{"doi":"10.1101/2021.09.06.21263162","title":"Susceptibility to postmortem (co)-pathologies in antemortem atrophy-based subtypes of Alzheimer’s disease","abstract":"Abstract Objectives To investigate whether antemortem atrophy-based subtypes of Alzheimer’s disease (AD) may be differentially susceptible to individual or concomitance of AD and non-AD (co)-pathologies, assessed neuropathologically at postmortem. Methods We selected 31 individuals from the AD neuroimaging initiative with: an antemortem magnetic resonance imaging scan evaluating brain atrophy available within two years before death; an antemortem diagnosis of AD dementia or prodromal AD; and postmortem neuropathological confirmation of AD. Antemortem atrophy-based subtypes was modeled as a continuous phenomenon in terms of two recently proposed dimensions: typicality (ranging from limbic-predominant AD to hippocampal-sparing AD subtypes) and severity (ranging from typical AD to minimal atrophy AD subtypes). Postmortem neuropathological evaluation included global and regional outcomes: AD hallmark pathologies of amyloid-beta and tau; non-AD co-pathologies of alpha-synuclein Lewy body and TDP-43; and the overall concomitance across these four (co)-pathologies. Partial correlation and linear regression models were used to assess the association between antemortem atrophy-based subtypes and postmortem neuropathological outcomes. Results We observed significant global and regional associations between antemortem typicality and postmortem (co)-pathologies including tau, alpha-synuclein Lewy bodies and TDP-43. Antemortem typicality demonstrated stronger regional associations with concomitance of multiple postmortem (co)-pathologies in comparison to antemortem severity. Our findings suggest the following susceptibilities of atrophy-based subtypes: limbic-predominant AD towards higher burden of tau and TDP-43 pathologies while hippocampal-sparing AD towards lower burdens; limbic-predominant AD and typical AD towards higher burden of alpha-synuclein Lewy body pathology while hippocampal-sparing AD and minimal-atrophy AD towards lower burdens. Discussion Through a direct antemortem-to-postmortem validation, our study highlights the importance of understanding heterogeneity in AD in relation to concomitance of AD and non-AD pathologies. Our findings provide a deeper understanding of both global and regional vulnerabilities of the biological subtypes of AD brain towards (co)-pathologies. Relative involvement of both AD hallmark and non-AD (co)-pathologies will enhance prevailing knowledge of biological heterogeneity in AD and could thus, contribute towards tracking disease progression and designing clinical trials in the future.","journal":"medRxiv","year":2021,"id":226476,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.8053,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":252021,"name":"Daniel Ferreira","orcid":"0000-0001-9522-4338","position":1,"is_corresponding":false},{"id":12184,"name":"Simon Frerich","orcid":"0000-0002-8275-6113","position":2,"is_corresponding":false},{"id":393890,"name":"J‐Sebastian Muehlboeck","orcid":null,"position":3,"is_corresponding":false},{"id":241103,"name":"Michel J. Grothe","orcid":"0000-0003-2600-9022","position":4,"is_corresponding":false},{"id":252034,"name":"Eric Westman","orcid":"0000-0002-3115-2977","position":5,"is_corresponding":false},{"id":243718,"name":"for the Alzheimer’s Disease Neuroimaging Initiative","orcid":null,"position":6,"is_corresponding":false},{"id":260775,"name":"Rosaleena Mohanty","orcid":"0000-0001-6499-1251","position":0,"is_corresponding":true}],"reference_count":42,"raw_metadata":null,"created_at":"2026-07-18T23:54:34.185847Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}