Background: Insulin resistance (IR) is a major risk factor for Alzheimer’s disease (AD) and is primarily driven by obesity, another AD risk factor. The biological mechanism by which IR predisposes to AD is unknown. Genetic clustering analyses of type 2 diabetes (T2D) loci can help characterize which mechanism of impaired insulin action may be involved in AD and related traits.
Method: We constructed five genetic clusters related to IR (Obesity, Lipodystrophy, Liver/Lipid, ALP [alkaline phosphatase] negative, and Hyper-Insulin Secretion) based on a recent clustering analysis of T2D loci (PMID: 36538063). We evaluated the association of each cluster with the Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) and neurological traits (AD, dementia, general cognitive function, and four brain MRI volumes) in >38k participants (36% men, mean age 55yrs (14.5)) with diverse race or ethnicity, from the Trans-Omics for Precision Medicine (TOPMed) Program. We conducted both pooled and race/ethnicity-stratified association analyses (European-50%, African-American-22.5%, and Hispanic/Latino-21%). We used logistic or linear mixed-effect models, adjusted for age, sex, study, and the first 11 genetic principal components. We accounted for relatedness and allowed for heterogeneous variances across studies.
Result: We confirmed the association of each IR genetic cluster with HOMA-IR in the pooled analysis (2.6E-66≤P≤2E-4) as well as in group-stratified analyses (6.3E-39≤P≤0.05), except for the Hyper-Insulin Secretion cluster in African-Americans (P=0.30). The genetic clusters were not significantly associated with neurological outcomes after adjusting for multiple testing (P=0.05/Ngroups/Nclusters/Noutcomes=0.05/4/5/7=3.6×10-4). We observed nominal associations (P<0.05) for two genetic clusters. The Lipodystrophy cluster was negatively associated with intracranial volume in the pooled analysis (beta=-0.51, P=0.003) as well as in European (beta=-0.47, P=0.02) and Hispanic/Latino (beta=-1.23, P=0.01) participants. The Hyper-Insulin Secretion cluster was negatively associated with hippocampal volume in Hispanic/Latino participants (beta=-0.005, P=0.03), and positively associated with AD and dementia (OR=1.02 [1.001-1.038], P=0.03) in European participants.
Conclusion: Our findings are consistent with the literature suggesting that IR may be associated with lower brain volumes and increased AD risk. Our analyses shed light on two biological mechanisms of impaired insulin action potentially involved in AD and related traits, with genetic associations that may differ by race or ethnicity.
Funding: R00AG066849