Skip Navigation LinksHome > ADCS > Alzheimer's Insights: an ADCS Blog  
 
    

Alzheimer's Insights:
an ADCS Blog


  Recent Post

Thursday, September 30, 2010

The Changing View of the Role Tau Plays in AD Pathology


As we move forward in our understanding of the underlying mechanisms of Alzheimer's disease, insights are constantly emerging from many different fronts. The disease is quite complex, and facts discerned by each new discovery must be assembled into an ever evolving theory. Sometimes, results that initially seem to be at odds with previous findings, turn out to be integral to a clearer understanding of the disease.

In the field of AD research, there have been two competing hypotheses regarding the molecular basis of the pathology behind the disease: that of abnormal beta-amyloid metabolism in the brain versus abnromal tau protein processing. It is now believed by many that tau is affected downstream from an initial abnormality in beta-amyloid.

This week, research conducted at Washington University and published in the journal PLoS Genetics, indicated a strong link between a specific genetic variant, a higher level of tau protein, and more rapid disease progression. These findings support the idea that tau proteins are a key driver of Alzheimer's pathology and imply that treatments targeting tau might delay disease progression. Not only has tau been shown to act downstream of Aß, several experiments have shown that cognition in mouse models can be improved by intervening at the level of tau.

This research may lead to new treatment targets with agents that regulate tau production; it may lead to diagnostic approaches to identify patients at risk of rapid progression; and it may lead to a more generally robust understanding of the entire pathological process of AD.

Cruchaga C, Kauwe JS, Mayo K, Spiegel N, Bertelsen S, Nowotny P, Shah AR, Abraham R, Hollingworth P, Harold D, Owen MM, Williams J, Lovestone S, Peskind ER, Li G, Leverenz JB, Galasko D, Alzheimer’s Disease Neuroimaging Initiative, Morris JC, Fagan AM, Holtzman DM, Goate AM. SNPs associated with cerebrospinal fluid phospho-tau levels influence rate of decline in Alzheimer’s disease. PLoS Genetics. 2010 Sep 16;6(9).

Michael S. Rafii, MD, PhD
Associate Medical Director, Alzheimer's Disease Cooperative Study
 
Author: Michael Rafii MD, PhD at 12:06 PM 0 Comments

Wednesday, September 22, 2010

Regional Differences in Brain Energy Metabolism Linked to Beta-Amyloid Deposition


Dear Readers,

Recent work from research groups led by Marcus Raichle and Mark Mintun at Washington University in St. Louis, Missouri, provides an explanation for why some areas of the brain are more vulnerable to beta-amyloid deposition. Using PET scans that measure glucose, as well as PET scans that measure beta-amyloid, they found that the same regions that accumulate beta-amyloid in AD brains are distinguished in healthy young adults by their distinctive energy metabolism. Instead of metabolizing glucose to its end products—carbon dioxide and water—these regions make extensive use of glycolysis. This is an alternative glucose metabolic pathway that produces less energy, but does so faster. The results suggest a link between patterns of energy use in the brain and later regional brain vulnerability to Alzheimer's disease. Their key finding is that beta-amyloid deposition significantly correlated with the regions of glycolysis in young brains.

The researchers found that glycolysis occurred predominantly in regions of the brain collectively known as the default mode network (DMN). The default mode network is active in resting, but reduces its activity during goal-directed tasks. The DMN is critical in multiple cognitive processes, particularly in memory encoding and retrieval. Intriguingly, DMN regions are some of the first to accumulate plaque in AD brains. People who carry the ApoE4 risk allele for Alzheimer’s show distinct patterns of brain activity in this network, again suggesting a relationship between metabolism in this area and susceptibility to AD.

The next step will be to use animal models to see if manipulating glucose metabolism affects beta-amyloid accumulation. If so, that would imply a causal link between glycolosis and beta-amyloid deposition.

Vlassenko AG, Vaishnavi SN, Couture L, Sacco D, Shannon BJ, Mach RH, Morris JC, Raichle ME, Mintun MA. Spatial correlation between brain aerobic glycolysis and amyloid beta deposition. Proc Natl Acad Sci USA. 2010 Sep 13.


Michael S. Rafii, MD, PhD
Director, Memory Disorders Clinic
Assistant Professor of Neurosciences
Associate Medical Director, Alzheimer's Disease Cooperative Study
Attending Neurologist, Shiley-Marcos Alzheimer's Disease Research Center
University of California, San Diego
 
Author: Michael Rafii MD, PhD at 10:20 AM 0 Comments

Wednesday, September 15, 2010

Brain Atrophy and B Vitamins


Brain atrophy involves the loss of neurons. Some degree of atrophy and subsequent brain shrinkage is common with old age, even in people who are cognitively healthy. However, this atrophy is accelerated in people with mild cognitive impairment and even faster in those who ultimately progress from mild cognitive impairment to Alzheimer’s disease.

Many factors have been implicated in affecting the rate of brain atrophy, one of which is high levels of an amino acid in the blood called homocysteine. Studies have shown that raised levels of homocysteine increase the risk of Alzheimer’s disease. In a recent randomised controlled trial, researchers investigated the role of vitamin B in regulating levels of homocysteine. They specifically wanted to test whether lowering homocysteine through giving high doses of vitamin B for two years could reduce the rate of brain atrophy in people with pre-existing mild cognitive impairment.

Volunteers aged 70 and over with concerns about their memory were recruited for this study. It was specified that volunteers should have a diagnosis of mild cognitive impairment (MCI), defined using specific criteria. These included a concern about memory that did not interfere with activities of daily living and pre-specified scores on some cognitive scales assessing word recall and fluency.

The study excluded people with a diagnosis of dementia, who were taking anti-dementia drugs or who had active cancer. People taking folic acid and vitamin B6 or B12 above certain doses were also excluded.

Every six months, the volunteers were randomly assigned to receive either high-dose oral vitamin B tablets (0.8 mg folic acid, 0.5 mg vitamin B12 and 20 mg vitamin B6) or placebo pills during the two-year period. The participants, their partners and all staff directly involved in the study were unaware which pills participants were taking. The double blind nature of the study was important as it eliminated potential biases associated with the patients’ or researchers’ knowledge of which treatment was being received.

MRI scans were performed at the start of the study and again after two years. The researchers used these scans to calculate the rate of brain atrophy each year. A total of 271 people were randomly assigned a treatment, although five did not start the study. A similar proportion from each treatment group dropped out along the course of the study. The researchers measured adherence to the study treatments by counting returned tablets. For the main analysis of brain shrinkage, the researchers used data on 168 people (85 receiving active treatment and 83 receiving placebo) who had completed an MRI at both the start and at follow-up. The analyses took into account a variety of factors that may be linked to brain atrophy or use of vitamin B, which the researchers had tested and found to be important. These factors were age, blood pressure, initial brain volume and concentration of homocysteine at the start of the study.

Treatment with vitamin B tablets had notable effects on the levels of homocysteine in the blood, reducing it by 22.5%. Levels of homocysteine increased by 7.7% in the placebo group. Overall, treatment with B vitamins for a period of 24 months led to a reduction in the rate of brain atrophy. After the age of the participants was taken into account, the rate of shrinkage in people receiving the vitamins was 30% less than in the placebo group (0.76% shrinkage and 1.08% shrinkage respectively). The effect was greater in people who were more compliant with taking their medication and in those who started with the highest levels of homocysteine. The researchers also found that, overall, the safety of vitamins was good with no adverse events.

The researchers concluded that they have shown that a “simple and safe treatment” can slow down the accelerated rate of brain atrophy in people with mild cognitive impairment. This is an important but early study in establishing the effects of vitamin B on the stages of brain atrophy that precede Alzheimer’s disease. It assessed the effects of the vitamin on the rate of brain shrinkage, a process that has been linked to old age, mild cognitive impairment and Alzheimer’s disease in other studies. Although other studies have found that the rate of brain atrophy is linked to cognitive decline, this particular study did not assess whether the participants’ brain changes translated into changes of cognitive ability or memory.

This was a well-conducted, albeit small, study. It was a randomized controlled trial, which is the most appropriate way to assess the effects of a new treatment. No study is perfect, though, and the researchers highlighted some shortcomings:

• The treatment was a combination of three B vitamins, so the researchers could not determine whether these have different effects individually.

• The study was not set up to assess the effects of treatment on cognition, but only on the rate of change in brain measurements.

This study will pave the way for future research into the use of vitamin B to prevent Alzheimer’s disease. Based on the evidence gathered so far, it is too early to claim that vitamin B can prevent clinical disease, but these results are promising. It is also interesting to note that this is a major study that exemplifies the use of potential biomarkers such as imaging, in therapeutic trials for MCI and AD.


A, Smith SM, de Jager CA et al. Homocysteine-Lowering by B Vitamins Slows the Rate of Accelerated Brain Atrophy in Mild Cognitive Impairment: A Randomized Controlled Trial. PLoS One 5(9): e12244

Michael S. Rafii, M.D., Ph.D.
Associate Medical Director, ADCS Medical Core
 
Author: Michael Rafii MD, PhD at 1:27 PM 0 Comments

Wednesday, September 08, 2010

A New target for Alzheimer's Disease and the Potential Role of Gleevec


Dear Readers,

As readers of this blog will recall, years of research have revealed that ß-amyloid is produced by the cleavage of a very large protein found throughout the body called amyloid precursor protein, or APP, by the enzyme gamma-secretase. An obvious ‘target’ for pharmaceutical intervention would be the development of gamma-secretase inhibitors: Blocking cleavage of APP by gamma-secretase to form amyloid-ß would prevent this abnormal accumulation in the brain, and prevent ß-amyloid from exerting its presumed toxic effects on the brain. However, there have been a recent series of failures in clinical trials involving gamma-secretase inhibition for mild to moderate AD.

The Nobel Prize winning neuroscientist Paul Greengard and his laboratory at The Rockefeller University published a paper in Nature last week describing the discovery of the “gamma-secretase activating protein” or GSAP *. The paper shows 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 Eli Lilly's phase III drug 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.

This finding points to a potential refinement of current thinking. It is clear that gamma-secretase has multiple roles, some of which are essential and others which lead to overproduction of ß-amyloid. Several clinical trials are now ongoing based on injection of monoclonal antibodies against amyloid-ß, the abnormal protein building up in the brain, with the hopes that the antibody/amyloid–ß complex will be cleared by normal immune mechanisms. Perhaps combination therapy, inhibition of GSAP to prevent new amyloid-ß formation along with an antibody approach to clear existing plaques, is the best hope of slowing progression of the disease.

* He, G., Luo, W., Li, P., et al. Gamma-secretase activating protein is a therapeutic target for Alzheimer’s disease. Nature. 467: 95-98. 2010.

Michael Rafii, M.D., Ph.D
Associate Medical Director, ADCS
 
Author: Michael Rafii MD, PhD at 3:18 PM 0 Comments

<< 1 >> 

Archive

Helpful Sites

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.