Lipid-regulatory mechanisms drive cerebrovascular disease in asymptomatic individuals at low risk for late-life dementia

Abstract Background Cerebrovascular lesions, particularly white matter hyperintensities (WMH), are often found in middle-aged individuals with a low cardiovascular risk profile. Understanding modifiable mechanisms leading to cerebrovascular disease is fundamental for implementing preventive strategies. This study aimed to elucidate the biological mechanisms underlying the presence of WMH in cognitively unimpaired (CU) middle-aged individuals. Methods We included 1,072 CU participants from the ALFA study with a low cardiovascular risk profile for late-life dementia based on the CAIDE score. We assessed genetic predisposition to WMH using polygenic scoring (PRS WMH ). Covariate-adjusted Spearman’s rank correlation tests evaluated the association between the PRS WMH and white matter hyperintensities volumes (WMHV). A logistic regression model was performed to explore the association between the PRS WMH and WMH severity, as measured with the Fazekas score. An enrichment analysis of the PRS-annotated genes unveiled the biological mechanisms leading to WMH burden. Group-specific effects were explored based on dementia-related cardiovascular risk factors. Results Genetic predisposition to WMH was associated with larger WMHV, even after controlling for confounders, but was not associated with WMH severity. Lipid-related biological processes were driving WMH genetic risk. Individuals genetically predisposed to WMH, who displayed larger WMHV, were either hypercholesterolemic, older than 55 or with lower educational attainment. Interpretation Lipid-related mechanisms contribute to WMH in individuals at low cardiovascular risk for late-life dementia. These individuals should be considered for lifestyle- and lipid-modifying therapies to prevent dementia later in life. Funding “La Caixa” Foundation, the TriBEKa Imaging Platform, the Universities and Research Secretariat of the Catalan Government, the Spanish Research Agency.