Association of brain pathology with the progression of frailty in older adults.

OBJECTIVE We tested the hypothesis that brain pathology is associated with the rate of progression of physical frailty in older adults. METHODS A total of 791 older adults participating in the Religious Orders Study and Memory and Aging Project had annual clinical evaluations from which a previously established composite measure of physical frailty was derived and brain autopsy after death. A uniform neuropathologic examination included the assessment of macroinfarcts, microinfarcts, atherosclerosis, arteriolosclerosis, Alzheimer disease and Lewy body pathology, and nigral neuronal loss. RESULTS Mean follow-up before death was 6.4 years and age at death was 88.5 years. More than 95% of cases had evidence of one or more brain pathologies. In a linear mixed-effect model controlling for age, sex, and education, frailty increased at approximately 0.12 unit/year (estimate 0.117, SE 0.035, p < 0.001). The rate of progression of frailty was accelerated with increasing age (estimate 0.002, SE 0.001, p = 0.012). In separate models, the presence of macroinfarcts, Alzheimer disease and Lewy body pathology, and nigral neuronal loss was associated with a more rapid progression of frailty (all p values ≤0.010). When these 4 brain pathologies were considered together in a single model, Alzheimer disease pathology, macroinfarcts, and nigral neuronal loss showed independent associations with the rate of progression of frailty and accounted for more than 8% of the variance unexplained by demographic variables alone. CONCLUSION The accumulation of common brain pathologies contributes to progressive physical frailty in old age.