Mendelian randomization study of diabetes and dementia in the Million Veteran Program

Alzheimers Dement. 2023 Oct;19(10):4367-4376. doi: 10.1002/alz.13373. Epub 2023 Jul 7.

Abstract

Introduction: Diabetes and dementia are diseases of high health-care burden worldwide. Individuals with diabetes have 1.4 to 2.2 times higher risk of dementia. Our objective was to evaluate evidence of causality between these two common diseases.

Methods: We conducted a one-sample Mendelian randomization (MR) analysis in the US Department of Veterans Affairs Million Veteran program. The study included 334,672 participants ≥65 years of age with type 2 diabetes and dementia case-control status and genotype data.

Results: For each standard deviation increase in genetically predicted diabetes, we found increased odds of three dementia diagnoses in non-Hispanic White participants (all-cause: odds ratio [OR] = 1.07 [1.05-1.08], P = 3.40E-18; vascular: OR = 1.11 [1.07-1.15], P = 3.63E-09, Alzheimer's disease [AD]: OR = 1.06 [1.02-1.09], P = 6.84E-04) and non-Hispanic Black participants (all-cause: OR = 1.06 [1.02-1.10], P = 3.66E-03, vascular: OR = 1.11 [1.04-1.19], P = 2.20E-03, AD: OR = 1.12 [1.02-1.23], P = 1.60E-02) but not in Hispanic participants (all P > 0.05).

Discussion: We found evidence of causality between diabetes and dementia using a one-sample MR study, with access to individual level data, overcoming limitations of prior studies using two-sample MR techniques.

Keywords: Alzheimer's disease; Mendelian randomization; all-cause dementia; genetics; instrumental variable; type 2 diabetes; vascular dementia.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Aged
  • Alzheimer Disease* / epidemiology
  • Alzheimer Disease* / genetics
  • Diabetes Mellitus, Type 2* / epidemiology
  • Diabetes Mellitus, Type 2* / genetics
  • Genome-Wide Association Study
  • Humans
  • Mendelian Randomization Analysis
  • Polymorphism, Single Nucleotide
  • Risk Factors
  • Veterans*