Biomarkers.

Background: Selective corticolimbic vulnerability to tau pathology in Alzheimer's disease (AD) underlies clinicopathologic heterogeneity. The goal of this presentation will be to examine spatial heterogeneity of tangle distribution on a continuum through the utility of the corticolimbic index (CLix).

Method: We will discuss the development of CLix in the Florida Autopsied Multi-Ethnic (FLAME) cohort, which sought to collapse the spatial distribution of thioflavin-S tangle counts in AD (n=1361) to assign a continuum: hippocampal sparing with cortical predominance (<10), representative/typical (≥10 to <30), and limbic predominant with cortical sparing (≥30). The relationship with atypical, non-amnestic clinical presentations will be described. Relevant clinical measures, including age at symptomatic onset and longitudinal decline on mini-mental state examination (MMSE) will be examined. Digital pathology measures of AD (tau [AT8, GT-38], amyloid-β [6F/3D]) and glial activation (astrogliosis: GFAP, activated microglia/macrophage: CD68) will be shown in hippocampus and association cortices (n=60). To further extend these findings to the antemortem space, CLix score will be examined in an independent, autopsied neuroimaging group (n=93).

Results: Lower CLix score correlated with younger age at symptomatic onset (R=0.39, p<0.001), faster MMSE decline (R=0.27, p<0.001), and associated with non-amnestic clinical presentations (median=13 vs. 21, p<0.001). Lower CLix score correlated with greater hippocampal volume on MRI (R=-0.45, p<0.001) and higher flortaucipir-PET uptake (e.g., posterior cingulate-precuneus cortex: R=-0.74, p<0.001). Advanced tangle maturity burden (GT-38) differed across all regions (p<0.001). Hippocampal sparing AD exhibited higher cortical tau pathology and reduced cortical activated microglia/macrophage.

Conclusions: Corticolimbic tangle distribution links with AD clinical features and neuroimaging changes. Reduced activated microglia/macrophage in association cortices of relative hippocampal sparing AD may contribute to higher tau burden. Corticolimbic vulnerability should be considered for personalized therapies targeting immune dysregulation.