Polygenic risk of type 2 diabetes is associated with Vascular Dementia but not with Alzheimer's Disease: a Prospective Cohort Study

Background: and Objectives Type 2 diabetes and dementia are associated, but their causal relationship is unclear. Genetic studies, i.e. using polygenic risk scores (PRS) or Mendelian Randomization (MR), and validated dementia endpoints with high diagnostic precision (instead of register-based diagnoses) may clarify causal links between these two entities. Methods We tested associations between PRS for type 2 diabetes, fasting glucose, fasting insulin and HbA 1c on the one hand and dementia on the other in 29139 adults (mean age 55) followed for 20–23 years. Dementia diagnoses were validated and included all-cause dementia, Alzheimer’s Disease (AD) and Vascular Dementia (VaD) as well as mixed dementia. We also tested causal associations between type 2 diabetes and dementia forms through 2-sample-MR analyses. Results Seven different PRSs (including SNPs with different significance thresholds) for type 2 diabetes were tested. A PRS including N = 4891 SNPs with p-value < 5e-04 showed strongest association with the different outcomes, including all-cause dementia (Hazard Ratio [HR] 1.11; Bonferroni corrected p = 3.6e-03), mixed dementia (HR 1.18; Bonferroni corrected p = 3.3e-04) and VaD cases (HR 1.28; Bonferroni corrected p = 9.6e-05). Associations were stronger for non-carriers of the AD risk gene APOE ε4. 2-sample-MR analyses could, however, not confirm a causal link between genetic risk markers of type 2 diabetes and dementia outcomes. Conclusions Polygenic risk of type 2 diabetes is associated with dementia risk, in particular VaD. Associations were strongest for non-carriers of APOE ε4. However, 2-sample-MR findings did not support a causal relationship between type 2 diabetes and VaD.