Amyloid-linked versus age-driven copathologies in Alzheimer’s dementia: differential associations with APOE ε4

The mechanisms by which apolipoprotein E ( APOE ) drives copathologies in established Alzheimer’s disease (AD) dementia via amyloid-dependent versus age-driven pathways remain unresolved. Analyzing data from 11,897 autopsied individuals from the National Alzheimer's Coordinating Center, with copathology analyses restricted to amyloid-positive AD dementia, we show that APOE effects followed two distinct trajectories. Cerebral amyloid angiopathy exhibited a striking ε4 dose-response (OR = 5.76, 95% CI: 4.20–7.96, p < 0.001; for ε4/ε4 compared to ε3/ε3), whereas arteriolosclerosis and atherosclerosis risk increased with age, independent of APOE haplotype. Lewy body pathology showed modest APOE associations restricted to limbic/amygdalar-predominant forms and was related to dementia duration, suggesting AD-mediated secondary synucleinopathy. TDP-43 pathology was associated with chronological age, demonstrating regional progression with minimal APOE dependence. These findings suggests that in amyloid-positive AD dementia, APOE ε4 selectively amplifies amyloid-related pathology, particularly cerebral amyloid angiopathy, while other copathologies accumulate through age-driven, APOE haplotype-independent processes.