American Diabetes Association
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A diabetes genetic risk score is associated with all cause dementia and clinically diagnosed vascular dementia in the Million Veteran Program

posted on 2022-08-30, 18:18 authored by Elizabeth M Litkowski, Mark W. Logue, Rui Zhang, Brian R Charest, Ethan M. Lange, John E. Hokanson, Julie A. Lynch, Marijana Vujkovic, Lawrence S Phillips, Leslie A. Lange, Richard L. Hauger, Sridharan Raghavan, the VA Million Veteran Program (MVP)


Objective: Diabetes and dementia are diseases of high healthcare burden worldwide, and studies have shown that diabetes is associated with increased relative risk of dementia. We set out to examine whether type 2 diabetes-associated genetic variants were associated with dementia and if they differed by race/ethnicity or clinical dementia diagnosis.

Research Design and Methods: We evaluated associations of two type 2 diabetes genetic risk scores (GRS and GRS-NonAPOE: a score without rs429358, a variant associated with Alzheimer’s disease [AD]) with three classifications of clinical dementia diagnoses in the Million Veteran Program (MVP): all-cause-dementia, vascular dementia (VaD), and AD. We conducted our analysis stratified by European (EUR), African (AFR), and Hispanic (HIS) race/ethnicities. Results: In EUR, we found associations of the GRS with all-cause-dementia (OR = 1.06, P = 1.60e-07), and clinically diagnosed VaD (OR = 1.12, P = 5.2e-05) but not clinically diagnosed AD (OR = 1.02, P = .43). The GRS was not associated with any dementia outcome in AFR or HIS. When testing with GRS-NonAPOE, we found that effect size estimates in EUR increased and P values decreased (for all-cause-dementia OR = 1.08, P = 2.6e-12; for VaD OR = 1.14, P = 7.2e-07and for AD OR = 1.06, P = .018). For AFR, the association of GRS-NonAPOE and clinically diagnosed VaD (OR = 1.15, P = .016) was statistically significant.  There were no significant findings for HIS. Conclusions: We found evidence suggesting shared genetic pathogenesis of diabetes with all-cause-dementia and clinically diagnosed VaD. 


EML is supported by US National Institutes of Health award P30DK116073, and by funds from the Boettcher Foundation’s Webb-Waring Biomedical Research Program. Phenotype development in MVP was supported by US Department of Veterans Affairs award BLR&D 1 I01BX004192 (MWL PI). LSP is supported in part by VA awards CSP #2008, I01 CX001899, I01 CX001737, and I01 BX005831; NIH awards R01 DK127083, R03 AI133172, R21 AI156161, U01 DK098246, UL1 TR002378; and a Cystic Fibrosis Foundation award PHILLI12A0. RLH is supported by the Million Veteran Program MVP022 award # I01 CX001727, VISN-22 VA Center of Excellence for Stress and Mental Health (CESAMH), and National Institute of Aging RO1 grants AG050595 (The VETSA Longitudinal Twin Study of Cognition and Aging VETSA 4), AG05064 (Effects of Androgen Deprivation Therapy on Preclinical Symptoms of Alzheimer’s Disease), and AG065385 (Novel Antagonists of the N-terminal Domain of the CRF Receptor Type 1 for Alzheimer’s Disease). SR is supported by US Department of Veterans Affairs award IK2-CX001907, by US National Institutes of Health award P30DK116073, and by funds from the Boettcher Foundation’s Webb-Waring Biomedical Research Program. This research is based on data from the Million Veteran Program, Office of Research and Development, Veterans Health Administration, and was supported by awards MVP003, MVP009, MVP015, and MVP022. This publication does not represent the views of the Department of Veteran Affairs or the United States Government.