Abstract
INTRODUCTION: This study investigates the inter-related roles of hippocampal neuronal loss (HNL), limbic-predominant age-related TAR-DNA binding protein of 43 kDa (TDP-43) encephalopathy neuropathologic changes (LATE-NC), and Alzheimer's disease neuropathologic changes (ADNC) on cognitive decline. METHODS: Participants underwent annual cognitive testing and autopsy. HNL, ADNC, LATE-NC, and other age-related pathologies were evaluated. Regression and mixed-effects models examined the association of HNL with ADNC and LATE-NC, and separately with cognitive decline. Path analyses examined the extent to which associations of LATE-NC and ADNC with cognitive decline were attributable to HNL. RESULTS: LATE-NC was associated with more severe HNL, but ADNC was associated only after excluding subjects with hippocampal sclerosis (HS). HNL was associated with faster decline in global cognition and episodic, semantic, and working memory. In path analyses, about 61% of the association of LATE-NC with cognitive decline was attributable to HNL, whereas for ADNC it was mostly independent of HNL. DISCUSSION: HNL has an independent contribution to cognitive decline and acts as a major step in LATE-NC-related cognitive decline. HIGHLIGHTS: Hippocampal neuronal loss (HNL) is associated with cognitive decline. HNL is a prominent feature of limbic-predominant age-related TDP-43 encephalopathy neuropathologic changes (LATE-NC) and less so with Alzheimer's disease neuropathologic changes (ADNC). HNL acts as a major pathway in cognitive decline for LATE-NC. Differential mechanisms in hippocampal degeneration are associated with LATE-NC versus ADNC.