Associations of plasma biomarkers of Alzheimer’s disease pathology with modifiable risk factors and cognitive and functional outcomes: evidence from cross-sectional prediction and latent path analyses in the Bio-Hermes-001 cohort

Abstract Introduction Plasma biomarkers of Alzheimer’s Disease and Related Dementias (ADRD) pathology may help clarify associations between modifiable risk factors (MRFs) and cognitive and functional impairment. Methods Cross-sectional data from 1002 adults (mean age 72.0 ± 6.7) enrolled in the Bio-Hermes-001 study were analysed. First, block regression models assessed the added predictive value of MRFs and ADRD plasma biomarkers on cognitive (Mini-Mental State Examination, [MMSE]) and functional outcomes (Functional Activities Questionnaire, [FAQ]), beyond MRFs alone. Second, latent path analysis (LPA) examined potential pathways linking MRFs, ADRD biomarkers, and cognition and functional outcomes. Results ADRD biomarkers significantly improved prediction models for MMSE (Δ R 2 = 0.11) and FAQ scores (Δ R 2 = 0.11). Indirect effects consistent with mediation were observed for depression ( B = -0.05), BMI ( B = 0.02), and tobacco use ( B = 0.14) in relation to cognitive and functional outcomes. Discussion ADRD biomarkers are relevant to pathways linking MRFs with cognitive and functional outcomes and have potential for risk stratification and prevention research. Longitudinal studies are needed to determine temporal relationships and clarify potential causal mechanisms.