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Thursday, October 24, 2013

Getting Enough Zssss, Sleep and Alzheimer's Risk


Dear Readers,

This week, two separate reports about sleep illustrate its importance in brain health and the risk for Alzheimer’s disease (AD). The first paper is from Johns Hopkins University, where self-reported sleep duration was compared with beta-amyloid measured by PET scans. The researchers found that shorter sleep duration was associated with greater beta-amyloid deposition, as was poor sleep quality. The association between poor sleep and AD has been reported before, but there has been no study looking at the amyloid deposits in relation to sleep.
The data in this study showed that participants reporting more than seven hours of sleep have the least beta-amyloid burden, those reporting less than six hours have the most, and those reporting between six and seven hours have an intermediate level of burden.

The results are consistent with animal research that shows sleep deprivation leads to increased beta-amyloid production and deposition. The study’s main limitation is that because it is cross-sectional, and not longitudinal, it is not possible to tell whether sleep disturbance precedes beta-amyloid deposition, or occurs in conjunction or even as a result of it. Nonetheless, shorter sleep duration and poor sleep quality are associated with a greater beta-amyloid accumulating in the brain.

The second paper is from researchers at the University of Rochester, who asked the fundamental question, what is the biological purpose of sleep? Their work is quite elegant and technically challenging, so much so that it was published earlier this week in the prestigious journal, Science. Essentially, the work demonstrates that during sleep, the brain cleans itself and removes waste that accumulates during wakefulness. Remember that as brain cells work, they metabolize chemicals, neurotransmitters, glucose, and a variety of other biological substances as a byproduct. The paper involved careful measurements of these biochemical changes in the cerebrospinal fluid (CSF) of mice during wakefulness versus sleep.

Specifically, the researchers looked at the brain of sleeping mice using a two-photon microscope, which can image the movement of fluids, including dyes, through the brain. The researchers injected a green dye into the brain of sleeping mice through a catheter. After half an hour, the mice were awakened and injected with a red dye that the two-photon microscope could easily distinguish from the green. By tracking the movements of red and green dye throughout the brain, the researchers found that large amounts of CSF flowed into and out of the brain during sleep, but not during the awake state. Next, the team injected dye-labeled, beta-amyloid proteins into the brains of sleeping mice and awake mice and found that during sleep, CSF cleared away beta-amyloid twice as quickly. This was a very robust and reproducible finding.

So, what we have with these two studies, though conducted independently, is that they both seem to shed light on a possible mechanism by which the restorative properties of sleep may remove beta-amyloid, and explain association between less sleep and the risk of Alzheimer’s disease.


Thanks for reading.

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 1:34 PM 0 Comments

Friday, October 11, 2013

Data, Dogma and the Move to Early Intervention in AD Clinical Research


Dear Readers,

Although we think of science as a method to better understand the rules by which the natural world works, scientific research usually proceeds on an uncertain path, where we believe we are making progress towards deeper understanding of biological processes, but are not always fully certain. The challenge is to stick with our ideas while at the same time comparing and contrasting them with data obtained from experiments that aim to advance these very same theories.

As case in point, the amyloid hypothesis remains the prevalent idea about the cause of Alzheimer’s disease. Genetic, molecular, pathological and advanced imaging data all point to an abnormality in amyloid biology that leads to this disease. However, clinical trials aiming to reduce amyloid in the brain, and therefore affect the progression of AD, have essentially failed. So, what is one to do when the data, seemingly, do not fit the dogma? Is the amyloid hypothesis wrong?

If there were individuals with AD who had no abnormality in amyloid in the brain, then perhaps we could start to abandon this hypothesis. However, this is not the case. In fact, the presence of abnormal amyloid is a requirement for the diagnosis of AD.

In fact, over the past 20 years, mechanisms have been identified that explain how amyloid damages the brain. In looking at recent clinical trial failures that have been aiming to treat AD by targeting amyloid, one thing is found to be in common amongst them: they required subjects to have symptoms of dementia or at least some level of cognitive impairment that indicates abnormal amyloid in the brain consistent with Alzheimer’s disease.

The limiting effect of intervening at this stage of AD cannot be overstated. By analogy, imagine waiting until a cancer reaches stage IV, which implies metastasis, before initiating treatment. In a strange but fortunate way, many cancers cause symptoms that bring patients to medical attention and therefore treatment before they metastasize, though this is not always the case. And in those patients where cancer is caught early, there is a better chance for a favorable prognosis.

The data from the studies conducted thus far indicate that AD behaves much the same way, with one caveat. Patients come to medical attention when the disease has spread quite substantially throughout the brain, and has already caused significant brain injury. In essence, the treatments for AD need to be given earlier in the disease.

Researchers are keenly aware of this fact and there are now multiple clinical trials being organized that will aim to lower amyloid in patients who have virtually no symptoms of cognitive impairment, and certainly have no dementia, yet. These individuals will be evaluated with the most accurate tools available to identify those people who are developing amyloid in the brain, despite showing no outward symptoms. And, as part of the studies, they will be offered anti-amyloid treatments to hopefully prevent the progression to cognitive impairment and dementia.

In the next few months we will be hearing about such studies, including the ADCS A4 (Anti-amyloid in Asymptomatic AD) trial, the Alzheimer’s Prevention Initiative (API) APO4 trial and others.

Stay tuned.
Thanks for reading.

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 12:17 PM 0 Comments

Thursday, October 03, 2013

New AD Gene Reported


As readers of this blog will recall, three genes have shown to harbor mutations that lead to familial AD—APP, PSEN1, and PSEN2. All of them affect the amyloid pathway, such that more beta-amyloid is produced as the secreted APP protein is cleaved. Now, Rudy Tanzi and colleagues from Massachusetts General Hospital have added a fourth gene to this list. It is ADAM10, the gene for the main alpha-secretase that cleaves the amyloid precursor protein (APP). As the protein APP is secreted by neurons, it is cleaved by enzymes, or molecular scissors. Cleavage by one enzyme, called beta-secretase leads to the production of toxic beta-amyloid. Cleavage by alpha-scretase does not. Instead of generating the toxic beta-amyloid fragment, cleavage with alpha-secretase produces a protein fragment that has been reported to protect and stimulate the generation of neurons in brain.

Dr. Tanzi’s group previously identified two rare mutations in ADAM10 that lead to familial late-onset Alzheimer's disease in seven families. Now, in the recent paper published in the journal Neuron, they report evidence that these mutations cause APP to undergo more cleavage by beta-secretase, thereby increasing beta-amyloid production and leading to Alzheimer’s disease.

What does this all mean for developing AD therapies?

Perhaps by increasing ADAM10 activity, and consequently, alpha-secretase activity, we might help to reduce the beta-secretase cleavage of APP. That is, drugs that either block beta-secretase and/or drugs that activate alpha-secretase may represent a rational mechanism to reduce or even prevent beta-amyloid production. The biggest challenges in this type of drug development include the ability to target, in the brain, the alpha-secretase and beta-secretase enzymes in an exquisitely specific manner, without affecting other enzymes.

Beta-secretase inhibitors are currently in mid-stage clinical trials, and there is great optimism about this treatment strategy for Alzheimer’s disease.


Thanks for reading.


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 4:03 PM 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.