Common neuropathologic change drivers of hippocampal sclerosis of ageing.

Hippocampal sclerosis of aging (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 etiology 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 analyzed 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 modeling 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 with HS-A independent of LATE-NC underlines the importance of vascular factors in the etiology of HS-A.