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Monday, December 27, 2010

Alzheimer’s Disease: 2010 Year in Review

In this final blog of the year, we would like to review some of the highlights of what has happened in the AD world, and the new directions that we will likely be heading into in 2011.

This year Medivation’s Dimebon, which started life as a Russian antihistamine and showed some promise against Alzheimer’s, failed in its first late-stage clinical trial. Later in the year, Eli Lilly halted development of semagacestat after the compound actually worsened cognition in Alzheimer’s patients. Semagacestat targeted the enzyme gamma-secretase, and the media reported the finding as shaking confidence in the major hypothesis about what causes Alzheimer’s and how to treat it– the amyloid hypothesis. But the final word on the amyloid hypothesis will come from other anti-amyloid trial results in the next year, including BMS-708163, Bristol Myers Squibb’s potent gamma-secretase inhibitor being tested in ‘prodromal AD.’ At least two more drug companies are planning to launch such prodromal AD studies in 2011.

The Nobel Prize winning neuroscientist Paul Greengard and his laboratory at The Rockefeller University published a paper in Nature describing the discovery of the “gamma-secretase activating protein” or GSAP . The paper showed that GSAP interacts with both the enzyme gamma-secretase and amyloid precursor protein (APP). From their results, they hypothesize that this protein is specific for this cleavage, and will not affect any of the other essential activities of gamma-secretase. Indeed, they show that addition of excessive GSAP or lack of GSAP had no effect on the cleavage of notch (a protein whose cleavage may have negative health effects) by gamma-secretase, but addition of GSAP tremendously increased the cleavage of APP by gamma-secretase to form amyloid-ß.

Perhaps the most exciting finding of the paper is the discovery of the mechanism of action of imatinib, or Gleevec, an approved anti-cancer drug that previously had been observed to prevent amyloid-ß formation by an unknown mechanism. It turns out Gleevec blocks GSAP. Following the recent failure of Semagacestat that inhibited gamma secretase, and the ensuing round of questions that the failure spawned about the validity of the amyloid hypothesis, this is reassuring news. It gives clarity to some possible reasons why there have been such challenges with gamma-secretase inhibition. With the discovery of this new protein, it is suggested that we might be able to turn off the harmful activities of gamma-secretase while allowing its beneficial activities to continue.

Avid Radiopharmaceuticals tested florbetapir (formerly 18F AV-45)and demonstrated 100 percent accuracy in detecting brain amyloid. It is expected that Avid’s amyloid PET Scan technology (now owned by Eli Lilly), will be FDA approved this coming year.

A flurry of papers were published on Apolipoprotein E e4 (apoE4), the most important genetic risk factor for sporadic Alzheimer’s disease. As readers of this blog will recall, the apoE protein exists in three major forms (apoE2, E3, E4) and the risk for getting AD differs with each form, E4>E3>E2. ApoE4 binds directly to beta-amyloid and forms a complex. Work published this year showed that the binding of ApoE4 to beta-amyloid shifts the removal of beta-amyloid out of the brain from a rapid export pathway, to a very slow pathway, resulting in poor beta-amyloid clearance from brain, and hence, its accumulation. Furthermore, researchers showed that not only does ApoE4 lead to accumulation of beta-amyloid in the brain, but it also seems to be routing it to synapses where it leads to synapse dysfunction.

The Alzheimer’s Disease Neuroimaging Initiative(ADNI) continues to provide us with greater, and more detailed information about AD. Papers were published demonstrating even greater accuracy in predicting conversion from normal cognition to MCI, and MCI to AD by looking at a combination of biomarkers including hippocampal atrophy on MRI, as well as spinal fluid proteins such as beta-amyloid and tau.

For the first time in 25 years, there is a proposal to change the criteria for Alzheimer’s disease, part of a new movement to diagnose and, eventually, treat the disease earlier. The new guidelines include criteria for three stages of the disease: preclinical disease, mild cognitive impairment due to Alzheimer’s disease and, lastly, Alzheimer’s dementia. Under the new guidelines, for the first time, diagnoses will aim to identify the disease as it is developing by using results from the biomarkers mentioned above.

Beginning in January of 2011, Medicare will reimburse primary care physicians to perform "detection of cognitive impairment" evaluation at the Welcome to Medicare visit and subsequent annual visits.

Finally, more clinical trials are planned in 2011, including the ADCS Resveretrol study, and numerous industry studies targeting beta-amyloid. We are optimistic that there will be great developments in the field of AD in 2011. Stay Tuned.

Michael Rafii, MD, PhD
Associate Medical Director
Alzheimer's Disease Cooperative Study

Author: Michael Rafii MD,PhD at 1:07 PM 0 Comments

Wednesday, December 15, 2010

HDL and Alzheimer’s Disease

According to researchers at Columbia University, people with high levels of HDL cholesterol (the "good" form), are 60% less likely to develop AD. The researchers followed 1,130 seniors with no history of memory loss or dementia and measured their cholesterol levels every 18 months for four years. When the researchers compared the cholesterol levels of study participants with and without Alzheimer’s, they found that those with the highest HDL counts, over 55 mg/dL, had about a 60% reduced risk of developing the disease compared to those whose levels were under 39 mg/dL.

Their findings support the theory that high levels of HDL cholesterol are correlated with lower incidence of AD. The study was published earlier this week in the Archives of Neurology and sheds more light on the interactions between cholesterol and AD.

Apolipoprotein E (apoE), as readers of this blog will recall, participates in the mobilization and distribution of cholesterol among various tissues of the body, including the brain. In humans, there are three common isoforms of apoE: apoE2, apoE3, and apoE4. ApoE4 differs from apoE3, the most common isoform of apoE. A single e4 allele is sufficient to increase the risk of developing atherosclerosis, and also Alzheimer’s disease. The e4 allele results in slightly elevated plasma LDL cholesterol levels and a small but significant decrease in plasma HDL levels. HDL is one of the major carriers of protein in and out of the brain, and also binds to beta-amyloid.

This finding further advances the idea that the interplay between cholesterol, cholesterol-carrying proteins such as apoE and HDL, and beta-amyloid may be critical in the development of AD. This study has important strengths. It is a prospective cohort study designed for the diagnosis of cognitive decline that has complete clinical and neuropsychological evaluation at each interval.
Guidelines recommend that men raise HDL levels that are under 40 mg/dL and that women increase HDL numbers under 50 mg/dL. An HDL of 60 mg/dL or higher is optimal.

Michael Rafii, MD, PhD
Associate Medical Director
Alzheimer’s Disease Cooperative Study

* Association of Higher Levels of High-Density Lipoprotein Cholesterol in Elderly Individuals and Lower Risk of Late-Onset Alzheimer Disease. Christiane Reitz et al., Arch Neurol. 2010;67(12):1491-1497.

Author: Michael Rafii MD,PhD at 2:00 PM 0 Comments

Wednesday, December 08, 2010

Walking and the Risk of Cognitive Decline

Researchers from the University of Pittsburgh analyzed the relationship between walking and brain structure in 426 people: 299 cognitively healthy adults, 83 people with MCI, and 44 people with Alzheimer's dementia. The researchers monitored how far each of the patients walked in a week. After 10 years, all patients underwent 3-D MRI exams to identify changes in brain volume.

When they entered the study in 1989-1990, participants were asked how many city blocks they walked in an average week, whether for exercise, chores, or any other reason. Follow-up questionnaires every three years showed that the number of blocks walked remained steady over time. In addition, participants were given a brief test of cognitive skills at various times throughout the study, with the final one five years after the second MRI scan.

As shown by MRI, brain volume was preserved in healthy adults who walked at least 72 city blocks, or 6 miles, per week. Cognitive exam scores showed walking six miles a week was associated with a 50% decline in Alzheimer's risk over 13 years. Walking more than 72 blocks a week offered no additional benefit. Cognitively impaired people needed to walk at least 58 city blocks, or approximately 5 miles, per week to maintain brain volume and slow cognitive decline. Over 10 years, scores on the 30-point cognitive test dropped by an average of five points in cognitively impaired patients who were sedentary, compared with one point in those who walked 5 miles per week.

The relationship between walking and preserved brain volume persisted even after the analysis was adjusted to take into account other risk factors for dementia, including age, gender, and high blood pressure.
The findings showed across the board that greater amounts of physical activity were associated with greater brain volume.

Michael S. Rafii, MD, PhD
Associate Medical Director, Alzheimer's Disease Cooperative Study

*Raji CA, et al "Physical activity and brain structure in healthy aging and cognitive impairment" RSNA 2010.

Author: Michael Rafii MD,PhD at 3:26 PM 0 Comments

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About Us

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.