Genomics link obesity and type 2 diabetes to Alzheimer's disease to unveil novel biological insights
Cunha, C.; Garcia-Urena, M.; Sanz Martlnez, R.; J. Romero-Lado, M.; Axisa, P.-P.; Fernandez, M. V.; Andreassen, O. A.; 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.
Show abstract
Body mass index (BMI), type 2 diabetes (T2D) and associated cardiometabolic features modify Alzheimers 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.
Matching journals
The top 6 journals account for 50% of the predicted probability mass.
Similar papers in this journal
Similar papers in this journal
- Atlas of genetic effects in human microglia transcriptome across brain regions, aging and disease pathologies 98%
- Large meta-analysis of genome-wide association studies expands knowledge of the genetic etiology of Alzheimer’s disease and highlights potential translational opportunities 98%
- Spatial and single-nucleus transcriptomic analysis of genetic and sporadic forms of Alzheimer's Disease 97%
Similar papers in this journal
Similar papers in this journal
- Mitochondrial complex III-derived ROS amplify immunometabolic changes in astrocytes and promote dementia pathology 95%
- Proteome-wide Mendelian randomization implicates nephronectin as an actionable mediator of the effect of obesity on COVID-19 severity 94%
- Interaction of sortilin with apolipoprotein E3 enables neurons to use long-chain fatty acids as alternative metabolic fuel 94%
Similar papers in this journal
- The molecular impact of cigarette smoking resembles aging across tissues 95%
- Refining epigenetic prediction of chronological and biological age 94%
- Identification and drug-induced reversion of molecular signatures of Alzheimers disease onset and progression in AppNL-G-F, AppNL-F and 3xTg-AD mouse models 94%
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.