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

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 (PRSWMH). Covariate-adjusted Spearman’s rank correlation tests evaluated the association between the PRSWMH and white matter hyperintensities volumes (WMHV). A logistic regression model was performed to explore the association between the PRSWMH 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. ### Competing Interest Statement Juan Domingo Gispert has served as a consultant for Roche Diagnostics and Prothena Biosciences; he has given lectures at symposiums sponsored by General Electric, Philips, Esteve, Life-MI and Biogen; he received research support from GE Healthcare, Roche Diagnostics, and Hoffmann-La Roche; and he is currently full-time employee in AstraZeneca. ### Clinical Trial NCT02485730 ### Funding Statement 'La Caixa' Foundation, the TriBEKa Imaging Platform, the Universities and Research Secretariat of the Catalan Government, the Spanish Research Agency. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethics committee of 'Parc de Salut Mar' Barcelona gave ethical approval for the Alzheimer's and Families study. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors. * AD : Alzheimer’s disease ALFA : ALzheimer’s and Families APOE : Apolipoprotein E BMI : Body mass index CAC : Coronary artery calcification CAIDE : Cardiovascular Risk Factors, Aging, and Incidence of Dementia CEPT : Cholesteryl Ester Transfer Protein CHD : Coronary heart disease CU : Cognitively unimpaired CVD : Cardiovascular Disease CVRF : Cardiovascular Risk Factors DNA : Deoxyribonucleic acid DBP : Diastolic blood pressure GWAS : Genome-wide association studies LDL : Low-density lipoprotein MRI : Magnetic resonance imaging PRS : Polygenic risk score SBP : Systolic blood pressure SNP : Single nucleotide polymorphism TIV : Total intracranial volume WMH : White matter hyperintensities WMHV : White matter hyperintensities volumes