Background: Cancer and Alzheimer's disease are common diseases in aging populations. Intriguingly, prior research has reported a lower incidence of Alzheimer's disease dementia among individuals with a history of cancer. Both are prevalent and lethal conditions. The current study was conducted to investigate the association of cancer history with neuropathological and cognitive features. Methods: Data were drawn from elderly, longitudinally evaluated participants in a community-based cohort study of aging and dementia who came to autopsy at the University of Kentucky Alzheimer's Disease Research Center. The data were linked to the Kentucky Cancer Registry, which is a population-based state cancer surveillance system, to obtain cancer-related data. We examined the relationship between cancer history, clinical dementia diagnoses, Mini-Mental State examination test scores, and neuropathological features using inverse probability weighting to address confounding and selection bias. Results: Included participants (n = 785) had a mean ±SD age of death of 83.8 ±8.6 years; 60.1% were female. Positive cancer history was determined in 190 (24.2%) participants. The prevalence of at least one APOE ε4 allele was lower among participants with cancer history compared to cancer-free participants (32.6% vs 42.0%, P = 0.0063). Participants with cancer history had lower odds of MCI/Dementia, and higher cognitive test scores (e.g., comparing MMSE scores evaluated at six and < two years prior to death., P < 0.001). Cancer history was also associated with reduced odds of intermediate (III/IV) or severe (V/VI) Braak Neurofibrillary tangle stages, moderate/frequent neuritic plaques, moderate/frequent diffuse plaques, and moderate/severe cerebral amyloid angiopathy (all P<0.05). By contrast, TDP-43, √é±-synuclein, and cerebrovascular pathologies were not associated with cancer history. Conclusion: In this study, we showed that cancer history was associated with a lower burden of Alzheimer's disease pathology and clinical dementia. These findings provide an additional basis of support for prior epidemiological research reporting a protective association between cancer and Alzheimer's disease-type dementia.

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