AUTHOR=Ware Erin B. , Morataya Cristina , Fu Mingzhou , Bakulski Kelly M. TITLE=Type 2 Diabetes and Cognitive Status in the Health and Retirement Study: A Mendelian Randomization Approach JOURNAL=Frontiers in Genetics VOLUME=12 YEAR=2021 URL=https://www.frontiersin.org/journals/genetics/articles/10.3389/fgene.2021.634767 DOI=10.3389/fgene.2021.634767 ISSN=1664-8021 ABSTRACT=Background

Type 2 diabetes mellitus (T2DM) and dementia are leading causes of mortality and disability in the US. T2DM has been associated with dementia; however, causality has not been clearly established. This study tested inferred causality between T2DM and dementia status using a Mendelian randomization approach.

Methods

Participants (50+ years) from the 2010 wave of the Health and Retirement Study of European or African genetic ancestry were included (n = 10,322). History of T2DM was self-reported. Cognitive status (dementia, cognitive impairment non-dementia, or normal cognition) was defined from clinically validated cognitive assessments. Cumulative genetic risk for T2DM was determined using a polygenic score calculated from a European ancestry T2DM genome-wide association study by Xue et al. (2018). All models were adjusted for age, sex, education, APOE-ε4 carrier status, and genetic principal components. Multivariable logistic regression was used to test the association between cumulative genetic risk for T2DM and cognitive status. To test inferred causality using Mendelian randomization, we used the inverse variance method.

Results

Among included participants, 20.9% had T2DM and 20.7% had dementia or cognitive impairment. Among European ancestry participants, T2DM was associated with 1.66 times odds of cognitive impairment non-dementia (95% confidence interval: 1.55–1.77) relative to normal cognition. A one standard deviation increase in cumulative genetic risk for T2DM was associated with 1.30 times higher odds of T2DM (95% confidence interval: 1.10–1.52). Cumulative genetic risk for T2DM was not associated with dementia status or cognitive-impaired non-dementia in either ancestry (P > 0.05); lack of association here is an important assumption of Mendelian randomization. Using Mendelian randomization, we did not observe evidence for an inferred causal association between T2DM and cognitive impairment (odds ratio: 1.04; 95% confidence interval: 0.90–1.21).

Discussion

Consistent with prior research, T2DM was associated with cognitive status. Prevention of T2DM and cognitive decline are both critical for public health, however, this study does not provide evidence that T2DM is causally related to impaired cognition. Additional studies in other ancestries, larger sample sizes, and longitudinal studies are needed to confirm these results.