Evaluating Physical Frailty as a Marker of Cognitive Health in Older Adults without Dementia

Physical frailty is associated with adverse health outcomes in older adults, including cognitive decline; however, the underlying biological and pathophysiological mechanisms linking frailty to neuropathological biomarkers remain underexplored, particularly in older adults without dementia. This study examined associations between physical frailty and cognitive performance and biomarkers based on the amyloid, tau, and neurodegeneration (ATN) framework in a sample of community-dwelling older adults without dementia. Using baseline data from a randomized controlled trial, we conducted a secondary cross-sectional analysis of 137 sedentary adults aged 60-85 years with insomnia symptoms and Montreal Cognitive Assessment scores above 17. Frailty was measured using the Johns Hopkins Frailty Assessment Tool. Cognitive performance was assessed with the CogState computerized battery, and plasma biomarkers-including amyloid beta 42/40 ratio (Aβ42/Aβ40), total tau (t-tau), and neurofilament light chain (NfL)-were quantified using Single Molecule Array (Simoa) technology in a subsample (n = 98). In adjusted models, frail participants demonstrated significantly lower global cognition, processing speed, and attention compared to robust individuals. Prefrail participants did not show significant differences in cognitive performance. For biomarkers, prefrail individuals had significantly lower Aβ42/Aβ40 ratios in unadjusted models, and frail individuals showed significantly higher NfL levels in adjusted models. No significant associations were found for t-tau. These findings suggest that physical frailty is linked to both cognitive impairment and early neurobiological changes in older adults without dementia. Incorporating frailty assessments alongside biomarker evaluation may enhance early detection of Alzheimer's-related changes and guide timely interventions to mitigate cognitive decline.