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.

Keywords: amyloid; hippocampus; memory; neurodegeneration; oldest-old; tau.

Figure 1

Odds ratios of predictors for outcome of HS-A in demographic and APOE ε4 model, with and without LATE-NC included as a predictor. Odds ratios (ORs) for model with demographic and APOE ε4 variables without LATE-NC as a predictor (grey) and with LATE-NC as a predictor (blue). ORs refer to different scales for different variables: for age, OR is per decade; for education, OR is per 4 years; for sex, it is the OR of male (female as reference); for APOE ε4, it is the average OR for each additional ε4 allele; and for LATE-NC, it is the average OR between adjacent levels. Half-eye plots with density of marginal distribution for coefficient and mean (black dot), 66% (thick black line) and 95% (thin black line) credibility intervals. Models including LATE-NC as a predictor (blue) appear above and on top of models not including LATE-NC as a predictor (grey). Vertical solid line denotes OR = 1. x-axis on log scale. HS-A = hippocampal sclerosis of ageing; LATE-NC = limbic-predominant age-related TDP-43 encephalopathy neuropathologic change.

Figure 2

Odds ratios of neuropathological change predictors for outcome of HS-A in models with and without adjusting for LATE-NC. (A) Average odds ratios (OR) between adjacent levels for ordinal neuropathological change (NC) predictors. (B) OR for binary NC predictors. Each row represents separate models adjusting for listed NC, with and without LATE-NC in model, except for Lewy bodies (LBs; B, bottom), where each row represents a different category of LBs from the same model using a reference of no LBs. Half-eye plots with density of marginal distribution for coefficient and mean (black dot), 66% (thick black line) and 95% (thin black line) credibility intervals. Models adjusting for LATE-NC (blue) appear above and on top of models not adjusting for LATE-NC (grey). Vertical solid line denotes OR = 1. Models adjusted for age at death, sex and years of education. x-axis on log scale. ADNC = Alzheimer’s disease NC; Arterio. = arteriolosclerosis; Athero. = atherosclerosis; CAA = cerebral amyloid angiopathy; Diff. = diffuse; Hem. = haemorrhages; HS-A = hippocampal sclerosis of ageing. Inf. = infarct; LATE-NC = limbic-predominant age-related TDP-43 encephalopathy NC; OB = olfactory bulb; WMR = white matter rarefaction.

Figure 3

Odds ratios of global cerebrovascular neuropathologic change predictors for outcome of HS-A by severity level. Each row represents the levels of mild/moderate/severe, and the dots/lines show the coefficients for each of the global cerebrovascular neuropathologic changes (NCs) [atherosclerosis, arteriolosclerosis and white matter rarefaction (WMR)] from the model for each where LATE-NC was included as a predictor. Interval plots with mean (dot), 66% (thick line) and 95% (thin line) credibility intervals. Vertical solid line denotes odds ratio = 1. Models adjusted for age at death, sex and years of education. x-axis on log scale. Arterio. = arteriolosclerosis; Athero. = atherosclerosis; HS-A = hippocampal sclerosis of ageing; LATE-NC = limbic-predominant age-related TDP-43 encephalopathy NC.

Figure 4

Odds ratios of neuropathologic change predictors for outcome of HS-A in those without LATE-NC (‘none’) and those with LATE-NC stage 2. (A) Average odds ratios (OR) between adjacent levels for ordinal neuropathologic change (NC) predictors. (B) OR for binary NC predictors. The Venn diagrams on either side show the proportion of participants used for the analysis, with (lighter colour) and without (darker colour) HS-A. Each row represents separate models for the listed NC for models in LATE-NC—stage 2 (blue) or LATE-NC—none (lime green), except for Lewy bodies (LBs; B, bottom), where each row represents a different category of LBs from the same model using a reference of no LBs. Half-eye plots with density of marginal distribution for coefficient and mean (black dot), 66% (thick black line) and 95% (thin black line) credibility intervals. Models within participants with LATE-NC stage 2 (blue) appear above and on top of models within participants without LATE-NC (green). Vertical solid line denotes OR = 1. Models adjusted for age at death, sex and years of education. x-axis on log scale. ADNC = Alzheimer’s disease NC; Arterio. = arteriolosclerosis; Athero. = atherosclerosis; CAA = cerebral amyloid angiopathy; Diff. = diffuse; Hem. = haemorrhages; HS-A = hippocampal sclerosis of ageing; Inf. = infarct; LATE-NC = limbic-predominant age-related TDP-43 encephalopathy NC; OB = olfactory bulb; WMR = white matter rarefaction.

Figure 5

Odds ratios of predictors for outcome of HS-A in combined model. Odds ratios (OR) for various predictors for model adjusting for relevant demographic variables, APOE ε4 and neuropathologic changes (NCs). ORs refer to different scales for different variables: for age, OR is per decade; for education, OR is per 4 years; for sex, it is the OR of male (female reference); for APOE ε4, it is the average OR for each additional ε4 allele; for LATE-NC/Athero./Arteriolo., it is the average OR between adjacent levels; and for old microinfarcts, it is the OR of presence (absence reference). Half-eye plots with density of marginal distribution for coefficient and mean (black dot), 66% (thick black line) and 95% (thin black line) intervals. Vertical solid line denotes OR = 1. x-axis on log scale. Athero. = atherosclerosis; Arteriolo. = arteriolosclerosis; HS-A = hippocampal sclerosis of ageing; Inf. = infarct; LATE-NC = limbic-predominant age-related TDP-43 encephalopathy NC; Pres. = presence.