The Intra‐ and Inter‐regional Relationship Between Alzheimer’s Disease Neuropathologic Change (ADNC) and Limbic‐predominant Age‐related TDP‐43 Encephalopathy Neuropathological Change (LATE‐NC)

Abstract

AbstractBackgroundLimbic‐predominant age‐related TDP‐43 encephalopathy neuropathological change (LATE‐NC) is found in over half of pathologically confirmed Alzheimer’s disease (AD) dementia cases. However, the region‐specific relationship between AD neuropathologic change (ADNC) and LATE‐NC remains unclear. Here, we investigated the intraregional and interregional associations between ADNC and LATE‐NC.MethodsWe analyzed multi‐regional postmortem neuropathology data from the Religious Orders Study and the Rush Memory and Aging Project (ROSMAP). Quantitative ADNC burden was assessed with amyloid‐β (Aβ) and tau immunohistochemistry in 8 brain regions. The Aβ burden was averaged across all regions, given strong inter‐regional correlations. Semi‐quantitative LATE‐NC burden was assessed with TDP‐43 immunohistochemistry in 7 brain regions, scored in 6 grades. Hippocampal sclerosis (HS) was defined as a severe neuronal loss in a mid‐hippocampal coronal section, irrespective of ADNC or LATE‐NC burden. We assessed the association between regional LATE‐NC and global Aβ burden, adjusting for APOE ε4, age at death, and sex. Then, we tested the intra‐ and inter‐regional associations between LATE‐NC and tau, adjusting for Aβ, APOE ε4, age at death, and sex. We performed a post‐hoc subgroup analysis in participants without HS.ResultsWe analyzed the data from n = 1264 deceased ROSMAP participants (Table 1). Global Aβ was positively associated with LATE‐NC in most regions (Fig.1A). Interestingly, even after accounting for Aβ and APOE ε4, tau and LATE‐NC were positively associated within the entorhinal (t = 7.29, p = 5.4×10−13) and midfrontal cortex (t = 4.33, p = 1.6×10−5) but not within the hippocampus (Fig.1B, bold boxes). Tau and LATE‐NC were positively correlated across most interregional pairs (Fig.1B) except for negative associations between hippocampal tau (CA1/subiculum) and frontal LATE‐NC. There was no association between hippocampal tau and frontal LATE‐NC in the HS(‐) subgroup (n = 1143; inferior frontal, p = 0.67; midfrontal, p = 0.15), suggesting that extensive hippocampal neuronal loss in HS(+) cases could have artifactually driven the negative association between hippocampal tau and frontal LATE‐NC.ConclusionsAβ was positively associated with LATE‐NC in most regions. Even after adjusting for Aβ and APOE ε4, tau was positively associated with LATE‐NC across most regions, except for hippocampal tau and frontal LATE‐NC. Further studies are required to determine the underlying mechanisms linking ADNC and LATE‐NC.