Vascular contribution to the preclinical Alzheimer’s disease pathological changes: Insights from the EPAD cohort

Abstract

AbstractBackgroundThe role of cardiovascular risk factors and cerebral small vessel disease (CSVD) on the sequences of Alzheimer’s Disease (AD) pathological events remains to be determined.MethodWe included 1592 non‐demented participants from EPAD‐LCS (Table‐1). Linear models were used to study associations between the Framingham score (FRS) and CSF‐Aβ1‐42; CSVD indices (visual assessment for perivascular spaces [PVS] in the basal ganglia [BG] and centrum‐semiovale [CS], periventricular and deep white matter hyperintensities [WMHs], presence of lobar or deep cerebral microbleeds [CMBs], and lacunes, and quantification of global and lobar WMH volumes) and Aβ1‐42 and p‐Tau181, including an interaction between CSVD indices and Aβ1‐42 for the latter. Hippocampal volumes (HCV) were quantified using LEAP. Structural equation models (SEM) were used to assess the association between clinical variables as described in Figure‐1. Models were corrected for age, sex, site and multiple comparisons.ResultHigher FRS scores were associated with lower CSF Aβ1‐42 (β = ‐0.18; p<0.001) and higher P‐tau181 (β = 0.21; p<0.001). Aβ1‐42 was negatively associated with all CSVD markers (all p<0.001; Figure‐2).We found stronger association between Aβ1‐42 and P‐tau181 in participants with higher Fazekas deep and periventricular (p‐interaction<0.005) scores, and higher regional WMH (all p‐interactions<0.005) volumes.Using SEM, the CSVD‐burden latent factor fully mediated the association between FRS and Aβ1‐42 (indirect effect: β = ‐0.03; p<0.001). Aβ1‐42 did not significantly predict the CSVD‐burden latent factor. We observed a significant direct effect of Aβ1‐42 on P‐tau181 levels (β = ‐0.14; p<0.001) and HCV (β = 0.06; p<0.05), and of P‐tau181 levels onto HCV (β = ‐0.05; p<0.05). A significant indirect, but not direct, effect of the latent factor on both P‐tau181 (indirect effect: β = 0.36; p < 0.05) and HCV (indirect effect: β = ‐0.24; p < 0.05) through Aβ1‐42 was observed.ConclusionExpression of cerebrovascular pathology fully mediates the effects of vascular risk factors on amyloid and accelerates manifestation of downstream biomarkers in the preclinical phases of AD, stressing the importance of vascular‐protective treatments.