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

Abstract

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.

Figure 1. Person-specific paths of progressive frailty

The figure is organized according to the age of the participant at each evaluation; the length of each line relative to the x-axis indicates the total years of observation for that individual. The figure is estimated for a 25% random sample of the cohort and shows smoothed person-specific paths estimated from a random-effects model with a term for time and controlled for age, sex, education, and their interaction with time.

Figure 2. Effect of more brain pathology on the predicted paths of frailty

Predicted path of frailty for 4 participants with increasing brain pathology. 1) Predicted path of frailty for a participant with low level of Alzheimer disease (AD) pathology (10th percentile) (black line; slope = 0.081 unit/year). 2) Predicted path of frailty for a participant with a high level of AD pathology (90th percentile) (blue line: slope = 0.110 unit/year). 3) Predicted path of frailty for a participant with a high level of AD pathology (90th percentile) and macroinfarcts (red line: slope = 0.134 unit/year). 4) Predicted path of frailty for a participant with a high level of AD pathology (90th percentile), macroinfarcts, and severe nigral neuronal loss (green line: slope = 0.194 unit/year).