Summary: New analysis finds elevated amyloid plaque is not merely a risk factor but an early stage of Alzheimer’s disease, detectable years before symptoms appear.
Clusters of a sticky protein — amyloid plaque — in the brain predict cognitive decline years before clinical symptoms emerge, according to a new USC-led study.
Researchers at the Keck School of Medicine of USC analyzed a decade of data and found that older adults who are cognitively normal but have elevated brain amyloid experience faster declines in cognition consistent with early Alzheimer’s disease. While amyloid plaques have long been viewed as a risk marker, this study frames elevated amyloid as an early, preclinical stage of the disease.
“To have the greatest impact on the disease, we need to intervene against amyloid, the basic molecular cause, as early as possible,” said Paul Aisen, senior author of the study and director of the USC Alzheimer’s Therapeutic Research Institute (ATRI). “This study is a significant step toward the idea that elevated amyloid levels are an early stage of Alzheimer’s, an appropriate stage for anti-amyloid therapy.”
The preclinical period—when amyloid is elevated but symptoms are not yet apparent—can be longer than the symptomatic dementia stage. Michael Donohue, lead author and associate professor of neurology at USC ATRI, emphasized that demonstrating the disease begins before symptoms is essential for justifying and designing early intervention trials.
Researchers compared this preclinical amyloid state to high cholesterol: a largely silent warning that precedes catastrophic events, but one that can be treated early to prevent irreversible damage. The goal is to remove or reduce amyloid during this asymptomatic window to slow or halt progression to clinical Alzheimer’s.
The amyloid problem
The study notes that approximately one in three people over age 65 have elevated brain amyloid. Based on the observed progression rates, most people with elevated amyloid are likely to develop symptomatic Alzheimer’s within ten years. If prevalence estimates included this preclinical stage, the number of Americans affected by Alzheimer’s-related brain changes would more than double from the commonly cited 5.4 million.
Published in the Journal of the American Medical Association, the analysis used longitudinal data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI), with USC ATRI serving as the coordinating center. USC is also heavily involved in clinical trials targeting early, preclinical stages of sporadic Alzheimer’s, including trials focused specifically on anti-amyloid therapies.
“We need more studies looking at people before they have Alzheimer’s symptoms,” Aisen said. “Many drug trials have failed because they intervened too late. The time to intervene is when the brain is still functioning well—when people are asymptomatic.”
Although the study found a clear association between elevated amyloid and later cognitive decline, it did not establish direct causation. Age remains the strongest known risk factor: most Alzheimer’s cases appear after age 60.
The tipping point
The research team followed 445 cognitively normal participants in the United States and Canada, measuring brain amyloid by cerebrospinal fluid assays or positron emission tomography (PET). Of these participants, 243 had normal amyloid levels and 202 had elevated amyloid. The average age was 74, and participants completed standardized cognitive assessments over an observation window that spanned up to 10 years (median follow-up was about 3.1 years).
By year four, 32 percent of those with elevated amyloid had developed cognitive changes consistent with early Alzheimer’s, compared with 15 percent of those with normal amyloid. In a smaller subgroup analyzed at year ten, projections indicated 88 percent of people with elevated amyloid would show significant cognitive decline, versus 29 percent of the normal-amyloid group.
Those in the elevated-amyloid group were, on average, older, had fewer years of education, and a higher proportion carried at least one copy of the ApoE4 gene, a known genetic risk factor for Alzheimer’s.
Alzheimer’s disease research and early detection
USC researchers have also developed sensitive cognitive measures to detect early decline. The Preclinical Alzheimer Cognitive Composite (PACC) combines several standardized tests to capture subtle cognitive changes before dementia becomes apparent. These outcome measures are increasingly used in trials aimed at early intervention and drug development for Alzheimer’s disease.
ATRI and USC are working to establish a regulatory and scientific framework to support early-intervention trials, which are essential for testing anti-amyloid strategies when they are most likely to be effective.
Study contributors and funding
Key contributors to the study include Reisa Sperling, Ronald Petersen, Chung-Kai Sun, and Michael Weiner, among others. Funding sources reported include Biomarkers Across Neurodegenerative Disease, the Alzheimer’s Association, the Michael J. Fox Foundation, the Weston Brain Institute, ADNI, and the National Institutes of Health.
Abstract (condensed)
This longitudinal analysis of 445 cognitively normal adults from ADNI evaluated whether baseline elevation of brain amyloid—measured by PET or cerebrospinal fluid—predicts later Alzheimer-related cognitive decline. Over a median 3.1-year follow-up, elevated baseline amyloid was associated with greater risk of decline on composite cognitive measures (including the PACC), MMSE, and Clinical Dementia Rating scores. While the findings suggest elevated amyloid marks a higher likelihood of future cognitive impairment, the clinical significance and longer-term outcomes require further study.
Study title: Association Between Elevated Brain Amyloid and Subsequent Cognitive Decline Among Cognitively Normal Persons. Published online June 13, 2017.