Genomics link obesity and type 2 diabetes to Alzheimer’s disease to unveil novel biological insights

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.

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Publication Details

Journal
medRxiv
Published
2026-02-12
DOI
https://doi.org/10.64898/2026.02.10.26344393
Primary Topic
Genetic Associations and Epidemiology
Type
article
Field-Weighted Citation Impact
0.00
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article

Genomics link obesity and type 2 diabetes to Alzheimer’s disease to unveil novel biological insights

Sarah A. Pendergrass, Sven J. van der Lee, César Cunha, EADB et al.
medRxiv
Genetic Associations and Epidemiology
article

Genomics link obesity and type 2 diabetes to Alzheimer’s disease to unveil novel biological insights

Sarah A. Pendergrass, Sven J. van der Lee, César Cunha, EADB, Raquel Sanz Martĺnez, Maria J. Romero-Lado, Mario Garcia-Ureña, Ruth Frikke-Schmidt, Cornelia van Duijn
article en

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.

medRxiv
Uppsala University (SE), University of Copenhagen (DK), Oslo University Hospital (NO), University Health Network (CA), University of Antwerp (BE), Inserm (FR), University of Eastern Finland (FI), University of Cologne (DE), University of Oslo (NO), University of Toronto (CA), Aristotle University of Thessaloniki (GR), Université de Lille (FR), University Hospital Bonn (DE), Institut Pasteur de Lille (FR), Novo Nordisk Foundation (DK), Instituto de Salud Carlos III (ES), German Center for Neurodegenerative Diseases (DE), Erasmus MC (NL), Copenhagen University Hospital (DK), Rigshospitalet (DK), Centre Hospitalier Universitaire de Lille (FR), Universitat Internacional de Catalunya (ES), University of Oxford (GB), Biomedical Research Networking Center on Neurodegenerative Diseases (ES), Normandie Université (FR), Amsterdam Neuroscience (NL), Institute for Neurodegenerative Disorders (US), Centro San Giovanni di Dio Fatebenefratelli (IT), VIB-UAntwerp Center for Molecular Neurology (BE), Amsterdam University Medical Centers (NL), University Hospital Cologne (DE), Fundacion Centro De Investigacion De Enfermedades Neurologicas (ES), VIB-KU Leuven Center for Brain & Disease Research (BE), Ontario Brain Institute (CA), Université de Rouen Normandie (FR), Cardiff University (GB), Vrije Universiteit Amsterdam (NL), Erasmus University Rotterdam (NL)
Good health and well-being
Openalex Percentile: Top 56%
Genetic Associations and Epidemiology
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