Distinct Frailty Phenotypes Are Associated with Cognitive Performance and Brain Structure in Alzheimer’s Disease

Background/Objectives: Frailty is a well-established risk factor for cognitive decline and dementia, yet how its distinct physical, functional, and psychosocial components relate to brain health in Alzheimer’s disease (AD) remains poorly understood. This proof-of-concept study aimed to identify data-driven frailty factors and examine their cross-sectional associations with cognition and brain structure in biomarker-confirmed AD. Methods: Forty-eight adults with amyloid-β (Aβ)-positive AD underwent comprehensive clinical assessments, neuropsychological testing, dual-energy X-ray absorptiometry, and 3.0T magnetic resonance imaging of the brain. Exploratory factor analysis (EFA) was applied to characterize the underlying structure of physical (body composition measures), functional (performance-based metrics), and psychosocial (patient-reported outcomes) frailty domains. Multiple linear regression analysis was used to examine associations between extracted frailty factors and cognition (memory and executive function) and neuroanatomy (total gray matter and hippocampal volumes), adjusting for age, sex, education, APOE4 status, and total intracranial volume. Results: EFA revealed eight distinct frailty factors. Psychological distress was associated with worse memory (p=0.02) and smaller hippocampal volume (p=0.05). Physical and social limitations were associated with smaller total gray matter volume (p=0.03). Cognitive-motor dual-task performance was associated with superior executive functioning (p=0.002) and larger total gray matter volume (p=0.01). Lean mass was associated with larger hippocampal volume (p=0.0004). Conclusions: Distinct frailty factors exhibited specific cognitive and neuroanatomical signatures in AD. These preliminary findings underscore the multifaceted nature of frailty and suggest unique mechanistic pathways through which it may influence brain health. Larger longitudinal studies are warranted to validate these results and inform clinically relevant interventions.