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Friday, December 23, 2011

Reducing ApoE Lowers Beta-amyloid Levels in Brains of Mice

In a paper published this week in the Journal of Neuroscience, Dr David Holtzman and colleagues at the Washington University School of Medicine provide strong evidence that less ApoE is better, at least with regards to beta-amyloid levels in the brain. They report that, in mice, lowering the levels of ApoE4 results in fewer amyloid plaques. The results imply that ApoE-lowering treatments have a place among proposed AD therapies, including immunotherapy, gene therapy, as well as beta-, and gamma- secretase inhibitors.

The genetically engineered mice had about half the amount of ApoE protein in the brain. They also had less than half the amount of beta-amyloid, and a dramatic reduction in Amyloid plaques. Interestingly, they also had about 95 percent less microglial activation. Readers of this blog will recall that microglia are the immune cells in the brain, and their over-activation is thought to accelerate the damage to brain cells observed in AD. Moreover, a dose-dependent effect was seen with lowering ApoE4, the strongest risk gene for sporadic AD.

It is believed that the different forms of ApoE (2, 3 and 4) appear to regulate the removal of beta-amyloid from the brain, and they do so with different efficiencies. It has been shown that ApoE4 seems to be the slowest in removing beta-amyloid from the brain, which may be why it confers the most genetic risk.

Experiments are planned to increase ApoE levels in the brain and see what happens to beta-amyloid levels. If they go up, then there is good evidence that by modulating ApoE levels with medications, we might be able to modify beta-amyloid levels in the brain.

Kim J, Jiang H, Park S, Eltorai AEM, Stewart FR, Yoon H, Basak JM, Finn MB, Holtzman D. Haploinsufficiency of Human APOE Reduces Amyloid Deposition in a Mouse Model of Amyloid-ß Amyloidosis. The Journal of Neuroscience, 2011 December 10; 31(49):18007–12
Author: Michael Rafii MD,PhD at 11:43 AM 0 Comments

Wednesday, December 14, 2011

Weight Change & Cognitive Function: Results from the Women’s Health Initiative

Dear Readers,

It is very rare in the course of a community talk on lifestyle factors and their relation to cognitive function, that I don’t discuss the “Big 3” - hypertension, diabetes and obesity. Some studies have suggested that dementia risk is greater in those who are obese. Other studies have suggested central adiposity may be protective against cognitive impairment and dementia in older women while others have suggested that lower weight may be associated with greater cognitive decline. In a recent article from Driscoll and colleagues, the authors attempted to characterize the relationship between changes in weight and waist circumference with cognitive function.

A total of 2238 women participating in the Women’s Health Initiative (WHI) were followed longitudinally, in a sub-study called WHISCA (Women’s Health Initiative Study of Cognitive Aging). The women enrolled in this study underwent detailed cognitive assessments, anthropometric measurements [weight, height, waist circumference, waist/hip ratio] and questionnaires regarding caloric intake using a Food Frequency Questionnaire. Other demographic characteristics that were assessed were level of education, cardiovascular risk factors [hypertension, smoking, history of stroke, heart disease, diabetes, alcohol intake] and depression. Cognitive tests measured global cognitive function, verbal and figural memory, attention and working memory, spatial ability and fine motor speed. Other variables assessed were race, education in yrs (range 0-30), and the history or presence of medical conditions (heart disease, TIA, stroke, hypertension, diabetes, and Parkinson’s disease).

At each WHI visit, staff obtained measurements of height and weight to calculate BMI, and also filled out a food questionnaire. Waist circumference was measured at baseline and year one. The investigators had measurements through the WHI follow and before entry in to WHISCA. Those who gained weight occurred more in younger women, those who were smokers at baseline, those who had lower wait/hip ratios and no hypertension. When the women were grouped according to weight gain, (>5% gain), weight lost (>5% loss) or remaining stable before enrollment, women with prior weight loss had a slightly lower cognitive score compared to women who had stable weight or those who had gained weight. When weight was grouped according to either any weight loss (<10% or >10%) or weight gain (<10% or >10%), women with >10% weight loss performed significantly worse on cognitive tests, than both weight gain groups, and those with 10% weight loss performed significantly worse than women gaining <10%.

At the time of WHI enrollment, 10.6% of women reported that they were currently following a low calorie diet. A low calorie diet was associated with lower cognitive test scores for attention and working memory (p<0.001) and higher scores on fine motor speed. Self report food intake measured by the food frequency questionnaire, revealed that higher caloric intake was associated with better cognitive performance.

This study examined the association of weight gain/loss to cognitive function, in a large group of older women. The results suggest that there were no differences in cognitive performance between women who gained weight or whose weight remained stable over approximately 3.5 years. Worse cognitive performance was associated with weight loss, and this relationship was not modified by initial BMI. The findings from this study are provocative, as they add to the literature that suggests weight loss could potentially signal the beginning of cognitive decline and dementia, and that there is no specific evidence to suggest a relationship between obesity and cognitive decline. The major limitation of this study as suggested by the authors was that it was done in women only, thus not generalizable to a general population of men and women. Unfortunately, this study only included ~10% of minority women in the sample, and thus was not able to comment on any differential findings that may have been influenced by race/ethnicity. Additional longitudinal studies to confirm these associations are needed, and could shed light on potential mechanisms of how body weight is associated with cognitive function.

Here are 3 articles you can refer to, to learn about this study, and other studies examining the oldest old.

Driscoll I, Espeland MA, Wassertheil-Smoller S et al. Weight Change and Cognitive Function: Findings From the Women’s Health Initiative Study of Cognitive Aging. Obesity (2011)19, 1595-1600. Arch Neurol. 2011 68(5): 631-636.

Wolf P, Beiser A, Elias MF et al. Relation of obesity to cognitive function: improtance of central obesity and synergistic influence of concomitant hypertension. The Framingham Heart Study. Curr Alzheimer Res 2007; 4: 111-116.

Kerwin DR, Zhang Y, Kotchen JM et al. The cross sectional relationship between body mass index, waist hip ratio and cognitive performance in post menopausal women enrolled in the Women’s Health Initiative. J Am Geriatr Soc 2010: 58:1427-1432.

Thanks for reading.

Neelum T. Aggarwal, MD
Steering Committee Member, ADCS
Rush Alzheimer’s Disease Center
Rush Institute for Aging
Chicago, IL

Author: Neelum Aggarwal MD at 1:43 PM 0 Comments

Friday, December 09, 2011

Targeting Tau with a Vaccine


AD brains are characterized by the deposition of two hallmark proteins, the amyloid-ß protein and the microtubule-associated protein tau. Beta-amyloid is derived from the Amyloid precursor protein (APP) and is the major constituent of plaques, while abnormally phosphorylated (hyperphosphorylated) tau gives rise to neurofibrillary tangles. Beta-amyloid is closely associated with the onset of AD, but it is the tau pathology that correlates with its severity.

Frontotemporal dementia (FTD) describes a heterogeneous group of neurodegenerative disorders that are characterized by a broad spectrum of clinical symptoms including behavioral changes, language abnormalities and motor dysfunction. FTD is the second most common form of dementia before the age of 65. In FTD, tau pathology occurs in the absence of overt beta-amyloid deposition. In a subset of FTD, pathogenic mutations have been identified in the gene for tau.

Taken together, tau plays a central role in AD and FTD, making it an attractive drug target. I have discussed the relationship between beta-amyloid and tau in previous blogs.

This week, researchers at Sydney University’s Brain and Mind Research Institute have used active immunization against tau in aged mice that have been genetically engineered to have abnormal tau. (You will recall that active vaccination means injecting the abnormal protein into the bloodstream, to illicit and endogenous immune response, as opposed to passive immunization where pre-made antibodies against the abnormal protein are injected).

Three groups of mice were used in the study. Each group was formed according to age – 6 months, 12 months and 18 months. The older group was most similar to the more advanced stage of Alzheimer's disease. The mice were given three injections over 4 weeks and then evaluated 10 months later and assessed at the end of that period for the pathological hallmarks mentioned above.

This active vaccine treatment reduced both tau phosphorylation and neurofibrillary tangles, suggesting that therapeutic immunization against tau may prevent progression of disease, in FTD and perhaps AD as well.

Should this strategy prove to be effective, active vaccination will be a powerful tool in treating not only AD, but other neurodegenerative diseases including Frontotemporal dementia and Dementia with Lewy bodies and Parkinson’s disease, where vaccination would target alpha-synuclein, the main component of Lewy bodies.

Bi et al, Tau-Targeted Immunization Impedes Progression of Neurofibrillary Histopathology in Aged P301L Tau Transgenic Mice, PLoS One, December 8, 2011.

By Michael Rafii, MD, PhD
Director, Memory Disorders Clinic
Associate Medical Core Director
Alzheimer’s Disease Cooperative Study
University of California, San Diego
Author: Michael Rafii MD,PhD at 11:19 AM 0 Comments

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The Alzheimer's Disease Cooperative Study (ADCS) was formed in 1991 as a cooperative agreement between the National Institute on Aging (NIA) and the University of California, San Diego. The ADCS is a major initiative for Alzheimer's disease (AD) clinical studies in the Federal government, addressing treatments for both cognitive and behavioral symptoms. This is part of the NIA Division of Neuroscience's effort to facilitate the discovery, development and testing of new drugs for the treatment of AD and also is part of the Alzheimer's Disease Prevention Initiative.

The ADCS was developed in response to a perceived need to advance research in the development of drugs that might be useful for treating patients with Alzheimer's disease (AD), particularly drugs that might not be developed by industry.