Importance Mixed neuropathologies are common, and yet the full extent to which these pathologies coexist is not entirely clear. Objectives This study aims to identify distinct neuropathologic profiles in community-dwelling older adults and to examine associated cognitive trajectories over time. Design, Setting, and Participants This study included participants in 2 community-based cohort studies of aging and dementia. Participants were older adults without known dementia at enrollment who agreed to annual evaluations and brain donation. The Religious Orders Study started in 1994, and the Rush Memory and Aging Project started in 1997. Both studies are ongoing. Data were analyzed in May 2025. Exposures Annual uniform detailed evaluations for up to 30 years and brain autopsy and neuropathologic evaluation after death. Main Outcomes and Measures Neuropathologic evaluations assessed Alzheimer disease neuropathologic change (ADNC), Lewy bodies, limbic-predominant age-related transactive response DNA-binding protein 43 kDa encephalopathy neuropathologic change (LATE-NC), hippocampal sclerosis, infarcts, cerebral amyloid angiopathy, atherosclerosis, and arteriolosclerosis. Annual cognitive scores were derived from a battery of 19 tests that assessed multiple cognitive domains. Latent neuropathologic profiles were identified using hierarchical clustering, and longitudinal cognitive trajectories associated with each profile were estimated using functional mixed-effects models. Results A total of 1633 older adults were included in the study. The mean (SD) age at death was 90.4 (6.4) years, 1156 (70.8%) were female, and the mean (SD) years of education was 16.2 (3.6) years. A total of 46 participants (2.8%) self-reported as Black, 42 (2.6%) as Hispanic, and 1579 (96.6%) as White. More than 80% of individuals had mixed neuropathologies at autopsy, and 280 unique combinations of copathologies were identified. Hierarchical clustering revealed 5 distinct neuropathologic profiles: profile 1 (259 participants 15.9%) was characterized by a high burden of infarcts and vessel diseases, profile 2 (201 participants 12.3%) by high LATE-NC and hippocampal sclerosis, profile 3 (355 participants 21.7%) by high Lewy bodies, profile 4 (159 participants 9.7%) by high ADNC and amyloid angiopathy, and profile 5 (659 participants 40.4%) by low pathology overall. Cognitive trajectories differed across profiles in terms of both the rate of decline and the timing of the onset of decline with fastest decline observed for profile 2 and 4. Conclusions and Relevance In this cohort study, mixed neuropathologies were extremely common and complex. Compared with vascular conditions, degenerative pathologies clustered into distinct profiles. Profiles characterized by high burdens of ADNC and separately, LATE-NC and hippocampal sclerosis, had the most potent associations with cognitive decline.
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