Midlife Blood Amyloid Levels Tied to Late-Life Dementia

Midlife plasma amyloid beta (Aβ) levels in cognitively normal people were associated with risk of dementia or mild cognitive impairment (MCI) 25 years later, an analysis of a large community study showed.

Among 2,300 people, each standard deviation increase in plasma Aβ40 (67 pg/mL) at midlife was associated with 15% higher risk of late-life MCI or dementia (relative risk ratio [RRR] 1.15, 95% CI 1.01-1.29), reported Kevin Sullivan, PhD, MPH, of the University of Mississippi Medical Center in Jackson, and co-authors.

Every standard deviation increase in midlife plasma Aβ42 (10 pg/mL) was associated with 13% lower risk of later MCI or dementia (RRR 0.87, 95% CI 0.77-0.98), the researchers wrote in Neurology.

Doubling of the Aβ42/Aβ40 ratio at midlife up to the median level was associated with 37% lower risk of late-life MCI or dementia, (RRR 0.63, 95% CI 0.46-0.87), they added.

“A doubling of this ratio under this threshold at midlife was associated with a 37% lower risk of MCI or dementia, which is comparable to about 5 years of younger age, and a doubling of this ratio under this threshold at late-life was comparable to about 3 years younger age,” Sullivan said.

The results are promising, but “we are likely still a little ways off from these blood tests having any routine use in clinical care,” Sullivan told MedPage Today. “The far more likely and immediate use for these assays is in better recruitment and screening into Alzheimer’s disease clinical trials, specifically targeting individuals whose plasma Aβ levels suggest they may be at higher risk of current or future amyloid accumulation in the brain and cognitive impairment.”

“Although multiple studies have shown that plasma Aβ42/Aβ40 is correlated with established measures of brain amyloidosis, the field has needed large studies demonstrating that it predicts progression to dementia,” noted Suzanne Schindler, MD, PhD, of Washington University School of Medicine in St. Louis, who wasn’t involved with the research.

“The current study used an impressive cohort of 2,284 participants with a long period of follow-up and further supports the use of plasma Aβ42/Aβ40 as a predictor of future dementia,” Schindler told MedPage Today.

“One weakness is that plasma Aβ42 and Aβ40 were measured in 2014 using assays expected to have lower performance than more recent, high precision assays,” she noted. “However, the study did clearly demonstrate that lower plasma Aβ42/Aβ40 is associated with a higher risk of progression to mild cognitive impairment or dementia.”

The researchers evaluated 2,284 participants in the Atherosclerosis Risk in Communities (ARIC) cohort study who had normal cognition in midlife, with an average age of 59.2 at midlife assessments and 76.9 at late-life measurements. More than half of participants were female (57%) and 22% were Black.

Over 25 years of follow-up, 859 participants (38%) remained cognitively normal, 502 (22%) were classified as having dementia, 832 (36%) were classified as having MCI but not dementia, and 91 (4%) died without any cognitive impairment classification. Plasma Aβ42 and Aβ40 levels increased significantly from midlife to late-life on average, but changes were highly variable, the researchers said.

Measured at midlife, but not late-life, lower plasma Aβ42 was associated with higher risk of dementia and marginally higher risk of MCI. Higher plasma Aβ40 was associated with higher risk of MCI and dementia, whether measured at midlife or late-life. Associations were independent of age, sex, education, race, APOE4, and cardiovascular risk factors.

The analysis had several limitations, Sullivan and co-authors acknowledged. It used an older testing method to estimate plasma amyloid beta that may not be as precise as newer assays, and there may also have been some degree of survivor bias, since only participants with later measurements had plasma Aβ assayed at midlife.