Associations of neurodegenerative and cerebrovascular neuropathology with frailty in a diverse sample

Associations between neurodegenerative and cerebrovascular neuropathologies and frailty are not well understood, especially in diverse populations. This study investigated these associations in an admixed Brazilian cohort. This cross-sectional study included participants aged 60 + from the Brazilian Biobank for Aging Studies (2004-2024). Neuropathology data covered nine markers and a neuropathological comorbidity score (NPC). Frailty was measured using a frailty index from 33 health deficits, and cognitive impairment was defined as a Clinical Dementia Rating ≥ 0.5, both based on post-mortem informant reports with the next of kin. Linear regression models, adjusted for age, sex, education, race, and cognitive impairment, assessed associations between neuropathology and frailty. Effect modification by cognitive status was also explored. Among 1,370 participants (mean age = 78.4 ± 9.3 years; 53% women), 45% were frail, and 38% had cognitive impairment. Neurofibrillary tangles (NFT) (β = 0.005, 95%CI = 0.000-0.008, p = 0.036), Lewy body disease pathology (β = 0.008, 95%CI = 0.003-0.012, p = 0.001), lacunar infarcts (β = 0.032, 95%CI = 0.012-0.052, p = 0.002), siderocalcinosis (β = 0.015, 95%CI = 0.002-0.030, p = 0.023), and hyaline arteriolosclerosis (β = 0.034, 95%CI = 0.021-0.048, p < 0.001) were associated with frailty, independent of cognitive impairment. Higher NPC scores were linked to higher frailty with stronger associations observed among cognitively impaired participants (β = 0.007, 95%CI = 0.003-0.011, p = 0.001), as indicated by a p-value for interaction = 0.007. There was a more pronounced association between neuropathology and frailty among cognitively impaired participants for NFT (β = 0.007, 95%CI = 0.001-0.015, p = 0.020) and hyaline arteriolosclerosis (β = 0.052, 95%CI = 0.031-0.073, p < 0.001). Unlike other neuropathologies, hyaline arteriolosclerosis was associated with higher frailty levels in participants without cognitive impairment (β = 0.020, 95%CI = 0.002-0.038, p = 0.023). Our findings suggest that neuropathology affects frailty independently of cognitive status, although its impact is compounded by cognitive impairment. Moreover, cerebrovascular pathology's association with frailty in cognitively normal participants highlights the potential benefit of early cardiovascular risk management to reduce frailty risk, which is crucial in low- and middle-income countries considering the disproportionately high burden of cardiovascular and cerebrovascular conditions in these populations.