© 2017 The Author(s). Background: Mechanisms linking cognitive and physical functioning in older adults are unclear. We sought to determine whether brain pathological changes relate to the level or rate of physical performance decline. Methods: This study analyzed data from 305 participants in the autopsy subcohort of the prospective Adult Changes in Thought (ACT) study. Participants were aged 65+ and free of dementia at enrollment. Physical performance was measured at baseline and every two years using the Short Physical Performance Battery (SPPB). Data from 3174 ACT participants with ≥2 SPPB measurements were used to estimate two physical function measures: 1) rate of SPPB decline defined by intercept and slope; and 2) estimated SPPB 5 years prior to death. Neuropathology findings at autopsy included neurofibrillary tangles (Braak stage), neuritic plaques (CERAD level), presence of amyloid angiopathy, microinfarcts, cystic infarcts, and Lewy bodies. Associations (adjusted for sex, age, body mass index and education) between dichotomized neuropathologic outcomes and SPPB measures were estimated using modified Poisson regression with inverse probability weights (IPW) estimated via Generalized Estimating Equations (GEE). Relative risks for the 20th, 40th, and 60th percentiles (lowest levels and highest rates of decline) relative to the 80th percentile (highest level and lowest rate of decline) were calculated. Results: Decedents with the least vs. most SPPB decline (slope > 75th vs. < 25th percentiles) had higher SPPB scores, and were more likely to be male, older, have higher education, and exercise regularly at baseline. No significant associations were observed between neuropathology findings and rate of SPPB decline. Lower predicted SPPB scores 5 years prior to death were associated with higher risk of microinfarcts (RR = 3.08, 95%25 confidence interval (CI) 0.93-1.07 for the 20th vs. 80th percentiles of SPPB) and significantly higher risk of cystic infarcts (RR = 2.72, 95%25 CI 1.45-5.57 for 20th vs. 80th percentiles of SPPB). Conclusion: Cystic infarcts and microinfarcts, but not neuropathology findings of Alzheimer's disease, were related to physical performance levels five years before death. No pathology findings were associated with rates of physical performance decline. Physical function levels in the years prior to death may be affected by vascular brain pathologies.