Machine learning-based digital pathology demonstrates that APOE ε4 both promotes proteinopathy accumulation and modifies the pathological threshold for dementia onset.
The Subtype and Stage Inference (SuStaIn) algorithm identifies four distinct trajectories of Lewy pathology progression: brainstem-first, early amygdala, early cingulate, and neocortical-first.
Biological sex and APOE status interact to determine vulnerability; APOE ε3 carriers exhibit increased dementia risk from vascular factors and orthostatic hypotension when proteinopathy burden is low.
Spatial transcriptomics and proteomics reveal layer-specific neuronal vulnerability (Layer 5) and a conserved pro-inflammatory immune signature associated with the APOE ε4 allele.
