| Introduction |
Focus on prevention
The year 2007 entered the history books as a period of tremendous advances in Alzheimer research. These advances occurred on all fronts, encompassing areas as diverse as genetic risk factors for Alzheimer's, imaging studies to identify Alzheimer's in the living brain and blood tests that may one day be used to diagnose Alzheimer's.
As the largest private, nonprofit funding organization for Alzheimer research, the Alzheimer's Association played a key and highly visible role in nurturing research. This role included not only providing more than $21 million in funding for research grants, but also launching the Clinical Studies Initiative to explore ways to improve recruitment and retention of clinical study participants. In addition, the Association brought together researchers from around the world at the International Conference on Prevention of Dementia and convened two Research Roundtable meetings to spur collaborations in the field.
These research efforts paint only part of the picture of the Association's accomplishments in 2007. Many of the Association's other accomplishments, such as the introduction of the Champions Campaign and publication of the inaugural issue of Alzheimer's Disease Facts and Figures, feed into the Association's broader research efforts by increasing awareness of both the impact of the disease and the urgent need for escalated national funding to combat it.
Clinical studies are the basis for advancement of knowledge in all areas of medicine, but these studies are sometimes hampered by difficulty in recruiting individuals to participate. To better understand the issues at play when clinical study participation is being considered, the Alzheimer's Association in April 2007 launched the Clinical Studies Initiative.
While the scientific community recognizes the pivotal role that research participants play in advancing knowledge, the Alzheimer's Association's commitment extends beyond promoting that role to supporting the myriad needs of individuals with Alzheimer's. Beginning July 28, 2007, the Association hosted the first of four town hall meetings across the country to give people living with the early stages of the disease the opportunity to discuss issues they face and share helpful resources, programs and services. Part of the Association's Early Stage Initiative, these town hall meetings gave the Association and wider public the opportunity to learn from those who are still able to advocate for themselves. A "virtual" town hall meeting Web site was developed to ensure the widest possible access to the valuable perspectives shared.
The Alzheimer's Association took its commitment to individuals with Alzheimer's even further in 2007 when it asked the U.S. Food and Drug Administration (FDA) to give those directly affected by Alzheimer's a more active role in the review and approval of new drugs. In November the FDA expanded its Patient Consultant and Patient Representative Programs to include individuals in the early stages of Alzheimer's disease and their caregivers. "People who are living with this terrible disease have much to offer to the pharmaceutical industry, researchers and government regulators, and their voices must be heard," said Harry Johns, Alzheimer's Association president and CEO.
More than 1,000 scientists, physicians and policymakers gathered in Washington, D.C., June 9–12, 2007, at the second Alzheimer's Association International Conference on Prevention of Dementia. The 250-plus presentations addressed topics including emerging diagnostic strategies, drug discovery, risk factors and experimental therapies in clinical trials. During the conference the Centers for Disease Control and Prevention (CDC) and the Alzheimer's Association released the first National Public Health Road Map to Maintaining Cognitive Health.
The Road Map highlights the importance of maintaining and improving cognitive health to the overall health of the nation. CDC Director Julie L. Gerberding, M.D., M.P.H., told the gathering, "By embracing cognitive health as a priority issue, legislators and the public health community would be mobilized to study, identify and implement effective interventions that preserve it. Our challenge is to offer a coordinated and unified national effort. The Road Map meets that challenge by laying out a shared vision that builds on the foundation of the work done to date and shapes the work of the future."
The Road Map, available at http://www.cdc.gov/, provides strategies for assessing public perceptions about cognitive health, recommends particular actions to be taken to support cognitive health and calls for additional research to better understand the risk factors for cognitive decline and to design interventions to prevent it.
In the meantime, updates on research under way were much anticipated highlights of the conference. Many of the updates focused on anti-amyloid therapies. These are therapies that either reduce the production of the protein beta-amyloid that forms the hallmark plaques of Alzheimer's or that increase the clearance of beta-amyloid from the brain.
The makers of Alzhemed (Neurochem) announced that the U.S. clinical trial of the drug had been halted due to high data variations among trial sites that had invalidated the statistical model for evaluating the drug, which was designed to block aggregation of beta-amyloid into plaques. The clinical trial had been carried out at 67 sites and involved 1,052 individuals with Alzheimer's. Neurochem hoped to develop a new statistical model to lessen the impact of site variations, but in late August revealed that the FDA had deemed trial results inconclusive. The European trial, however, was continued until November, when it too was halted.
Myriad, the makers of Flurizan, reported results of a 12-month follow-on study to a Phase II trial. Flurizan reduces beta-amyloid by changing the activity of an enzyme involved in its production. After 24 months of treatment, people in the mildest stages of Alzheimer's who received the highest drug dose showed significant stabilization or improvement in cognition and function. Phase III studies were begun.
A Phase III study was also planned for LY450139, made by Lilly. Results of Phase II studies showed that the gamma-secretase inhibitor decreased beta-amyloid levels in both blood and spinal fluid.
Conference attendees also heard an update on AAB-001 (Bapineuzumab), made by Elan and Wyeth. Development of the drug was informed by preceding trials of the companies' drug AN-1792, the first anti-amyloid drug to reach clinical trials. A Phase II trial of AN-1792, delivered as a vaccine, was stopped in 2002 when 6 percent of study participants experienced brain inflammation. Researchers continued to collect data on participants and found that those who developed the highest levels of anti-amyloid antibodies appeared to have benefited from the vaccine. While AN-1792 was an "active vaccine" designed to stimulate production of beta-amyloid antibodies in participants, Bapineuzumab is a "passive vaccine" that delivers antibodies against beta-amyloid. The drug is expected to move into Phase III trials in 2008.
In addition to the research news presented at the International Conference on Prevention of Dementia, 2007 yielded advances that underscore the vast number of approaches taken by investigators to better understand Alzheimer's.
In the January 14, 2007, online Nature Genetics, researchers described results of a study implicating the gene SORL1 in late-onset Alzheimer's disease. The gene, also known as SORLA (sortilin-related, low-density lipoprotein receptor class A repeat-containing protein), is one of several involved in a cellular sorting process that sends amyloid precursor protein (APP) down one of two paths: a path in which it is recycled or a path that moves it to cell structures called endosomes where the enzymes beta- and gamma-secretase cut it apart, freeing the beta-amyloid peptide component of APP to leave the brain cell, combine with additional beta-amyloid and potentially form the amyloid plaques of Alzheimer's.
When researchers investigated the genes involved in APP sorting, only SORL1 was associated with an increased risk of Alzheimer's. The association between SORL1 and Alzheimer's was statistically significant in six of nine cohorts. The study results were based on genetic information from more than 6,800 individuals, 48 percent of whom had Alzheimer's. Researchers used single-letter changes in gene sequence (called SNPs for single nucleotide polymorphisms) to track SORL1 genes and found that Caucasians with Alzheimer's had one SNP, while African-Americans, Hispanics and Israeli Arabs with Alzheimer's had a different one. Their next step is to examine the areas around the SNPs to try to identify specific genetic variations that might lead to Alzheimer's.
An established technology for identifying Alzheimer's in the living brain will be an invaluable tool for early diagnosis of the disease and monitoring the effects of drugs designed to stop or slow its progression. Study results published in the March 2007 issue of Archives of Neurology demonstrated that significant strides are being made toward that goal. The article describes the first postmortem study of an individual with dementia who, before death, had undergone positron emission tomography (PET) after injection of Pittsburgh compound B (PIB), a radioactive dye. Because Alzheimer's can now only be definitively diagnosed on autopsy, a postmortem comparison of amyloid distribution was necessary to confirm the accuracy of PET-PIB. The study showed that the distribution of amyloid at autopsy matched the overall distribution on PET-PIB. If the accuracy of PET-PIB is replicated in additional, large studies, it could enable a definitive diagnosis of Alzheimer's in the living brain.
The impact of an even simpler test for Alzheimer's, such as a blood test, would be enormous. Researchers reported taking a step in that direction in an article appearing October 15, 2007, in the online Nature Medicine. They studied 120 proteins involved in cell-to-cell communication, looking for patterns that differed between people with and without Alzheimer's. They found that as few as 18 proteins were needed to identify an Alzheimer's-specific pattern. Among the 92 study volunteers, the protein pattern identified with 90 percent accuracy those who had clinically diagnosed Alzheimer's. In 47 volunteers with mild cognitive impairment, the pattern accurately identified 91 percent of volunteers who would go on to develop Alzheimer's during the follow-up period.
This is only one of several tests of this type in development. Further research is needed to determine their accuracy in large, diverse patient populations. But with every study, whether it revolves around genetics, imaging, blood tests or an array of other approaches, the scientific community takes a step closer to uncovering the causes of and potential treatments for Alzheimer's.
In the face of decreased federal funding for Alzheimer research, the Alzheimer's Association stepped up its efforts to provide financial support to investigators through its 2007 grants program. The Association awarded more than $21 million for 109 research projects from a competitive field of 639 applications from 42 states and 27 countries. Since the grants program began in 1982, it has provided more than $220 million for Alzheimer research. The grants program offers several types of awards, including the Zenith Award, which in 2007 provided an additional $200,000 per grant awarded, an increase from $250,000 to $450,000.
In July 2007 evidence of the Association's commitment to funding research grew when the Association, Cure Alzheimer's Fund and Lou Ruvo Brain Institute announced that they had joined forces to establish the Tomorrow's Leaders in Alzheimer's Disease Research Awards. The annual award program provides $100,000 to each of three outstanding new M.D. or Ph.D. investigators who have made pivotal contributions to basic understanding, early detection, treatment or prevention of Alzheimer's. The first awards will be given in 2008.
To speed research advances, the Association hosted two Research Roundtable meetings in Washington, D.C. The Roundtable facilitates collaborations between researchers in academia and industry. The May 30–31 meeting convened more than 90 members and invited guests to explore the academic-industry interface for Alzheimer's drug discovery, while the November 12–14 meeting focused on the latest diagnostic tools for early-risk assessment. This unique forum for the sharing of information continues to grow in popularity, with industry membership expanding in 2007.