Polygenic Risk for White Matter Hyperintensities is Associated with Early Cerebrovascular Events Partly Through Hemodynamic Measures in Cognitively Unimpaired Middle-Aged and Older Adults with Low Cardiovascular Risk

Patricia Genius^1,2,3,4*Blanca Rodríguez-Fernandez^1,2,3,5Carolina Minguillón^1,2,6Anna Brugulat-Serrat^1,2,6,7Jordi Huguet¹Manel Esteller^10,11,8,9Carole Sudre^12,13,14,15Marta Cortés-Canteli^16,17Catarina Tristão-Pereira¹⁶Inés García-Lunar^16,18Arcadi Navarro^1,19,20,3Juan Domingo Gispert^1,16,2,21Natalia Vilor-Tejedor^1,2,22,3*

• ¹Barcelonaβeta Brain Research Center (BBRC), Pasqual Maragall Foundation, C/ Wellington 30, Sant Martí, 08005, Barcelona, Spain
• ²Hospital del Mar Medical Research Institute, C/ Dr. Aiguader 88, 0800, Barcelona, Spain
• ³Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology (BIST), C/ Dr. Aiguader 88, 08003, Barcelona, Spain
• ⁴Doctoral School, PhD programme in Bioinformatics, University of Vic–Central University of Catalonia (UVic-UCC), Vic, Spain
• ⁵Autonomous University of Barcelona, Barcelona, Plaça Cívica, 08193 Bellaterra, Barcelona, Spain
• ⁶Centro de Investigación Biomédica en Red de Fragilidad y Envejecimiento Saludable (CIBERFES), Instituto de Salud Carlos III, C/ Monforte de Lemos 3-5. Pabellón 11, Planta 0, 28029, Madrid, Spain
• ⁷Global Brain Health Institute, 675 Nelson Rising Lane, Suite 190. San Francisco, CA 94158, University of California, San Francisco, United States
• ⁸Josep Carreras Leukaemia Research Institute (IJC), Ctra de Can Ruti, Camí de les Escoles, s/n, 08916, Badalona, Spain
• ⁹Institució Catalana de Recerca i Estudis Avançats (ICREA), Passeig Lluís Companys 23, 08010, Barcelona, Spain
• ¹⁰Physiological Sciences Department, School of Medicine and Health Sciences, University of Barcelona (UB), C/ Casanova 143, 08014, Barcelona, Spain
• ¹¹Centro de Investigación Biomédica en Red Cancer (CIBERONC), Av. Monforte de Lemos, 3-5, Pabellón 11, Planta 0, 28029, Madrid, Spain
• ¹²MRC Unit for Lifelong Health and Ageing, Department of Population Science and Experimental Medicine, Gower Street, University College London, London, United Kingdom
• ¹³Hawkes Institute, Department of Computer Science, Gower Street, University College London, London, United Kingdom
• ¹⁴Department of Neurodegenerative Disease, The Dementia Research Centre, UCL Queen Square Institute of Neurology, Gower Street, University College London, London, United Kingdom
• ¹⁵School of Biomedical Engineering and Imaging Sciences, King’s College London, Strand,, London, United Kingdom
• ¹⁶Centro Nacional de Investigaciones Cardiovasculares (CNIC), C./ Melchor Fernández Almagro 3, Fuencarral-El Pardo, 28029, Madrid, Spain
• ¹⁷Fuencarral-El Pardo, 28029 Madrid, Spain. Centro Internacional de Neurociencia Cajal (CINC), Consejo Superior de Investigaciones Científicas (CSIC), Av Leon 1, 28805, Alcalá de Henares, Madrid, Spain
• ¹⁸Cardiology Department, University Hospital La Moraleja, Madrid, Spain. CIBER de Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain
• ¹⁹Pompeu Fabra University, C/ de Ramon Trias Fargas 25-27, Sant Martí, 08005, Barcelona, Spain
• ²⁰Institute of Evolutionary Biology (CSIC-UPF), Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Pg. Marítim de la Barceloneta 37, Ciutat Vella, 08003, Barcelona, Spain
• ²¹Centro de Investigación Biomédica en Red Bioingeniería, Biomateriales y Nanomedicina, Instituto de Salud Carlos III, Av. Monforte de Lemos 3-5, Pabellón 11, Planta 0, 28029, Madrid, Spain
• ²²Radboud University Nijmegen Medical Center, Department of Genetics, Geert Grooteplein Zuid 10, 6525 GA, Nijmegen, Netherlands

White matter hyperintensities (WMH) are a hallmark of cerebrovascular disease. They are found in middle-aged individuals and are associated with risk of stroke and vascular dementia. Although traditional cardiovascular risk factors are linked to WMH, some individuals with low vascular risk according to conventional scales still show WMH burden, suggesting increased vulnerability. This study aimed to elucidate the biological mechanisms underlying WMH in cognitively unimpaired (CU) middle-aged and older individuals with low cardiovascular risk. We included 1,072 CU participants from the ALFA study with a low cardiovascular risk profile for late-life dementia (CAIDE-I score 9). We defined a multi-stage exploratory design to reveal potential biological pathways driving WMH. First, we estimated the genetic predisposition to WMH using polygenic scoring (PRSWMH) and used this score as a predictor of (a) WMHV as a quantitative measure of global and regional WMH burden and (b) pathological WMH levels (Fazekas score ≥ 2), to capture clinically relevant burden. Covariate-adjusted Spearman’s rank correlation tests evaluated the association between the PRSWMH and global and regional WMH volumes (WMHV), while logistic regression tested the association with pathological WMH. Second, group-stratified partial correlations (CAIDE-specific factors) identified groups with persistent genetic associations with WMH, beyond cardiovascular risk factors. Third, enrichment analysis of the PRS-annotated genes revealed the biological mechanisms underlying WMH. Finally, based on the enrichment analysis, we examined cardiometabolic traits as biomarkers of WMHV. Genetic predisposition to WMH was associated with larger WMHV after adjusting for age and sex, specifically in frontal areas. Larger WMHV was associated with poorer executive function. Group-stratified analyses showed significant correlations especially in older participants, those with hypercholesterolemia and those with lower educational attainment. Gene-set enrichment involved vascular, neuronal and cellular pathways. Blood pressure partially mediated the association between genetic risk for WMH and WMHV. These findings support a polygenic contribution to cerebrovascular burden and nominate cardiac function as a biological link along the heart-brain axis. While the PRSWMH is not yet clinically actionable, our results highlight hemodynamic monitoring as an early, testable intervention in genetically susceptible individuals, to help prevent cerebrovascular damage and cognitive impairment in healthy adults with low cardiovascular risk.