Grip strength modifies the association between blood-based alzheimer's biomarkers and cognitive function

Blood-based biomarkers are increasingly used to characterize Alzheimer's disease (AD)-related pathology, yet substantial heterogeneity exists in how biomarker burden relates to cognitive performance. Grip strength, a marker of frailty and functional reserve, may modify this relationship. We conducted a cross-sectional analysis of 348 participants from the Aging Adult Brain Connectome (AABC) study. Global cognition was assessed using the Preclinical Alzheimer Cognitive Composite (PACC). Plasma biomarkers included phosphorylated tau-217 (pTau₂₁₇), glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL), and total tau (tTau). Multiple linear regression models tested biomarker × grip strength interactions, adjusting for demographic factors, APOE ε4 status, cardiometabolic risk factors, body mass index, and creatinine. Sensitivity analyses included age-based propensity score matching and age-stratified models. Participants with low PACC were older, had lower grip strength, and higher plasma biomarker levels than those with normal cognition (all p < 0.001). In adjusted models, significant interactions between low grip strength and biomarkers were observed for pTau₂₁₇ (β =  - 0.046, p < 0.01), NfL (β =  - 0.002, p < 0.001), and GFAP (β =  - 0.005, p < 0.05). Age-matched showed attenuation of some interaction effects except for low grip strength and NfL. Age-stratified analyses showed a significant interaction for NfL among adults ≥ 65 years and for GFAP among those < 65 years. Grip strength moderated the association between plasma AD-related biomarkers and cognitive performance, supporting physical strength as an indicator of vulnerability. Integrating simple strength measures with blood biomarkers may improve cognitive risk stratification in community-dwelling adults.