Basic Science and Pathogenesis.

Background: Hippocampal neuronal loss (HNL), LATE neuropathologic changes (LATE-NC), and Alzheimer's disease (AD) are common neuropathological findings in older persons. However, the inter-relationship between AD, LATE-NC, HNL, and cognition is not well understood.

Method: Participants without known dementia (n = 420; mean age-at-death = 92 years, women = 72%) enrolled, in the Rush community-based cohorts and underwent annual cognitive testing and autopsy. At autopsy, the severity of HNL in the CA1-subiculum sector was semi-quantitatively graded from 0 (none) to 5 (severe) on H&E stain without regard to AD or LATE-NC pathology. Hippocampal sclerosis (HS) was defined as severe hippocampal neuronal loss (grade 5). Tau-tangle density, β-amyloid burden, LATE-NC, and other age-related pathologies were also recorded. Logistic regression and mixed-effect models adjusted for demographics and neuropathologies were used to examine the association of HNL with AD (tangles/ β-amyloid) and LATE-NC, and separately with cognitive decline. Path analyses examined the extent to which the associations of LATE-NC and tau tangles with cognitive decline was attributable to HNL.

Result: HNL was common: mild in 61%, moderate in 16%, and severe in 20% of participants. Advanced LATE-NC stage 2/3 and tau-tangles, but not β-amyloid pathology, were associated with worse hippocampal neuronal loss. More HNL was associated with faster decline in global cognition and four cognitive domains: episodic, semantic, and working memory and perceptual speed. These associations remained robust even after excluding participants with HS. LATE-NC and tangles were also associated with cognitive decline but the association between LATE-NC and cognitive decline was lost while the association of tangles with cognitive decline was partially attenuated after adding HNL in the model. The result from path anlayses suggested that two-thirds of the association between LATE-NC and cognitive decline was attributable to HNL whereas only 5% of the association of tau tangles was through HNL.

Conclusion: Our results support that HNL and tangles are the major contributors of cognitive dysfunction. LATE-NC is also associated with cognitive decline but may causes most dysfunction via HNL.