Genomics link obesity and type 2 diabetes to Alzheimer’s disease to unveil novel biological insights
Year: 2026
Type: preprint
Study design: Observational Study
Abstract: Body mass index (BMI), type 2 diabetes (T2D) and associated cardiometabolic features modify Alzheimer's disease (AD) risk, yet shared mechanisms remain poorly understood. Using sex- and age-stratified genotyping data for BMI and T2D, we investigate how these traits converge on shared genetic pathways to AD risk. Employing multi-trait, machine learning and single-cell transcriptomics, we identify sex-specific cardiometabolic liability linked to higher BMI-associated risk in women and T2D-driven risk in men. Variant-level analyses reveal AD risk associates with genetically-driven hypotension and hypoglycaemia. We identify 35 putative effector genes in seven independent loci colocalizing between BMI/T2D and AD, mapping to peripheral immune and metabolic tissues and cell-types. Pathway enrichment identifies druggable targets in calcium and potassium channel signaling. Across 81 approved drugs modulating shared risk genes, levosimendan - a calcium sensitizer for heart failure - inhibits tau oligomerization and emerges as a repurposing candidate. These findings elucidate sex-specific cardiometabolic drivers of AD, identify actionable biological pathways, and reveal drug candidates for AD prevention and treatment.
Source: medRxiv
Authors: César Cunha, Mario Garcia-Ureña, Raquel Martínez, María José Romero-Lado, Maria Victoria Fernandez, Ole A. Andreassen, Rebecca Sims, Magda Tsolaki, Kristel Sleegers, Mikko Hiltunen, Gaël Nicolas, Pascual Sánchez-Juan, Martin Ingelsson, Vilmantas Giedraitis, Roberta Ghidoni, Henne Holstege, Cornelia van Duijn, Sven van der Lee, Alfredo Ramirez, Céline Bellenguez, Jean-Charles Lambert, Ruth Frikke-Schmidt, EADB, Tuomas O. Kilpeläinen, Ruth J.F. Loos
Institutions: University of Copenhagen, Novo Nordisk Foundation Center for Basic Metabolic Research, Universitat Internacional de Catalunya, Oslo University Hospital, University of Oslo, Cardiff University, Aristotle University of Thessaloniki, University of Antwerp, VIB-UAntwerp Center for Molecular Neurology, University of Eastern Finland, Inserm, Université de Rouen Normandie, Instituto de Salud Carlos III, Biomedical Research Networking Center on Neurodegenerative Diseases, Fundacion Centro De Investigacion De Enfermedades Neurologicas, Uppsala University, University Health Network, University of Toronto, Krembil Brain Institute, Centro San Giovanni di Dio Fatebenefratelli, Amsterdam Neuroscience, VIB-KU Leuven Center for Brain & Disease Research, Vrije Universiteit Amsterdam, Amsterdam UMC Location Vrije Universiteit Amsterdam, KU Leuven, Erasmus MC, University of Oxford, University of Cologne, University Hospital Bonn, German Center for Neurodegenerative Diseases, Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases, University Hospital Cologne, Université de Lille, Institut Pasteur de Lille, Centre Hospitalier Universitaire de Lille, Copenhagen University Hospital, Rigshospitalet
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Awards: G2226480889, G2394265885, G3181893965, G4230908485, A Multi-Ancestry Study of Gene-Lifestyle Interactions and Multi-Omics in Cardiometabolic Traits, G4504918650, G4772171027, G9000008373, G9000053822, G9000142985, G9000158271, Biological Insights from Genetic Investigation of ANthropometric Traits (GIANT) Across the Allelic Spectrum
OpenAlex ID: W7128674584