Genomics link obesity and type 2 diabetes to Alzheimers disease to unveil novel biological insights

César Cunha; Mario García‐Ureña; Raquel Martínez; María J Romero-Lado; María Victoria Fernández; Ole A. Andreassen; Rebecca Sims; Magda Tsolaki; Kristel Sleegers; Mikko O. Hiltunen; Gaël Nicolas; Pascual Sánchez-Juan; Martin Ingelsson; Vilmantas Giedraitis; Roberta Ghidoni; Henne H. Holstege; Cornelia M. van Duijn; Sven J. van der Lee; Alfredo Ramı́rez; Céline Bellenguez; Jean‐Charles Lambert; Ruth Frikke‐Schmidt; EADB (Alzheimer Disease European DNA biobank); Tuomas O. Kilpeläinen; Ruth J. F. Loos

doi:10.64898/2026.02.10.26344393

Genetic & Genomic MedicinemedRxivAug 17, 2026

Preprint

Genomics link obesity and type 2 diabetes to Alzheimers disease to unveil novel biological insights

César Cunha iD, Mario García‐Ureña iD, Raquel Martínez iD, María J Romero-Lado iD, María Victoria Fernández iD, Ole A. Andreassen iD, Rebecca Sims iD, Magda Tsolaki iD, Kristel Sleegers iD, Mikko O. Hiltunen iD, Gaël Nicolas iD, Pascual Sánchez-Juan, Martin Ingelsson iD, Vilmantas Giedraitis iD, Roberta Ghidoni iD, Henne H. Holstege iD, Cornelia M. van Duijn iD, Sven J. van der Lee iD, Alfredo Ramı́rez iD, Céline Bellenguez iD, Jean‐Charles Lambert iD, Ruth Frikke‐Schmidt iD, EADB (Alzheimer Disease European DNA biobank), Tuomas O. Kilpeläinen iD, Ruth J. F. Loos iD

Abstract

Body mass index (BMI), type 2 diabetes (T2D) and related cardiometabolic features associate with Alzheimers disease (AD) risk, yet shared mechanisms remain poorly understood. By combining multi-trait, machine learning and single-cell transcriptomics with genotyping data for BMI and T2D, we investigate how these traits converge on shared genetic pathways to AD risk. Variant-level analyses reveal AD risk associates with genetically-driven hypotension and hypoglycaemia. We identify sixteen high-confidence effector genes in seven independent loci colocalizing between BMI/T2D and AD, mapping primarily to peripheral immune-metabolic tissues and cell-types. Eight high-confidence risk genes are currently targeted by ongoing therapeutic programmes, substantiating translatability relevance. Exploratory approaches using sex- and age-stratified genotyping data for BMI and T2D pinpoints potential sex-specific cardiometabolic liability linked to higher BMI-associated risk in women and T2D-driven risk in men. These findings elucidate shared cardiometabolic correlates with AD, prioritizes biological pathways, and reveal computationally-nominated drug candidates for preclinical testing.

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