Alzheimer's & other dementias
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.
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.
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.
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.
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.
 Zhou, H., Hu S., Matveev R., Yu Q., Li J., Khaitovich P., et al.
(2015). A Chronological Atlas of Natural Selection in the Human Genome during the Past Half-million Years.
 Desikan, R. S., Schork A. J., Wang Y., Thompson W. K., Dehghan A., Ridker P. M., et al.
(2015). Polygenic Overlap Between C-Reactive Protein, Plasma Lipids and Alzheimer's Disease.
 Xia, D., Watanabe H., Wu B., Lee S. Hun, Li Y., Tsvetkov E., et al.
(2015). Presenilin-1 Knockin Mice Reveal Loss-of-Function Mechanism for Familial Alzheimer’s Disease.
Neuron. 85(5), 967 - 981.
 Ashbrook, D. G., Williams R. W., Lu L., Stein J. L., Hibar D. P., Nichols T. E., et al.
(2014). Joint genetic analysis of hippocampal size in mouse and human identifies a novel gene linked to neurodegenerative disease.
BMC Genomics. 15(1),
 Kleinberger, G., Yamanishi Y., Suárez-Calvet M., Czirr E., Lohmann E., Cuyvers E., et al.
(2014). TREM2 mutations implicated in neurodegeneration impair cell surface transport and phagocytosis.
Science Translational Medicine. 6(243), 243ra86 - 243ra86.
An examination of the brains of three groups of deceased individuals (13 cognitively normal, aged 20-66; 16 non-demented older adults, aged 70-99; 21 individuals with Alzheimer's, aged 60-95) has found that amyloid starts to accumulate and clump inside basal forebrain cholinergic neurons in young adulthood. Other neurons didn't show the same extent of amyloid accumulation. Basal forebrain cholinergic neurons are the first to be affected, and to die, in aging and Alzheimer's.
 Baker-Nigh, A., Vahedi S., Davis E. Goetz, Weintraub S., Bigio E. H., Klein W. L., et al.
(2015). Neuronal amyloid-β accumulation within cholinergic basal forebrain in ageing and Alzheimer’s disease.
A large meta-analysis has concluded that having diabetes increases the chance that a person with mild cognitive impairment will progress to dementia by 65%.
There was no consistent evidence that hypertension or cholesterol levels increased the risk of someone with MCI progressing to dementia. Smoking was similarly not associated with increased risk, although the reason for this probably lies in mortality: smokers tend to die before developing dementia.
There was some evidence that having symptoms of psychiatric conditions, including depression, increased the risk of progressing to dementia.
There was some evidence that following a Mediterranean diet decreased the risk of an individual with amnestic MCI progressing to Alzheimer's, and that higher folate levels decrease the risk of progressing from MCI to dementia. The evidence regarding homocysteine levels was inconsistent.
The evidence indicates that level of education does not affect the risk of someone with MCI progressing to dementia.
Do note that all this is solely about progression from MCI to dementia, not about overall risk of developing dementia. Risk factors are complex. For example, cholesterol levels in mid-life are associated with the later development of dementia, but cholesterol levels later in life are not. This is consistent with cholesterol levels not predicting progression from MCI to dementia. Level of education is a known risk factor for dementia, but it acts by masking the damage in the brain, not preventing it. It is not surprising, therefore, that it doesn't affect progression from MCI to dementia, because higher education helps delay the start, it doesn't slow the rate of decline.
Do note also that a meta-analysis is only as good as the studies it's reviewing! Some factors couldn't be investigated because they haven't been sufficiently studied in this particular population (those with MCI).
The long-running Cache County study has previously found that 46% of those with MCI progressed to dementia within three years; this compared with 3% of those (age-matched) with no cognitive impairment at the beginning of the study.
More recently, data from the long-running, population-based Rotterdam study revealed that those diagnosed with MCI were four times more likely to develop dementia, over seven years. compared with those without MCI. Of those with MCI (10% of the 4,198 study participants), 40% had amnestic MCI — the form of MCI that is more closely associated with Alzheimer's disease.
The 2014 study also found that older age, positive APOE-ɛ4 status, low total cholesterol levels, and stroke, were all risk factors for MCI. Having the APOE-ɛ4 genotype and smoking were related only to amnestic MCI. Waist circumference, hypertension, and diabetes were not significantly associated with MCI. This may be related to medical treatment — research has suggested that hypertension and diabetes may be significant risk factors only when untreated or managed poorly.
 Cooper, C., Sommerlad A., Lyketsos C. G., & Livingston G.
(2015). Modifiable Predictors of Dementia in Mild Cognitive Impairment: A Systematic Review and Meta-Analysis.
American Journal of Psychiatry. 172(4), 323 - 334.
 Tschanz, J. T., Welsh-Bohmer K. A., Lyketsos C. G., Corcoran C., Green R. C., Hayden K., et al.
(2006). Conversion to dementia from mild cognitive disorder The Cache County Study.
Neurology. 67(2), 229 - 234.
de Bruijn, R.F.A.G. et al. Determinants, MRI Correlates, and Prognosis of Mild Cognitive Impairment: The Rotterdam Study. Journal of Alzheimer’s Disease, Volume 42/Supplement 3 (August 2014): 2013 International Congress on Vascular Dementia (Guest Editor: Amos D. Korczyn), DOI: 10.3233/JAD-132558.
Last year I reported on a finding that ten lipids in the blood could predict development of MCI or Alzheimer's within 2-3 years, with over 90% accuracy.
A French study involving 36 healthy older adults (60-80), prescreened for amyloid deposits in the brain to exclude people who might have preclinical Alzheimer’s disease, has found a linear increase in gray matter volume in proportion to the number of years of education (7-20 years). Specifically, increases were seen in the right superior temporal gyrus, anterior cingulate gyrus, and left insular cortex, and metabolism also increased proportionately with years of education in the anterior cingulate gyrus, as did functional connectivity between anterior cingulate gyrus and the right hippocampus, left angular gyrus, right posterior cingulate, and left inferior frontal gyrus. This increased connectivity was associated with improved cognitive performance.
The conclusion is that both the structure of the brain and its function in old age are increased in proportion to the number of years of education.
 Arenaza-Urquijo, E. M., Landeau B., La Joie R., Mevel K., Mézenge F., Perrotin A., et al.
(2013). Relationships between years of education and gray matter volume, metabolism and functional connectivity in healthy elders.
NeuroImage. 83, 450 - 457.
Data from 57,669 older Taiwanese patients (65+) with no dementia at the beginning of the 5-year study has found that the risk of developing dementia was inversely related to statin dosage. Those on the highest doses of statins were three times less likely to develop dementia. The potency of the statins was also a factor, with high potency statins such as atorvastatin and rosuvastatin giving the most benefit.
Nearly 10% developed dementia during the study.
“Statin use and the incidence of dementia in the elderly: a nation-wide data survey” was presented at the European Society of Cardiology 2013 Congress in Amsterdam.
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
 Fox, M., Knapp L. A., Andrews P. W., & Fincher C. L.
(2013). Hygiene and the world distribution of Alzheimer’s disease Epidemiological evidence for a relationship between microbial environment and age-adjusted disease burden.
Evolution, Medicine, and Public Health. 2013(1), 173 - 186.
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.
 Poole, S., Singhrao S. K., Kesavalu L., Curtis M. A., & Crean SJ.
(2013). Determining the Presence of Periodontopathic Virulence Factors in Short-Term Postmortem Alzheimer's Disease Brain Tissue.
Journal of Alzheimer's Disease. 36(4), 665 - 677.
A study involving 264 older adults with mild cognitive impairment has found that those with normal glucose levels (167; 63%) had less cognitive decline over 2 years than those with impaired (high) glucose levels (97; 37%). They also showed less brain shrinkage and were less likely to develop Alzheimer’s. The fasting glucose levels were classified according to the American Diabetes criteria.
 Vos, S JB., Xiong C., Visser P J., Jasielec M. S., Hassenstab J., Grant E. A., et al.
(2013). Preclinical Alzheimer's disease and its outcome: a longitudinal cohort study.
The Lancet Neurology. 12(10), 957 - 965.
A rat study supports the growing evidence of a link between type 2 diabetes and Alzheimer’s. In this study, 20 rats were fed a high-fat diet to give them type 2 diabetes. A subsequent test found that the diabetic rats had significantly poorer memories than the control group of rats on a healthy diet (the rats were taught to associate a dark cage with an electric shock; how long the rat continues to remember that the stimulus means a shock — as shown by their frozen reaction — is taken as a measure of how good their memory is; the diabetic rats froze for less than half the time of the controls).
The diabetic rats then had their brains (specifically, the hippocampus) injected with antibodies that disrupt amyloid-beta plaques. This produced no change in their behavior. However, when they were given antibodies that disrupt amyloid-beta oligomers (precursors of the plaques), the memory deficit was reversed, and they behaved the same as the healthy rats.
These findings suggest that the cognitive decline often seen in type 2 diabetes is not due to the disruption in insulin signaling, as thought, but rather the build-up of amyloid oligomers. Previous research has shown that the same enzymes break down both insulin and the oligomers, so when there’s a lot of insulin (which the enzymes prioritize), the enzymes don’t have as much opportunity to work on breaking down the oligomers. The oligomers collect, preventing the insulin from reaching their proper receptors in the hippocampus, which impairs cognitive function.
All this supports the idea that type 2 diabetes may be thought of as early-stage Alzheimer's. Obviously a lot more work needs to be done to confirm this picture, but certainly in the mean time, it can be taken as another reason to take type 2 diabetes very seriously.
McNay, E.C., Osborne, D., et al. 2014. Preliminary data presented at the Society for Neuroscience meeting in San Diego in November, 2013
A study of cell cultures taken from rodents’ cerebral blood vessels has found that, while cells exposed to either high glucose or amyloid-beta showed no changes in viability, exposure to both decreased cell viability by 40%. Moreover, cells from diabetic mice were more vulnerable to amyloid-beta, even at normal glucose levels.
The findings support evidence pointing to high glucose as a risk factor for vascular damage associated with Alzheimer’s, and adds weight to the view that controlling blood sugar levels is vital for those with diabetes.
 Carvalho, C., Katz P. S., Dutta S., Katakam P. V. G., Moreira P. I., & Busija D. W.
(2014). Increased Susceptibility to Amyloid-β Toxicity in Rat Brain Microvascular Endothelial Cells under Hyperglycemic Conditions.
Journal of Alzheimer's Disease. 38(1), 75 - 83.
Although it's well-established now that diabetes is a major risk factor for dementia, the reason is still not well understood. To test the hypothesis that epigenetic changes in the brain, affecting synaptic function, may be part of the reason, the brains of diabetics and others were examined post-mortem. Diabetics' brains were found to have significantly higher expression of a class of molecules (histone deacetylases class IIa) and this was associated with impaired expression of synaptic proteins.
This finding was confirmed in mice genetically engineered to develop an Alzheimer’s-type condition, who were induced to develop diabetes. The increase of HDAC IIa was associated with synaptic impairments in the hippocampus, through the work of amyloid oligomers.
Some 60% of Alzheimer's patients have at least one serious medical condition associated with diabetes.
 Wang, J., Gong B., Zhao W., Tang C., Varghese M., Nguyen T., et al.
(2014). Epigenetic Mechanisms Linking Diabetes and Synaptic Impairments.
Diabetes. 63(2), 645 - 654.
A seven-year study involving 2,067 older adults (average age 76 at start) has found that those with a high blood glucose level, whether or not they had diabetes, were more likely to develop dementia. Moreover, this was a linear relationship — meaning that the risk steadily increased with higher glucose levels, and decreased the lower it was. Thus, even those with ‘normal’ glucose levels were subject to this relationship, with those whose blood sugar averaged 115 milligrams per deciliter, having an 18% higher risk of dementia than those at 100 mg/dL. Other risk factors, such as high blood pressure, smoking, exercise, and education, were taken into account in the analysis.
The findings add weight to the idea that the brain is a target organ for damage by high blood sugar.
Over the course of the study, a quarter (524) developed dementia of some kind, primarily Alzheimer’s disease or vascular dementia. At the beginning of the study, 232 (11%) had diabetes, and a further 111 developed it by the end of the study. Nearly a third (32%) of those with diabetes at the beginning of the study developed dementia, compared to just under a quarter of those without (24.5%).
The journal article is freely available at http://www.nejm.org/doi/full/10.1056/NEJMoa1215740#t=article
 Crane, P. K., Walker R., Hubbard R. A., Li G., Nathan D. M., Zheng H., et al.
(2013). Glucose Levels and Risk of Dementia.
New England Journal of Medicine. 369(6), 540 - 548.
A study involving 128 patients with mild to moderate Alzheimer’s disease, which had specifically excluded those with known diabetes, found that 13% of them did in fact have diabetes, and a further 30% showed glucose intolerance, a pre-diabetic condition.
Turner presented his findings at the Alzheimer's Association International Congress in Boston on July 14.
A 12-year study involving 783 older adults with diabetes (average age 74) has found that 148 (19%) developed dementia. Those 61 patients (8%) who had a reported hypoglycemic event were twice as likely to develop dementia compared to those who didn’t suffer such an event (34% vs. 17%). Similarly, those with dementia were more likely to experience a severe hypoglycemic event.
The findings suggest some patients risk entering a downward spiral in which hypoglycemia and cognitive impairment fuel one another, leading to worse health
 Yaffe, K., CM F., N H., & et al
(2013). ASsociation between hypoglycemia and dementia in a biracial cohort of older adults with diabetes mellitus.
JAMA Internal Medicine. 173(14), 1300 - 1306.
In the first study to look at racial and ethnic differences in dementia risk among older adults with type 2 diabetes, Native Americans were 64% more likely to develop dementia than Asian-Americans, and African-Americans were 44% more likely. Asian-Americans had the lowest risk, and non-Hispanic whites and Latinos were intermediate.
The study involved 22,171 older adults (60+), of whom 3,796 patients (17%) developed dementia over the 10 years of the study. Almost 20% of the African-Americans and Native Americans developed dementia.
The ethnic differences were not explained by diabetes-related complications, glycemic control or duration of diabetes, or neighborhood deprivation index, body mass index, or hypertension.
 Mayeda, E. R., Karter A. J., Huang E. S., Moffet H. H., Haan M. N., & Whitmer R. A.
(2014). Racial/Ethnic Differences in Dementia Risk Among Older Type 2 Diabetic Patients: The Diabetes and Aging Study.
Diabetes Care. 37(4), 1009 - 1015.
A new review from The Cochrane Library, based on six trials involving 289 people, has concluded that exercise can improve cognition and the ability of older people with dementia to carry out daily activities, such as walking short distances or getting up from a chair. However, there was no clear effect of exercise on depression in older people with dementia, and the reviewers say that more evidence is needed to understand how exercise could reduce the burden on family caregivers and health systems.
Forbes D, Thiessen EJ, Blake CM, Forbes SC, Forbes S. Exercise programs for people with dementia. Cochrane Database of Systematic Reviews 2013, Issue 12. Art. No.: CD006489. DOI: 10.1002/14651858.CD006489.pub3.
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