Abstract Individuals with Down syndrome (DS) develop Alzheimer's disease neuropathological change (ADNC) by the age of 40 years, and most develop dementia by their early 50s. 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’s Coordinating Center (NACC) neuropathology forms in 63 adults with DS over 40 years. A secondary exploratory objective was to compare the neuropathological profiles between individuals with (n = 55) and without (n = 8) 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 ± 116 vs 1060 ± 108 g P = .0006), and severe hippocampal atrophy and locus coeruleus hypopigmentation were more frequent in those with dementia (P = .049, P = .009, respectively). Advanced Braak NFT stage, frequent neuritic plaques, and high ADNC were more frequent in individuals with dementia (P = .0001, P = .03, P = .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.
Flores-Aguilar et al. (Fri,) studied this question.