A4 Study: Elevated Amyloid an early Sign of Alzheimer’s Disease

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investigators discover a rare genetic variant shown to protect people who carry known genetic risk factors for Alzheimer's disease

The Anti-Amyloid Treatment in Asymptomatic Alzheimer’s Disease (A4) prevention study was created in 2014 to test whether the monoclonal antibody drug solanezumab reduces cognitive decline if given to individuals with elevated amyloid levels before signs of the disease are apparent. In its first publication, the group’s findings support the idea that higher amounts of amyloid protein in the brain represent early stage Alzheimer’s Disease (AD). Their investigation also revealed that the amount of amyloid in clinically normal older adults is associated with a family history of AD, lower cognitive test scores, and declining scores for daily cognitive function. Their findings were published in JAMA Neurology.

“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 NIA Director, Richard J. Hodes, M.D. “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 is funded as a public private partnership including NIH.

The goal of this first A4 study was to investigate the association of elevated amyloid with demographic and lifestyle factors, apolipoprotein E (APOE), reports of neuropsychological testing, and self- and study partner reports of cognitive function.

Prescreening information was collected from April 2014-December 2017 from more than 15,000 individuals. Of these 6,768 individuals underwent additional screening at 67 sites in the US, Canada, Australia and Japan. Using amyloid positron emission tomography (PET) imaging, the team studied 4,486 participants who were eligible for amyloid PET because they were clinically normal with a clinical dementia rating of zero, and cognitively unimpaired.  From this group, the study team and identified 1,323 individuals with elevated amyloid levels who were eligible to continue in the A4 study.

These 1,323 study participants were slightly older than those without higher amyloid levels but had no differences  in sex, education, marital or retirement status, or any self-reported lifestyle factors.  They were more likely to have a family history of dementia and also had at least one APOE ε4 allele, a known AD risk factor.

The researchers hope this screening data may be useful for future clinical and prevention studies. The authors write, “These results support the hypothesis that elevated amyloid represents an early stage in the Alzheimer continuum and demonstrate the feasibility of enrolling these high-risk participants in secondary prevention trials aimed at slowing cognitive decline during the preclinical stages of AD.”

The A4 Study is a public-private partnership, funded by the NIA, Eli Lilly, and several philanthropic organizations. The trial is coordinated by the University of Southern California’s Alzheimer’s Therapeutic Research Institute, with study sites in across the country.

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