A Diabetes Genetic Risk Score Is Associated With All-Cause Dementia and Clinically Diagnosed Vascular Dementia in the Million Veteran Program

Abstract

OBJECTIVE Diabetes and dementia are diseases of high health care burden worldwide, and studies have shown that diabetes is associated with an increased relative risk of dementia. We set out to examine whether type 2 diabetes–associated genetic variants were associated with dementia and whether they differed by race/ethnicity or clinical dementia diagnosis. RESEARCH DESIGN AND METHODS We evaluated associations of two type 2 diabetes genetic risk scores (GRS and GRS-nonAPOE: a score without rs429358, a variant associated with Alzheimer disease [AD]) with three classifications of clinical dementia diagnoses in the Million Veteran Program (MVP): all-cause dementia, vascular dementia (VaD), and AD. We conducted our analysis stratified by European (EUR), African (AFR), and Hispanic (HIS) races/ethnicities. RESULTS In EUR, we found associations of the GRS with all-cause dementia (odds ratio [OR] 1.06, P = 1.60e−07) and clinically diagnosed VaD (OR 1.12, P = 5.2e−05) but not with clinically diagnosed AD (OR 1.02, P = 0.43). The GRS was not associated with any dementia outcome in AFR or HIS. When testing with GRS-nonAPOE, we found that effect size estimates in EUR increased and P values decreased for all-cause dementia (OR 1.08, P = 2.6e−12), for VaD (OR 1.14, P = 7.2e−07), and for AD (OR 1.06, P = 0.018). For AFR, the association of GRS-nonAPOE and clinically diagnosed VaD (OR 1.15, P = 0.016) was statistically significant. There were no significant findings for HIS. CONCLUSIONS We found evidence suggesting shared genetic pathogenesis of diabetes with all-cause dementia and clinically diagnosed VaD.

Polygenic risk of type 2 diabetes is associated with incident vascular dementia: a prospective cohort study

“…Our study confirms what a number of epidemiological studies have shown previously, which is that type 2 diabetes is associated with an increased risk of dementia, in particular vascular dementia. 1 Similar to a study published very recently (in November 2022), 7 we also identify a link between PRS for type 2 diabetes and dementia (all-cause dementia and vascular dementia), which other previous studies have not been able to do. 5 , 6 One reason for this could be that we have well validated data on dementia diagnoses, while other genetic studies previously have used other ways of defining dementia or cognitive impairment (e.g.…”

“…These are very similar findings to a recent study with similar study design as ours. 7 This other study had a larger study sample size than ours, but did not analyse the dementia diagnoses longitudinally using time to event as outcome, and did not have validated dementia diagnoses. The findings in our two studies are in contrast to a meta-analysis that reported that APOE ε4 carriers are more vulnerable to diabetes-associated dementia.…”

“…Most PRS studies have so far not been able to identify an association between type 2 diabetes, or associated phenotypes such as insulin resistance, and dementia risk. 5 , 6 Two exceptions are a recent study where a PRS for type 2 diabetes was linked to vascular dementia 7 and a study on patients with major depressive disorder (but without type 2 diabetes) where there was a link between PRS for type 2 diabetes and impaired cognitive functioning. 8 A limitation of some previous studies on genetic risk markers of type 2 diabetes and dementia is that they have not used validated dementia end-points, but instead other outcomes related to dementia or cognitive decline, such as genetic risk markers of dementia, 5 cognitive test results 6 or dementia based on registered ICD diagnosis codes.…”

“… 8 A limitation of some previous studies on genetic risk markers of type 2 diabetes and dementia is that they have not used validated dementia end-points, but instead other outcomes related to dementia or cognitive decline, such as genetic risk markers of dementia, 5 cognitive test results 6 or dementia based on registered ICD diagnosis codes. 7 , 9 …”

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

“…[11–13] Our previous work in the Million Veteran Program (MVP) demonstrated that a genetic risk score (GRS) for type 2 diabetes (T2D) is associated with all-cause dementia and clinically diagnosed vascular dementia (VaD), and less strongly with clinically diagnosed AD. [14] Like prior observational studies, however, our study strictly assessed an association between T2D and all-cause, VaD, and/or AD without evaluating a causal relationship.…”