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Thursday, January 26, 2012

Exercise and Brain Amyloid Deposition

A sedentary lifestyle is associated with greater brain amyloid deposition among cognitively normal individuals with the E4 version of the apolipoprotein E (APOE) gene, according to a report published last week in the Archives of Neurology.

To examine the association between exercise and brain amyloid deposition among patients with and without the APOE4 allele, Denise Head, Ph.D., and colleagues from Washington University in St. Louis, tested for the APOE gene and administered a questionnaire on physical exercise engagement over the last decade to 201 cognitively normal adults (135 women) age 45 to 88 years. Samples of cerebrospinal fluid were collected from 165 participants and brain amyloid imaging was performed on 163 patients. Fifty-six of the volunteers, of various ages and both sexes, turned out to be positive for APOE4.

Patients who reported higher amounts of exercise had lower average levels of brain amyloid than did patients who reported lower amounts of exercise. Participants who were positive for the APOE4 gene had higher levels of brain amyloid compared with individuals negative for APOE4 gene.

The authors observed a novel interaction, such that a more sedentary lifestyle was associated with an even greater brain amyloid level in APOE4 carriers than for noncarriers. That is, those subjects with the APOE4 variant who rarely or never exercised had the most plaques, putting them at heightened risk for the memory loss of Alzheimer’s disease. Interestingly, the carriers of the APOE4 gene who reported walking or jogging for at least 30 minutes five times a week had plaque accumulation similar to that of subjects who were APOE4-negative. In essence, the APOE4 gene carriers mitigated their inherited risk for developing Alzheimer’s with frequent aerobic exercise.

From previous studies that I have written about in this blog, we know that APOE4 status is associated with an increased risk of cognitive decline and elevated amyloid deposition. In contrast, exercise engagement has been associated with reduced risk of cognitive decline and lower levels of amyloid deposition. This data suggests that exercise at levels recommended by the American Heart Association may be particularly beneficial in reducing the risk of brain amyloid deposition in cognitively normal APOE4-positive individuals. This study is yet another example of how genetics interact with environmental influences to affect risk of manifesting a particular disease. A randomized clinical trial of exercise in cognitively normal individuals will help answer this question more fully, and lead to an intervention that can potentially alter disease progression.

Head D, Bugg JM, Goate AM, Fagan AM, Mintun MA, Benzinger T, Holtzman DM, Morris JC. Exercise Engagement as a Moderator of the Effects of APOE Genotype on Amyloid Deposition. Arch Neurol. 2012 Jan 9.

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 10:05 AM 0 Comments

Tuesday, January 17, 2012

Recent Controversy Involving Resveratrol

Resveratrol was originally isolated from the roots of hellebore plant in 1940, but it attracted wider attention in 1992, when its presence was discovered in wine and was suggested as the explanation for the cardioprotective effects of wine, particularly red wine. Red wine contains more resveratrol than white wine because red wine is fermented with the skins, which contains resveratrol, whereas white wine is fermented after the skin has been removed.

Since the early 1990’s, resveratrol has been shown to have health benefits on multiple fronts, including cancer, inflammatory disease, cardiovascular, and even thought to affect longevity. Resveratrol is believed to be a strong antioxidant and, therefore, to contribute to the cardioprotective, anti-inflammatory, and neuroprotective properties of red wine intake.

Several epidemiological studies indicate that moderate consumption of red wine is associated with a lower incidence of dementia and Alzheimer's disease. The first study, published in 1997, reported that moderate to mild wine consumption was associated with a low risk of AD. Later, a study of individuals aged 65 years and older confirmed that intake of wine, but not other alcoholic drinks, was associated with a low risk of dementia, including AD. Furthermore, a prospective analysis of risk factors for AD in the Canadian population determined that wine consumption was the most protective variable against AD by reducing the risk of AD by 50%.

In the field of AD, recent work indicates that resveratrol reduces beta-amyloid accumulation in cell cultures. Resveratrol does not inhibit beta-amyloid production, since it has no effect on the beta-amyloid -producing enzymes beta- and gamma-secretases, but instead promotes the clearance of beta-amyloid from the brain.

Nearly 4,500 scientific articles have been published about functions and effects of Resveratrol in the body and various disease.

This past week, the media reported that a researcher who worked on the effects of resveratrol on cardiovascular health and longevity had fabricated data in many of his research projects. This scientific misconduct occurred only in the lab of this one researcher, who had a modest reputation in his field. The data do not appear to have any major impact at all on the larger body of scientific research involving resveratrol and related areas. Importantly, none of the research involved resveratrol in Alzheimer’s disease. The Alzheimer’s data comes from multiple, independent labs from around the world, and has been validated over the past 10 years. The data from the AD research has been so compelling, that a clinical trial has been funded by the NIH, after rigorous review. In addition, as with any and all clinical trials, the resveratrol in AD data has also been reviewed by the FDA.

Scientific integrity represents the core of the research enterprise, and it is unfortunate that this has occurred with regards to Resveratrol. The field will move on, continuing to strive towards finding a cure for this Alzheimer’s disease with the latest scientific advances.

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 2:04 PM 0 Comments

Thursday, January 12, 2012

Spinal Fluid Abnormalities Predict MCI Conversion to AD Almost 10 years in Advance

In the most recent issue of the Archives of General Psychiatry, Peder Buchhave, M.D., Ph.D, who is affiliated with Lund University and Skane University, Sweden, and colleagues report findings from a study of 137 patients with mild cognitive impairment (MCI) at baseline. The median follow-up was 9.2 years. During the follow-up, 72 patients (53.7 percent) developed AD and 21 (15.7 percent) progressed to other forms of dementia.

At the baseline, cerebrospinal fluid levels of beta-amyloid were reduced and two other biomarkers, total tau and phosphorylated tau protein levels were elevated in patients who converted to AD during follow-up compared with levels in patients who did not develop AD.

The study indicates baseline CSF beta-amyloid levels were equally reduced in patients with MCI who converted to AD within five years (the early converters) compared to those who converted later between five and 10 years. However, Total-tau and Phosphorylated-tau levels were significantly higher in early converters compared to later ones.

Readers of this blog will recall that there has been a lot of recent work focusing on the interplay between beta-amyloid and tau, specifically the dependency of beta-amyloid on phosphorylated tau protein to cause neurodegeneration. The work suggests that about 90 percent of patients with MCI who have these abnormal CSF biomarkers at baseline will develop AD within a period of about nine years.

Greater emphasis is being placed on early diagnosis, and certainly CSF analysis will continue to play an important part in this process.

P. Buchhave, L. Minthon, H. Zetterberg, A. K. Wallin, K. Blennow, O. Hansson. Cerebrospinal Fluid Levels of ß-Amyloid 1-42, but Not of Tau, Are Fully Changed Already 5 to 10 Years Before the Onset of Alzheimer Dementia. Archives of General Psychiatry, 2012; 69 (1): 98

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 3:38 PM 0 Comments

Tuesday, January 03, 2012

Alzheimer's 2011: A Year in Review

In this final blog I would like to review some of the highlights of what has happened in the AD world this past year, and the new directions that we will likely be heading towards in 2012.

This year we saw the publication of new diagnostic guidelines for AD formulated by committees sponsored by the National Institute on Aging and the Alzheimer’s Association. The NIA/AA also published guidelines for diagnosis of mild cognitive impairment due to Alzheimer’s disease, and for preclinical AD. These guidelines will be important tools for clinicians to diagnose AD in its earliest stages, and represent the first revision in 25 years.

An FDA advisory committee gave preliminary approval of the PET amyloid imaging ligand AV-45, citing work to be done to ensure consistency in reading PET scans. Full approval is expected sometime in 2012, if a uniform training program is implemented for radiologists interpreting the scans.

The European Medicines Agency announced the likely approval of hippocampal atrophy as a marker of early AD for the purpose of clinical trials. Much work has gone into linking hippocampal atrophy visualized by MRI, as an early and specific biomarker of neurodegeneration seen in AD.

IGAP—the International Genomics of Alzheimer’s Project, a transatlantic collaboration to create the most detailed map of genetic variants that link to AD was also launched in 2011. Meta analysis of genome-wide association studies (GWAS) revealed four new genetic risk variants for AD.

In terms of clinical trials, Gantenerumab, an antibody against beta-amyloid, was shown to clear plaques when given intravenously, according to results from a Phase 1 trial. The drug seems to be one of the most potent developed thus far in reducing plaques. A Phase 2 gene therapy trial for Parkinson’s disease was deemed a success. A similar Phase II gene therapy trial for AD, called the Nerve Growth Factor Study, is currently ongoing and recruiting. Multiple clinical trials, including the ADCS Phase III Resveratrol and Roche Phase II Gantenerumab trial are launching in 2012.

A very important paper by the Holtzman group at Washington University further established the relationship between ApoE4 genotype and decreased clearance of beta-amyloid from brain, both in humans and animal models. The idea that ApoE4 is less effective in removing beta-amyloid from the brain is not necessarily novel, per se, and had been previously shown. However, it had never been proven so convincingly and in such a complete manner in humans and animal models of AD. Together, the data suggest that ApoE variants contribute to a person’s risk for AD by affecting the clearance of beta-amyloid from the brain long before amyloid plaque deposition begins. Later in the year, the same group reported 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.

Results published in the Journal of the American Medical Association showed that women with sleep-disordered breathing (SDB)— pauses in breathing or reduced ventilation quality during sleep — are more likely to develop cognitive impairment five years later. The biology behind this finding may include hypoxia, or decreased oxygen delivery to certain parts of the brain, including the hippocampus which is critical in memory function. In addition, sleep fragmentation, which can interfere with memory consolidation, which occurs during certain stages of sleep, may also lead to cognitive problems. This study has really brought much needed attention to the evaluation of sleep as part of the work-up in individuals with Mild Cognitive Impairment.

We anticipate further progress in understanding the progression of the earliest stages of Mild Cognitive Impairment and AD with the Alzheimer’s Disease Neuroimaging Initiative (ADNI2), The Dominantly Inherited Alzheimers Network (DIAN) study and the Alzheimer’s Prevention Initiative (API) during 2012.

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 11:06 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.