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 how modifiable risk factors (MRFs) contribute to 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 ADRD neuropathology mediation pathways between MRFs and cognition and functional outcomes. Results: ADRD biomarkers significantly improved prediction models for MMSE (ΔR2 = 0.11) and FAQ scores (ΔR2= 0.11). Biomarkers of ADRD neuropathology mediated the impact of depression (B = -0.05), BMI (B = 0.02), and tobacco use (B = 0.14) on cognitive and functional outcomes. Discussion: ADRD biomarkers mediate key MRF effects on cognition and function, emphasising ADRD biomarker-driven preventive interventions targeting multiple MRFs. Longitudinal studies are needed to confirm causality.