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The objective of this study was to test whether common age-related neuropathology could account for the relation of chronic distress to dementia.In a selected cohort of more than 1000 older Catholic clergy members undergoing annual clinical evaluations, 326 persons died, of whom 306 (94%) underwent brain autopsy, the results of which were available in 219 (mean age at death = 85.4, standard deviation [SD] = 6.6; mean postmortem interval = 7.6 hours, SD = 6.9). A composite measure of chronic distress was constructed from standard measures of two traits, neuroticism and anxiety proneness, completed at baseline, and of depressive symptoms, completed annually. Dementia was diagnosed according to standard criteria and cognition was assessed with previously established composite measures based on a uniform clinical evaluation that took place a mean of 9.1 months before death (SD = 9.5). On postmortem examination, levels of amyloid-beta and tau-positive neurofibrillary tangles and the presence of Lewy bodies were quantified in six brain regions, and the number and location of chronic cerebral infarctions were noted.In analyses that controlled for age, sex, education, amyloid, tangles, Lewy bodies, and cerebral infarction, higher level of chronic distress was associated with a higher likelihood of dementia and lower level of cognition proximate to death. Chronic distress was not correlated with any form of neuropathology, including limbic, neocortical, and global indices, and did not modify the association of pathology with cognition.Chronic psychological distress is associated with late-life dementia but not with its leading causes, suggesting that novel neurodeteriorative mechanisms may be involved.