Education and Alzheimer Disease Genetic Risk in Associations of GLP-1 Receptor Agonists With Dementia Among Adults With Type 2 Diabetes

Objective

To evaluate whether educational attainment and Alzheimer disease genetic risk were associated with GLP-1 receptor agonist initiation and dementia incidence and whether adjustment for these measured factors materially changed the estimated association between GLP-1 receptor agonist initiation and incident dementia among adults with type 2 diabetes.

Research Design and Methods

We conducted an observational cohort study using linked electronic health record, survey, and genetic data from 14,364 All of Us Research Program participants with type 2 diabetes. We estimated associations of educational attainment and Alzheimer disease genetic risk with treatment initiation and incident dementia and compared GLP-1 receptor agonist initiators with initiators of non-sodium-glucose cotransporter 2 inhibitor second-line therapies, with a separate sodium-glucose cotransporter 2 inhibitor comparison. Models were estimated before and after additional adjustment for educational attainment, APOE ε4, and non-APOE genetic risk.

Results

Among 14,364 participants (mean age, 60.2 years; 54.2% female), the mean follow-up duration was 4.3 years. The estimated hazard ratio for dementia comparing GLP-1 receptor agonist initiation with non-SGLT2 inhibitor second-line therapy was 0.85 (95% CI 0.64-1.12) before adjustment for education or Alzheimer disease genetic risk and 0.84 (95% CI 0.64-1.12) after adjustment for educational attainment, APOE ε4, and non-APOE genetic risk.

Conclusions

Among adults with type 2 diabetes, adjustment for measured educational attainment and Alzheimer disease genetic susceptibility produced little change in the estimated association between GLP-1 receptor agonist initiation and incident dementia. These findings do not exclude confounding by these factors in other populations or residual confounding from socioeconomic, clinical, behavioral, and health-care-related factors.

Highlights

• Observational studies have reported associations between GLP-1 receptor agonist use and lower dementia risk, but important social and genetic factors are often unavailable in electronic health record data.

• We examined whether educational attainment and Alzheimer disease genetic susceptibility were associated with treatment initiation and dementia and whether adjustment for these factors changed GLP-1 receptor agonist–dementia estimates.

• Adding measured education and genetic susceptibility produced little change in the estimated conditional hazard ratios.

• These results do not exclude residual confounding and should not be interpreted as evidence that GLP-1 receptor agonists prevent dementia.