Neuropathological and vascular determinants of cerebral amyloid angiopathy risk: evidence from the NACC cohort

Cerebral amyloid angiopathy (CAA) is strongly associated with Alzheimer’s disease neuropathologic changes (ADNC), but its links with other brain pathologies remain unclear. We conducted a clinicopathological study of 3,267 participants from the National Alzheimer’s Coordinating Center (NACC) cohort. Neuropathological evaluations included potential risk factors for CAA, such as ADNC, Lewy body pathology (LBP), frontotemporal lobar degeneration (FTLD), and other neuropathologies. We found that ADNC and LBP were associated with increased odds of CAA, with the risk increasing according to ADNC severity and in cases of limbic/amygdala-predominant LBP. In contrast, FTLD, particularly the FTLD-TDP subtype, was inversely associated with CAA. Among other neuropathologies, CAA was positively associated with microinfarcts, arteriolosclerosis, white matter rarefaction, and hippocampus/cortical atrophy, but inversely associated with lobar atrophy and higher brain weight. In addition, APOE ε4 carriers with mixed ADNC, LBP, and FTLD exhibited the highest risk. Stronger associations between ADNC and CAA were observed in participants aged < 80 years and in males, whereas females demonstrated greater vulnerability to vascular- and atrophy-related correlates. Several neuropathology–CAA associations were also more pronounced among APOE ε4 carriers. These findings highlight the interplay of neurodegenerative, vascular, sex, and APOE ε4 in CAA susceptibility, with implications for risk stratification.