Alzheimer’s pathology mediates arteriolosclerosis and cerebral amyloid angiopathy associations with cognition

Abstract Vascular and neurodegenerative pathologies frequently co-occur in aging brains, yet the mechanisms linking vascular neuropathologies to cognitive impairment remain incompletely understood. We examined whether Alzheimer’s disease neuropathologic change (ADNC) and Lewy body disease (LBD) mediate or modify associations between vascular neuropathologies and domain-specific cognitive performance. The analytic sample included 1,269 decedents (mean age at death, 84.3 ± 9.1 years; 43.3% female; 94.7% White). At the last evaluation prior to death, 22.5% were cognitively normal, 2.4% were impaired but not mild cognitive impairment (MCI), 14.9% had MCI, and 60.2% had dementia. Vascular neuropathologies included arteriolosclerosis, atherosclerosis of the circle of Willis, cerebral amyloid angiopathy (CAA), gross infarcts/lacunes, and microinfarcts. Multivariable linear regression models evaluated associations with harmonized memory, executive function, and language z-scores adjusting for age at death, sex, education, and apolipoprotein E ε4 status. Effect modification by ADNC and LBD was tested. Mediation models estimated indirect and direct effects of vascular neuropathologies on cognition through ADNC or LBD using 5,000 bootstrap samples. Greater arteriolosclerosis severity was associated with worse memory (β=−0.16, 95% CI −0.23 to −0.09), executive function (β=−0.18, 95% CI −0.24 to −0.11), and language (β=−0.18, 95% CI −0.24 to −0.12; all p<0.001). CAA was strongly associated with poorer cognition across domains, including memory (β=−0.26, 95% CI −0.33 to −0.19; p<0.001). Atherosclerosis and infarcts showed more limited associations, while microinfarcts were not significantly associated with cognition. Mediation analyses indicated that ADNC statistically accounted for approximately 13–29% of the associations between arteriolosclerosis and cognition across domains and 64–91% of the associations between CAA and cognition. Direct effects of arteriolosclerosis remained significant, whereas CAA effects were largely explained by ADNC. Effect modification by ADNC and LBD was limited, although LBD attenuated associations of arteriolosclerosis and CAA with executive function. Mediation through LBD was not observed. This novel evidence shows that vascular neuropathologies influence cognition through defined pathways with statistically significant patterns of associations. In this autopsy-confirmed cohort, vascular neuropathologies showed different patterns of association with domain-specific cognitive performance and ADNC. A larger proportion of the association involving CAA was statistically accounted for by ADNC, whereas direct associations remained more apparent for arteriolosclerosis. This study clarifies how vascular and neurodegenerative processes interact to shape cognitive impact and inform mechanistic preventions.