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The frequency of co-pathologies in clinically and neuropathologically characterized adults with DS has not been systematically characterized. We characterized the frequency of ADNC and common co-pathologies, including cerebral amyloid angiopathy (CAA), Lewy pathology (LP), limbic predominant age-related TDP-43 encephalopathy neuropathological change (LATE-NC), hippocampal sclerosis (HS), and other cerebrovascular and macroscopic findings reported in standardized National Alzheimer\u2019s Coordinating Center (NACC) neuropathology forms in 63 adults with DS over 40\u00a0years. A secondary exploratory objective was to compare the neuropathological profiles between individuals with (n\u2009=\u200955) and without (n\u2009=\u20098) dementia from the same autopsy cohort. In the full autopsy cohort, cortical and hippocampal atrophy, and moderate-to-severe locus coeruleus hypopigmentation was a common finding. Pure ADNC, was present in only 29% of individuals. CAA was the most frequent co-pathology, present in approximately 84% of individuals followed by LP (21%), HS (19%), and LATE-NC (17%). Atherosclerosis and arteriolosclerosis were infrequent. In exploratory comparisons between dementia groups, brain weight was significantly lower in individuals with dementia than in those without (900\u2009\u00b1\u2009116 vs 1060\u2009\u00b1\u2009108\u00a0g P\u2009=\u2009.0006), and severe hippocampal atrophy and locus coeruleus hypopigmentation were more frequent in those with dementia (P\u2009=\u2009.049, P\u2009=\u2009.009, respectively). Advanced Braak NFT stage, frequent neuritic plaques, and high ADNC were more frequent in individuals with dementia (P\u2009=\u2009.0001, P\u2009=\u2009.03, P\u2009=\u2009.0016, respectively). LATE-NC and HS occurred exclusively in individuals with dementia, while LP and CAA were found in both groups. Individuals without dementia showed a less complex co-pathology profile than those with dementia. Our findings demonstrate that co-pathologies are present in people with DS, and that despite their genetic predisposition to AD, some individuals with DS may exhibit resilience and resistance mechanisms to AD.<\/jats:p>","DOI":"10.1007\/s00401-026-03028-z","type":"journal-article","created":{"date-parts":[[2026,5,15]],"date-time":"2026-05-15T15:58:06Z","timestamp":1778860686000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Frequency of mixed neuropathologies in individuals with Down syndrome with and without Alzheimer's dementia"],"prefix":"10.1007","volume":"151","author":[{"given":"Lisi","family":"Flores-Aguilar","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas 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