{"doi":"10.1093/brain/awaf158","title":"Common neuropathologic change drivers of hippocampal sclerosis of ageing","abstract":"Hippocampal sclerosis of ageing (HS-A)-severe cell loss and gliosis in the hippocampal formation-is a neuropathologic change (NC) that affects up to 20% of elderly persons with dementia. The aetiology of HS-A is heterogeneous, but HS-A is strongly associated with limbic-predominant age-related TDP-43 encephalopathy NC (LATE-NC). Other NCs have also been implicated in relation to HS-A, but these associations have been inconsistent across previous studies. Also, because LATE-NC and HS-A are so strongly associated, it is important to adjust for LATE-NC when examining associations between other NCs and HS-A. The goal of this study was to examine associations of other common NCs with HS-A, both before and after adjusting for LATE-NC. We analysed the National Alzheimer's Coordinating Center (NACC) neuropathology dataset and examined associations of Alzheimer's disease NC (ADNC), Lewy bodies (LB) and cerebrovascular NCs, with HS-A, adjusting for LATE-NC in multiple ways. We used Bayesian multilevel logistic regression models with monotonic modelling for ordinal predictors and report the odds ratios (OR) or average OR across levels (aOR), along with 95% credibility intervals (CI) as well as expected frequencies of HS-A for selected models and predictor levels. Of n = 1933 autopsy participants included (average age at death of 83 years, 51.3% women), HS-A was present in 278 (14.4%). LATE-NC was strongly associated with HS-A (aOR = 3.7, 95% CI = 2.8, 5.0). While ADNC showed a modest association with HS-A in models where LATE-NC was not included as a predictor (aOR = 1.4, CI = 1.1, 1.8), this association was reduced when adjusting for LATE-NC (aOR = 1.11, CI = 0.9, 1.5); results were similar for the ADNC-related A/B/C scores and limbic LBs. However, several cerebrovascular NCs were similarly associated with HS-A both without adjusting for LATE-NC [atherosclerosis aOR = 1.4, arteriolosclerosis aOR = 1.6, white matter rarefaction (WMR) aOR = 1.4] and with adjusting for LATE-NC (atherosclerosis aOR = 1.4, arteriolosclerosis aOR = 1.5, WMR aOR = 1.3). In a combined model, LATE-NC was strongly associated with HS-A, but global cerebrovascular NCs, as well as APOE-ε4 (increased odds) and education (decreased odds), were also associated with HS-A. Predicted HS-A frequency for predictor levels of no LATE-NC or global cerebrovascular NCs was 1.5% (CI = 0.6%, 3.1%), while it was 94.5% (CI = 84%, 99.5%) for LATE-NC stage 3 and severe global cerebrovascular NC levels. LATE-NC is likely the most important cause of HS-A. While ADNC seems to be associated with HS-A through its association with LATE-NC, the association of cerebrovascular NCs with HS-A independent of LATE-NC underlines the importance of vascular factors in the aetiology of HS-A.","journal":"Brain","year":2025,"id":513796,"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":9,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9523,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1376268,"name":"Jicheng Lou","orcid":null,"position":1,"is_corresponding":false},{"id":279706,"name":"William H. Yong","orcid":null,"position":2,"is_corresponding":false},{"id":270466,"name":"Elizabeth Head","orcid":"0000-0003-1115-6396","position":3,"is_corresponding":false},{"id":308297,"name":"María M. Corrada","orcid":"0000-0002-8168-8593","position":4,"is_corresponding":false},{"id":245009,"name":"Peter T. Nelson","orcid":"0000-0002-6161-1265","position":5,"is_corresponding":false},{"id":332143,"name":"S. Ahmad Sajjadi","orcid":"0000-0002-8960-2213","position":6,"is_corresponding":false},{"id":332142,"name":"Davis C. Woodworth","orcid":"0000-0002-6256-857X","position":0,"is_corresponding":true}],"reference_count":70,"raw_metadata":null,"created_at":"2026-07-19T02:48:23.284782Z","pmid":"40323260","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":[]}