Clinical and pathologic correlations of machine learning quantification of Aβ deposits across 3 brain regions of decedents with Alzheimer disease

Machine learning enables scalable quantification of neuropathology, offering deeper phenotyping of Alzheimer's disease (AD). In this validation study, we quantified amyloid-beta (Aβ) deposits, evaluating multiple brain regions across institutions, and evaluated associations with clinical, demographic, and genetic factors in persons pathologically diagnosed with AD. All linear models were adjusted for sex, age of death, ethnicity, and center. We analyzed densities (#/mm2) of cored plaques, diffuse plaques, and cerebral amyloid angiopathy (CAA) in 273 individuals from 3 Alzheimer's Disease Research Centers. Formalin-fixed paraffin-embedded sections of frontal, temporal, and parietal cortices were immunostained and digitized, generating 799 whole-slide images (WSIs). Following log transformation, mixed-effects modeling revealed the parietal cortex had the highest cored plaque densities (P < .001); the temporal cortex had the highest diffuse plaque (P < .001); CAA showed no regional differences. Wilcoxon rank-sum test, and covariates adjusted linear models showed ApoE ε4- status was associated with higher cored plaque densities in the temporal lobe (P = .04). ApoE ε4+ status was associated with diffuse plaques in the temporal lobe (P = .001), and CAA in the frontal lobe (P = .004). These findings provide further validation and provide exploratory associations advancing deeper phenotyping of AD.