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Wednesday, June 26, 2013

Dietary Saturated Fat’s Effect on ApoE May Increase Risk of AD

Dear Readers,

In a study published online this past Monday in the journal JAMA Neurology, researchers found that dietary saturated fat reduced the body's levels of apolipoprotein E, also called ApoE, which helps remove amyloid beta proteins out of the brain. Essentially, people who received a high-saturated-fat, high-sugar diet showed a change in their ApoE, such that the ApoE would be less able to help clear the amyloid. Readers of this blog will recall that ApoE4 status is associated with an increased risk of cognitive decline and elevated brain amyloid deposition. 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.

In a previously published diet intervention, the researchers showed that a diet high in saturated fat content and with a high glycemic index worsened CSF biomarkers of AD, lowered CSF insulin levels, and worsened some aspects of memory function, whereas a diet low in saturated fat content and with a low glycemic index had opposing effects.

In the current study, 20 seniors with normal cognition and 20 with mild cognitive impairment, a precursor to Alzheimer's disease, were studied. The patients were randomly assigned to diets that contained the same amount of calories but were either high or low in saturated fat. The high-saturated-fat diets had 45 percent of total energy coming from fat, and more than a quarter of the total fat came from saturated fats. In the low-saturated-fat diets 25 percent of energy came from fat, with saturated fat contributing less than seven percent to total fat.

After just one month, the diets caused changes in the amounts of amyloid beta and ApoE in the subjects spinal fluid such that there was more beta-amyloid present in those on the high saturated fat diet. This data is in line with previous studies showing a link between higher amyloid in the brain of patients with ApoE4 and that diets in high saturated fat seem to increase the risk of developing AD. With the results of this study, there is a possible elucidation of the mechanism at play, namely that saturated fats decrease ApoE’s ability to remove beta-amyloid from the brain, leading to its increasing levels in the brain (and spinal fluid that bathes the brain). Further studies on modulating beta-amyloid and ApoE with diet are pending.

Thanks for reading,

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 1:23 PM 0 Comments

Thursday, June 13, 2013

How Abeta-42 Contributes to Early Onset Alzheimer's

Dear Readers,

In a new study published in this week’s journal Science Translational Medicine, researchers from Washington University in St. Louis have shown that patients with genetic mutations that cause early-onset Alzheimer’s produce about 20 percent more of a specific form of beta-amyloid beta, called Abeta-42, than family members who do not have the Alzheimer’s mutation. This finding confirms previous findings observed in animal models of AD that show inherited forms of AD are due to an overproduction of beta-amyloid. As readers of this blog will recall, about 5% of all cases of AD are inherited, and due to mutations that affect the metabolism of the protein APP. All of these mutations lead to early-onset dementia, and are associated with the over-production of Abeta-42. The remaining 95% of AD, so called late-onset, is thought to be due to an under-excretion of Abeta-42 from the brain.

Researchers found another more surprising difference linked to Abeta- 42 in mutation carriers: signs that Abeta- 42 deposits into plaques much more quickly than other forms of beta-amyloid. Three forms account for most of the beta-amyloid found in the cerebrospinal fluid: Abeta 38, 40 and 42. The 38, 40 and 42 indicate the number of amino acids that make up each of these beta-amyloid protein species. It has been widely believed that Abeta- 42 is the most important contributor to Alzheimer’s disease. This study not only confirms this connection, but also quantifies the overproduction of Abeta -42 for the first time in AD subjects, and the increased amount of amyloid plaques at earlier ages.

Potter R, Patterson BW, Elbert DL, Ovod V, Kasten T, Sigurdson W, Mawuenyega K, Blazey T, Goate A, Chott R, Yarasheski KE, Holtzman DM, Morris JC, Benzinger TLS, Bateman RJ. Increased in vivo amyloid beta 42 production, exchange, and irreversible loss in presenilin mutation carriers. Science Translational Medicine, June 12, 2013.

Thanks for reading,

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 3:07 PM 0 Comments

Wednesday, June 05, 2013

Dementia Severity and Weight Loss

Dear Readers,

Multiple research studies, conducted in predominantly Caucasian populations, have discussed the association of weight loss to increased disability and mortality risk. These associations have been noted in persons with Alzheimer’s disease, with weight loss being associated with dementia severity. What has not been fully examined, and forms the basis for a recent paper by Albanese et al, is the association of dementia severity and weight loss in racial and ethnic diverse countries.

The surveys used in the 10/66 study were administered from January 2003 to July 2010 in urban and rural sites in Mexico, Peru, India and China and in urban sites in Cuba, Dominican Republic, Venezuela and Puerto Rico. Weight loss of clinical significance in older people was defined as >10 pounds (4.5 kg), and was obtained through self reporting by participants answering the questions of - “Have you lost more than 4.5 kg of body weight during the past 3 months?” Reported weight loss was confirmed by a second source in the case of cognitive impairment.

In addition to questions on weight loss, a Community Screening Instrument for Dementia (CSI-D), a modified version of the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD), a 10 word recall task and a Geriatric Mental State clinical interview was administered. Information regarding waist and arm circumference, dietary habits, physical activity and food insecurity (defined as a shortage of food that caused persistent hunger) were also obtained in addition to typical medical history data regarding stroke, diabetes, ischemic heart disease and hypertension.

In this paper, a total of over 16,000 persons were evaluated, and the prevalence of weight loss ranged from 2% in China to 26% in the Dominican Republic. Weight loss was lowest in those with a CDR of 0 and highest in those with a CDR of 2 or 3. Life circumstances and sociodemographics, lifestyle and health characteristics varied by country, but relatively little of this variation was associated with weight loss status.

Those with weight loss were older, more likely to be female and had a lower educational level, and were equally likely to live alone or with their spouse. Those who reported losing weight were less physically active and were more likely to have 3 or more physical impairments including severe GI disease, clinical diagnosis of stroke, diabetes and heart disease. Although country heterogeneity was low to moderate in fully adjusted models, increasing dementia severity was positively associated with reported weight loss in all countries.

This study is one of the few that was able to demonstrate that the association of weight loss with dementia and dementia severity was consistent across varied geographical areas and diverse cultures. The very large sample size and use of a dementia algorithm previously validated in over 20 countries, strengthens the validity of these findings.

The relevance of these findings not only suggests that prevention and treatment of weight loss in dementia patients’ may improve the health and cognitive status of patients across varied race/ethnic groups, but these findings may also have policy and economic ramifications. Low and middle income countries are expected to bear the brunt of the increased prevalence of dementia cases in the coming years. In these countries, where the prevalence of food scarcity and malnutrition are high, and health systems for dementia and financial services are scarce, it is conceivable that advocating for increased focus on caloric intake may slow down the progression of dementia or dementia severity in persons living in the community and/or those institutionalized. This in turn may lessen the financial and economic burden of the disease as it relates to costs of care or institutionalization.

Want to read more? Here are 3 articles that you should read to learn about this particular study or other research in this area.

Albanese E, Taylor C, Siervo M et al. Dementia severity and weight loss: A comparison across eight cohorts: The10/66 study. Alzheimer’s & Dementia (2013) 1-8

Ogunniyi A, Gao S, Unverzagt FW et al. Weight loss and incident dementia in elderly Yoruba Nigerians: a 10 year follow up study. Int Psychogeriatri 2011: 23:387-94

Stewart R, Masaki K, Xue QL et al. A 32 year prospective study of change in body weight and incident dementia: The Honolulu-Asia Aging Study. Arch Neurol 2005: 62: 55-60.

Thanks for reading.

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

Author: Neelum Aggarwal MD at 9:15 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.