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First Published Data From A4 Study Supports Amyloid as Target for Alzheimer’s Prevention
April 6, 2020

The first published data from the Anti-Amyloid Treatment in Asymptomatic Alzheimer’s Disease (A4) study supports the hypothesis that higher levels of the amyloid protein in the brain represent an early stage of Alzheimer’s disease.

Results of an analysis of participant screening data for the study, published in JAMA Neurology, also show that amyloid burden in clinically normal older adults is associated with a family history of disease, lower cognitive test scores, and reports of declines in daily cognitive function.

With completion expected in late 2022, the A4 study is an ongoing prevention trial launched in 2014 to test whether solanezumab, a monoclonal antibody, could slow cognitive decline associated with elevated brain amyloid if started before clinical symptoms appear.

“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 Richard J. Hodes, MD, National Institute on Aging (NIA), part of the National Institutes of Health, Bethesda, Maryland. “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 A4 study team was looking for cognitively normal participants with high levels of amyloid. They started by pre-screening more than 15,000 people who expressed interest in the trial. Of those 15,000, the researchers brought in 6,763 clinical trial volunteers for cognitive testing, clinical assessments, and genotyping. After excluding 2,277 participants for cognitive and/or medical reasons, researchers used amyloid positron emission tomography (PET) imaging with 4,486 participants to measure amyloid accumulation in the brain. The PET imaging revealed 1,323 with elevated amyloid levels who were eligible to continue in the A4 study.

“In 2014, A4 was a first-of-its-kind study because it used amyloid PET to identify cognitively normal people with high levels of brain amyloid,” said Laurie Ryan, PhD, NIA. “Before the availability of amyloid PET, other amyloid-targeting clinical trials may have been testing therapies in some people who didn’t have amyloid.”

Lead author Reisa A. Sperling, MD, Brigham and Women’s Hospital, and Harvard Medical School, Boston, Massachusetts, noted that the screening data of all 4,486 participants who had PET imaging is now available to the research community. This new data will help improve efficiency of screening and enrolment of other trials designed to prevent Alzheimer’s in people without symptoms.

“A4 demonstrates that prevention trials can enrol high-risk individuals -- people with biomarkers for Alzheimer’s who are cognitively normal,” said Dr. Ryan. “Ultimately, precision medicine approaches will be essential.”

Reference: https://jamanetwork.com/journals/jama/fullarticle/10.1001/jamaneurol.202...

SOURCE: National Institutes of Health