This study investigates the neuropathology of probable Alzheimer's disease (AD) and mild cognitive impairment (MCI) in a large community-based sample. The authors examined 483 autopsied participants from the Religious Orders Study and the Rush Memory and Aging Project, including those with probable AD, MCI, or no cognitive impairment. The results show that clinically probable AD is often a heterogeneous disorder, with nearly 90% of cases confirmed pathologically, but almost half exhibiting mixed pathologies, most commonly AD with macroscopic infarcts. In MCI, over half had a pathologic diagnosis of AD, and mixed pathologies were also common. The presence of additional pathologies, such as cerebral infarcts and neocortical Lewy bodies, significantly increases the likelihood of a diagnosis of MCI or probable AD. The study highlights the importance of recognizing mixed pathologies in both probable AD and MCI, as they contribute to cognitive impairment and may influence risk factor assumptions and clinical trial interpretations.This study investigates the neuropathology of probable Alzheimer's disease (AD) and mild cognitive impairment (MCI) in a large community-based sample. The authors examined 483 autopsied participants from the Religious Orders Study and the Rush Memory and Aging Project, including those with probable AD, MCI, or no cognitive impairment. The results show that clinically probable AD is often a heterogeneous disorder, with nearly 90% of cases confirmed pathologically, but almost half exhibiting mixed pathologies, most commonly AD with macroscopic infarcts. In MCI, over half had a pathologic diagnosis of AD, and mixed pathologies were also common. The presence of additional pathologies, such as cerebral infarcts and neocortical Lewy bodies, significantly increases the likelihood of a diagnosis of MCI or probable AD. The study highlights the importance of recognizing mixed pathologies in both probable AD and MCI, as they contribute to cognitive impairment and may influence risk factor assumptions and clinical trial interpretations.