Abstract Objective: To examine the spectrum of neuropathology in persons from the Rush Memory and Aging Project, a longitudinal community-based clinical-pathologic cohort study. Methods: The study includes older persons who agreed to annual clinical evaluation and brain donation. We examined the neuropathologic diagnoses, including Alzheimer disease (AD) (NIA-Reagan Criteria), cerebral infarctions, and Parkinson disease/Lewy body disease (PD/LBD), in the first 141 autopsies. We calculated the frequency of each diagnosis alone and mixed diagnoses. We used logistic regression to compare one to multiple diagnoses on the odds of dementia. Results: Twenty persons (14.2%) had no acute or chronic brain abnormalities. The most common chronic neuropathologic diagnoses were AD (n = 80), cerebral infarctions (n = 52), and PD/LBD (n = 24). In persons with dementia (n = 50), 38.0% (n = 19) had AD and infarcts, 30.0% (n = 15) had pure AD, and 12% each had vascular dementia (n = 6) and AD with PD/LBD (n = 6). In those without dementia (n = 91), 28.6% (n = 26) had no chronic diagnostic abnormalities, 24.2% (n = 22) had pure AD, and 17.6% (n = 16) had infarctions. In persons with dementia, over 50% had multiple diagnoses (AD, PD/LBD, or infarcts), whereas, in persons without dementia, over 80% had one or no diagnosis. After accounting for age, persons with multiple diagnoses were almost three times (OR = 2.8; 95% CI = 1.2, 6.7) more likely to exhibit dementia compared to those with one pathologic diagnosis. Conclusion: The majority of community-dwelling older persons have brain pathology. Those with dementia most often have multiple brain pathologies, which greatly increases the odds of dementia.