New Genetic Associations Between Alzheimer's Disease and Its Key Risk Factors

Introduction This study aimed to explore shared genetic architectures underlying Alzheimer's disease (AD) and its known risk factors. Methods Significant common variants between AD and its risk factors were identified using GWAS data. The 1000 Genomes Project genotyping data enabled the detection of linkage disequilibrium (LD) blocks and haplotype structures. Functional impact assessments, protein–protein interaction analyses, pathway mapping and enrichment studies were performed. Results Sixteen significant variants across nine genes were associated with AD and at least one risk factor ( p ≤ 5 × 10 −8 ). Genes APOE, ABCA1 and TOMM40 showed strong associations with AD (adjusted p = 9.75 × 10 −9 ). High‐confidence interactions were identified among these genes, as well as APP and LRP1, within the AD pathway. Variant rs429358 ( p ≤ 3 × 10 −15 ) on the APOE gene was linked to AD, metabolic syndrome (MetS), diabetes, waist‐to‐hip ratio (WHR) and ageing. Variant rs2075650 ( p ≤ 6 × 10 −9 ) on TOMM40 correlated AD risk with MetS, WHR and body mass index (BMI). Variants rs483082 ( p ≤ 2 × 10 −32 ) and rs71352238 ( p ≤ 1 × 10 −11 ) on APOC1 and TOMM40 were associated with AD and MetS. Variants rs4420638 ( p ≤ 2 × 10 −34 ) and rs1800978 ( p ≤ 2 × 10 −9 ) on APOC1 and ABCA genes were associated with AD and WHR. The rs13237518 ( p ≤ 5 × 10 −11 ) was associated with AD risk in diabetic patients. Furthermore, the rs4277405 ( p ≤ 9 × 10 −20 ) associated AD with cardiovascular disease (CVD). Haplotypic structures were also identified for all these variants ( D ′ and r 2 ≥ 0.8). Discussion This study identifies genetic variants and LD blocks on APOE, ABCA1, TOMM40 and APOC1 genes shared between AD and its risk factors, revealing common genetic links and potential shared susceptibility pathways.