Genomics link obesity and type 2 diabetes to Alzheimer's disease to unveil novel biological insights.
Cunha C., Garcia-Ureña M., Sanz Martĺnez R., J Romero-Lado M., Fernandez MV., Andreassen OA., Sims R., Tsolaki M., Sleegers K., Hiltunen M., Nicolas G., Sanchez-Juan P., Ingelsson M., Giedraitis V., Ghidoni R., Holstege H., van Duijn C., van der Lee S., Ramirez A., Bellenguez C., Lambert J-C., Frikke-Schmidt R., EADB ., O Kilpeläinen T., J F Loos R.
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.