Comparative analyses of Alzheimer's disease blood biomarkers and cognitive domains
Abstract INTRODUCTION Whether Alzheimer's disease (AD) blood biomarker–cognition associations differ across cognitive domains, analytic context, and biomarker modeling strategy in population‐based cohorts is unclear. METHODS In 1170 older adults from the Health and Retirement Study Harmonized Cognitive Assessment Protocol (HRS‐HCAP), we examined cross‐sectional (2016) and prospective (2016 to 2022) associations of blood phosphorylated tau at threonine 181 (p‐tau181), glial fibrillary acidic protein (GFAP), neurofilament light (NfL), and amyloid beta 42/40 ratio (Aβ42/40) with memory, executive function, language, visuospatial ability, and global cognition using individual‐biomarker, principal component analysis‐derived composite, and multi‐biomarker panel models. RESULTS Cross‐sectionally, NfL and GFAP showed the broadest associations with cognitive performance. In simultaneous models of baseline‐adjusted follow‐up cognition, p‐tau181 was associated with lower memory (β = −0.080, q < 0.001) and global cognition (β = −0.066, q < 0.001), while GFAP was associated with lower executive function (β = −0.047, q = 0.007), memory (β = −0.047, q = 0.032), and global cognition (β = −0.066, q = 0.002). NfL and Aβ42/40 were not independently associated after mutual adjustment. P‐tau181 also showed relative domain selectivity between memory and executive function. Relative model support differed by cognitive domain and analytic context. DISCUSSION AD blood‐based biomarker–cognition associations were domain‐differentiated and context‐dependent: Concurrent associations did not reliably indicate associations with cognition 6 years later, and only p‐tau181 showed formal evidence of relative memory‐versus‐executive selectivity. Exploratory pairwise comparisons highlighted p‐tau181 + GFAP for follow‐up memory and global cognition, warranting independent evaluation.