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‘A4’ Study Links Beta-Amyloid to Early Alzheimer’s

May 6, 2020

The first data from a new study that is looking at the brains of cognitively normal adults at increased risk of developing Alzheimer’s disease puts a new spotlight on beta-amyloid, a toxic protein that builds up in the brains of those with Alzheimer’s disease.

Researchers found that in healthy adults, elevated levels of beta-amyloid in the brain were associated with a variety of Alzheimer’s disease risk factors, including older age, a family history of Alzheimer’s disease, and the presence of the APOE-E4 gene allele. People with higher levels of beta-amyloid also tended to score lower on tests of memory and thinking skills and, in questionnaires, reported subtle changes in their cognitive skills.

The findings lend some support to the theory that beta-amyloid buildup plays a causative role in Alzheimer’s onset, and is not just a byproduct of brain damage from the disease process.

The study, called A4, for Anti-Amyloid in Asymptomatic Alzheimer’s Disease, was started in 2014 to test whether an experimental drug called solanezumab, given before symptoms appear, may be effective in slowing memory and thinking problems and preventing Alzheimer’s onset. The drug targets beta-amyloid, a hallmark of Alzheimer’s. 

Many drugs that target beta-amyloid have been tested in previous studies, with little success. But scientists think that these drug treatments may have been started too late in the disease process, after damage to the brain has become too extensive to be reversed. The A4 study, being conducted at 67 medical centers in the United States, Canada, Australia and Japan, is starting giving the drug before any symptoms appear, but as beta-amyloid is beginning to build up.

Scientists hope that future treatments for Alzheimer’s may be most effective if given early in the course of disease, before buildup of beta-amyloid and damage to the brain becomes extensive.

Currently available drugs for Alzheimer’s can ease symptoms for a time but do not stem the inexorable decline of the disease. Unlike those drugs, solanezumab is designed to halt disease progression and preserve thinking and memory skills. The trial is scheduled to be completed in 2022.

“A major issue for amyloid-targeting Alzheimer’s disease clinical trials, and one that is being addressed with the A4 study, is that previous trials may have been intervening too late in the disease process to be effective,” said Dr. Richard J. Hodes, director of the NIA. “A4 is pioneering in the field because it targets amyloid accumulation in older adults at risk for developing dementia before the onset of symptoms.” The findings were published in JAMA Neurology.

Researchers working on the A4 study began by pre-screening more than 15,000 cognitively normal men and women who were interested in joining the trial. Many were eliminated because of various health problems. They eventually identified 1,323 who showed elevated levels of beta-amyloid on PET scans, a specialized type of brain scan.

In addition to the A4 study, the National Institute on Aging is helping to fund about 230 clinical trials of various drugs and other interventions to treat Alzheimer’s disease. More than 100 are focused on non-pharmacological interventions like diet, exercise and cognitive training. In addition to drugs that target beta-amyloid, other studies are looking at drugs that protect nerves, quell inflammation, or target tau, another protein that builds up in the brains of those with Alzheimer’s disease.

Research foundations, including the Fisher Center for Alzheimer’s Research Foundation, continue to fund research into the underlying causes of Alzheimer’s disease. Better understanding of the causes of Alzheimer’s will lead to better treatments, and one day a cure.

By ALZinfo.org, The Alzheimer’s Information Site. Reviewed by Marc Flajolet, Ph.D., Fisher Center for Alzheimer’s Research Foundation at The Rockefeller University.

Source: Sperling RA et al. Association of Factors With Elevated Amyloid Burden in Clinically Normal Older Individuals in the A4 Study Screening Cohort. JAMA Neurology. April 6, 2020

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