What is the association of plasma biomarker (amyloid-β 42 to amyloid-β 40 [Aβ42:Aβ40] ratio, phosphorylated tau at threonine [p-tau181], neurofilament light [NfL], glial fibrillary acid protein [GFAP]) changes from midlife to late life with all-cause dementia?
Findings In this retrospective analysis of prospectively collected plasma biomarkers from 1525 adults from the Atherosclerosis Risk in Communities study, only Alzheimer disease (AD)–specific (Aβ42:Aβ40, p-Tau181) biomarkers in midlife demonstrated significant long-term associations with late-life dementia. In late life, each of the biomarkers and their change from midlife were significantly associated with incident all-cause dementia.
Meaning AD-specific biomarkers’ association with dementia starts in midlife whereas late-life measures of AD, neuronal injury, and astrogliosis biomarkers are all associated with dementia.
Importance Plasma biomarkers show promise for identifying Alzheimer disease (AD) neuropathology and neurodegeneration, but additional examination among diverse populations and throughout the life course is needed.
Objective To assess temporal plasma biomarker changes and their association with all-cause dementia, overall and among subgroups of community-dwelling adults.
Design, Setting, and Participants In 1525 participants from the US-based Atherosclerosis Risk in Communities (ARIC) study, plasma biomarkers were measured using stored specimens collected in midlife (1993-1995, mean age 58.3 years) and late life (2011-2013, mean age 76.0 years; followed up to 2016-2019, mean age 80.7 years). Midlife risk factors (hypertension, diabetes, lipids, coronary heart disease, cigarette use, and physical activity) were assessed for their associations with change in plasma biomarkers over time. The associations of biomarkers with incident all-cause dementia were evaluated in a subpopulation (n = 1339) who were dementia-free in 2011-2013 and had biomarker measurements in 1993-1995 and 2011-2013.
Exposure Plasma biomarkers of amyloid-β 42 to amyloid-β 40 (Aβ42:Aβ40) ratio, phosphorylated tau at threonine 181 (p-tau181), neurofilament light (NfL), and glial fibrillary acidic protein (GFAP) were measured using the Quanterix Simoa platform.
Main Outcomes and Measures Incident all-cause dementia was ascertained from January 1, 2012, through December 31, 2019, from neuropsychological assessments, semiannual participant or informant contact, and medical record surveillance.
Results Among 1525 participants (mean age, 58.3 [SD, 5.1] years), 914 participants (59.9%) were women, and 394 participants (25.8%) were Black. A total of 252 participants (16.5%) developed dementia. Decreasing Aβ42:Aβ40 ratio and increasing p-tau181, NfL, and GFAP were observed from midlife to late life, with more rapid biomarker changes among participants carrying the apolipoprotein E epsilon 4 (APOEε4) allele. Midlife hypertension was associated with a 0.15-SD faster NfL increase and a 0.08-SD faster GFAP increase per decade; estimates for midlife diabetes were a 0.11-SD faster for NfL and 0.15-SD faster for GFAP. Only AD-specific biomarkers in midlife demonstrated long-term associations with late-life dementia (hazard ratio per SD lower Aβ42:Aβ40 ratio, 1.11; 95% CI, 1.02-1.21; per SD higher p-tau181, 1.15; 95% CI, 1.06-1.25). All plasma biomarkers in late life had statistically significant associations with late-life dementia, with NfL demonstrating the largest association (1.92; 95% CI, 1.72-2.14).
Conclusions and Relevance Plasma biomarkers of AD neuropathology, neuronal injury, and astrogliosis increase with age and are associated with known dementia risk factors. AD-specific biomarkers’ association with dementia starts in midlife whereas late-life measures of AD, neuronal injury, and astrogliosis biomarkers are all associated with dementia.
JAMA. Published online July 28, 2024. doi:10.1001/jama.2024.6619
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