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

Litkowski EM, Logue MW, Zhang R, Charest BR, Lange EM, Hokanson JE, Lynch JA, Vujkovic M, Phillips LS, Hauger RL, Lange LA, Raghavan S, VA Million Veteran Program (MVP). Mendelian randomization study of diabetes and dementia in the Million Veteran Program. Alzheimer's & dementia : the journal of the Alzheimer's Association. 2023 Oct 1; 19(10):4367-4376.

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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.




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