Midlife and Late-Life Alzheimer Disease Blood Biomarkers and 11-Year Cognitive Decline

BACKGROUND AND OBJECTIVES: Plasma biomarkers of Alzheimer disease (AD) neuropathology (amyloid-β42 to amyloid β40 [Aβ42/40] ratio, phosphorylated tau at threonine [p-tau181]), neurodegeneration (neurofilament light [NfL]), and neuroinflammation (glial fibrillary acidic protein [GFAP]) in late-life are associated with cognitive decline. Whether these biomarkers in midlife are predictive of subsequent cognitive decline, and whether they are associated with different cognitive domains, is uncertain. In this study, we investigated associations of midlife and late-life plasma Aβ42/40, p-tau181, NfL, and GFAP with late-life change in domain-specific (memory, language, and executive function) and global cognitive function. METHODS: We performed a prospective cohort analysis of the Atherosclerosis Risk in Communities Neurocognitive Study (ARIC-NCS). Outcome follow-up was from ARIC visit 5 (2011-2013) to visit 9 (2021-2022). We included all individuals from ARIC field centers (Jackson, Mississippi; Forsyth County, North Carolina; Washington County, Maryland; and Minneapolis suburbs, Minnesota) with biomarkers measured from stored specimens in midlife (visit 3, 1993-1995, mean age 59.0 years) and late-life (visit 5, 2011-2013, mean age 76.8 years). Aβ42/40, p-tau181, NfL, and GFAP were measured with the Quanterix Simoa platform and standardized to visit 3 to facilitate cross-biomarker comparisons of their rate of change from midlife to late-life. We estimated change in memory, language, executive function, and global cognition factor scores from visit 5 to visit 9 with linear mixed-effect models. RESULTS: In 1,515 included participants, 60.7% (n = 920) were female and 25.5% (n = 387) were Black. Each SD increase in p-tau181 in midlife was significantly associated with faster late-life memory decline (β = -0.030 [95% CI -0.059 to -0.001] SD. Midlife Aβ42/40, NfL, and GFAP were not associated with subsequent decline in any cognitive domain. In late-life, p-tau181, NfL, and GFAP were significantly associated with faster decline in different cognitive domains, with the strongest associations seen with memory (β = -0.091 [95% CI -0.123 to -0.058] SD; β = -0.064 [95% CI -0.106 to -0.023] SD; and β = -0.048 [95% CI -0.082 to -0.013] SD, respectively). DISCUSSION: Midlife p-tau181 was associated with faster 11-year memory decline beginning 20 years later in the ARIC cohort, which underscores a potentially long prodromal phase of cognitive decline that could precede dementia onset. In late-life, biomarkers for AD, neurodegeneration, and neuroinflammation were associated with faster decline across different cognitive domains, but associations remained strongest for p-tau181 and memory.