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Wednesday, January 14, 2015

Alzheimer’s Disease: 2014 Year in Review


Dear Readers,

It is hard to believe that this installment marks the fifth annual Year in Review for the ADCS blog. As I have done previously, I would like to review some of the highlights of what has happened in the AD research world in the past year and discuss some of the new directions that we will likely be heading towards in 2015.

But first, I would like to provide you with a backdrop of AD research in the past five years to present a context in which developments are occurring. Without question, the onward progression towards earlier identification of AD with non-invasive biomarkers has been the area in which the greatest strides have been made. Specifically, the ability to identify the presence of amyloid plaques and neurofibrillary tangles through the use of PET imaging has allowed numerous improvements to be realized in AD research. This includes earlier identification of disease decades before the onset of symptoms. In addition, it permits for making a more accurate diagnosis, which is of paramount importance in clinical drug development. Finally, the study of these imaging capabilities in individuals with genetic forms of AD that is familial (early-onset) and Down syndrome, provide the best opportunity for discovering new biomarkers of Alzheimer’s disease in its earliest stages.

Despite this advance, clinical drug development is only now benefitting from and incorporating these techniques into clinical trial designs in order to select appropriate study participants. In the past five years, we have witnessed the launch of clinical trials for prodromal Alzheimer’s disease where patients have mild cognitive impairment, and most recently preclinical Alzheimer’s disease, where patients are completely asymptomatic. This movement towards intervention early in the course of disease, combined with more accurate diagnosis will undoubtedly pave the way towards finding treatments that work.

Trials and Tribulations

At the end of 2014, we saw the halting of the Phase 3 trial of the investigational antibody gantenerumab in prodromal Alzheimer’s disease due to a lack of benefit compared to placebo. As readers of this blog will recall, antibodies against beta-amyloid are being tested as treatments for AD because they remove beta-amyloid from the brain. The trial, called SCarlet RoAD, was the first Phase 3 study that used the new guidelines for diagnosing prodromal AD using biomarkers. In mid 2014, the Phase 2 trials of crenezumab failed to meet primary endpoints of cognition and function. Much like solanezumab, this antibody showed some evidence of a cognitive benefit at the highest dose in the mildest patients. Both the gantenerumab and crenezumab trials were well designed and properly conducted. Clinical trials of BACE inhibitors, drugs that actually prevent production of beta-amyloid, as opposed to removing it as antibodies do, continue to move ahead in mild AD and prodromal AD clinical trials and hold great promise.

Brain Imaging

Just as important as the research world, in 2014, the FDA approved the third PET imaging tracer to allow for imaging amyloid plaques in the brain in the clinics. This means that florbetaben, florbetapir and flutemetamol are approved for the evaluation of amyloid plaques in patients. A negative scan essentially rules out AD. Researchers continue to actively gather data to show the meaning and usefulness of a positive amyloid scan in clinical practice. As readers of this blog will recall, the Centers for Medicare & Medicaid Services does not recommend reimbursement of amyloid PET scans in clinical settings. In the meantime, more data from large studies continue to add to the evidence that people with amyloid in their brains are much more likely to suffer cognitive decline in subsequent years and develop AD dementia.

Young Blood

In a study published in 2014 in the journal Nature Medicine, researchers at Stanford University School of Medicine looked at changes in the brains of old mice given the blood of young mice. They also compared how the old mice performed on standard tests of memory after they had received infusions of plasma – the cell-free part of blood – from young mice, versus no plasma at all. By transferring young plasma into an old mouse once every three days for three weeks, they found that old mice injected with plasma from young mice outperformed untreated old mice in two separate memory tests. Specifically, after a day of training, the mice treated with plasma from young mice averaged about 25 percent better than those of mice injected with aged plasma. Moreover, the treated mice also showed more neurogenesis (new brain cell production), synaptic density (brain cell communication) and less inflammation.

In a separate study published the same day in the prestigious journal Science, work from the Harvard Stem Cell Institute demonstrated that young blood reinvigorated blood vessels in the brains of old mice. In the treated old mice, the volume of blood vessels in the brain almost doubled. They formed new branches and allowed more blood to flow through them towards various brain regions. This, in turn, led to an increase in the number of stem cells in the brain. From the studies, it appears that young blood contains ‘pro-youthful’ factors that can reverse age related brain impairments while old blood may contain ‘pro-aging’ factors that lead to age-related brain impairment. Researchers continue to look at these exciting studies as indication that unknown factors in blood may affect AD, raising the possibility that new treatment modalities may exist.

Funding

In 2014, the Accelerating Medicines Partnership, a group consisting of NIH and 10 industry partners, pledged nearly $130 million to study biomarkers in AD. At the same time, the U.S. Congress set aside an additional $80 million for the NIA, part of a total of about $500 million to be spent on AD research. Although these are fantastic developments, research funding for AD still pales in comparison with many other diseases such as cancer, which garners ten times as much, $5 Billion per year.

So, where are we headed in 2015?

The ongoing Anti-Amyloid in Asymptomatic Alzheimer’s disease (A4) clinical trial is actively enrolling participants in a landmark study aimed at preventing cognitive symptoms in AD. This project will also help answer questions about amyloid’s role in AD and when treatments should be administered. In 2015, much more work on blood–based tests for AD is anticipated, particularly confirmation of protein panels reported in 2013 and 2014 that may reflect brain amyloid status. Imaging of tau, the main component of neurofibrillary AD tangles, will also be a major target. Researchers will look at its usefulness in predicting cognitive decline, as will clinical trials of new compounds targeting tau specifically.

We look forward to keeping you updated on the world of Alzheimer’s research in the upcoming year and are optimistic that there will be great developments in 2015. Stay tuned.



Thanks for reading,


Michael Rafii, MD, PhD
Director, Memory Disorders Clinic
Medical Core Director
Alzheimer’s Disease Cooperative Study
University of California San Diego
 
Author: Michael Rafii MD,PhD at 2:29 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.