, Boston, and Bonn, Germany.

The study was reported in Molecular Psychiatry, 6 (4), pages 413-419.

Gene marker for late-onset Alzheimer's disease nearer discovery

Three independent studies have linked late-onset Alzheimer's disease to a locus on chromosome 10 that affects processing of the amyloid-beta protein, a peptide important in the formation of the characteristic amyloid plaques found in the brains of people with Alzheimer's disease. Researchers are optimistic the precise gene will be found in the next few years.
Before this, a particular form of the apolipoprotein E (APOE) gene on chromosome 19 has been the only widely recognized genetic risk factor in late onset Alzheimer’s disease. There is also some evidence of a risk factor gene on a region of chromosome 12.
So far, three genes have been found that are linked to the rare early-onset Alzheimer's (when symptoms appear before age 60).

The findings are reported in the Dec. 22 issue of Science.