TY - JOUR

T1 - Type-2 diabetes and risk of dementia

T2 - observational and Mendelian randomisation studies in 1 million individuals

AU - Thomassen, Jesper Qvist

AU - Tolstrup, Janne Schurmann

AU - Benn, Marianne

AU - Frikke-Schmidt, Ruth

PY - 2020

Y1 - 2020

N2 - AimsIn observational studies, type-2 diabetes is associated with increased risk of dementia; however, the causal nature of this association remains unanswered. In an unselected nationwide study of all Danes, we wanted to test whether type-2 diabetes is associated with dementia subtypes, and to test whether potential associations are of a causal nature.MethodsIn the current study of nationwide observational registry data in all Danes above the age of 65 years (n = 784 434) combined with genetic consortia data on 213 370 individuals, we investigated the associations between type-2 diabetes and Alzheimer's disease, vascular dementia, unspecified dementia and all-cause dementia, and whether observational associations were of a causal nature by applying a two-sample Mendelian randomisation strategy. We addressed key biases inherent in Mendelian randomisation approaches.ResultsImportant confounders (age, ethnicity, size of community, region, civil status and education level) were captured on all 784 434 individuals and adjusted for in the models. Multifactorial adjusted hazard ratios were 1.13 (1.06-1.21) for Alzheimer's disease, 1.98 (1.83-2.14) for vascular dementia, 1.53 (1.48-1.59) for unspecified dementia and 1.48 (1.44-1.53) for all-cause dementia in persons with type-2 diabetes v. without. Results were similar for men and women. The two-sample Mendelian randomisation estimate for the association between the genetic instrument and Alzheimer's disease was 1.04 (0.98-1.10), consistent with sensitivity estimates, addressing pleiotropy, measurement bias and weak instrument bias.ConclusionsIn a nationwide study of all Danes above the age of 65 years, we show that type-2 diabetes is associated with major subtypes of dementia - with particularly strong associations for vascular dementia and unspecified dementia - the two types of dementia with the most obvious vascular pathologies. Although the present two-sample Mendelian randomisation approach using genetic consortia data suggests that type-2 diabetes is not a direct cause of Alzheimer's disease, we were unable to test the causal nature of type-2 diabetes for vascular dementia and unspecified dementia, because no publicly available genetic consortia data yet exist for these dementia endpoints. The causal nature of type-2 diabetes for dementia with vascular pathologies is pivotal questions to solve for future public health recommendations and therapeutic advice.

AB - AimsIn observational studies, type-2 diabetes is associated with increased risk of dementia; however, the causal nature of this association remains unanswered. In an unselected nationwide study of all Danes, we wanted to test whether type-2 diabetes is associated with dementia subtypes, and to test whether potential associations are of a causal nature.MethodsIn the current study of nationwide observational registry data in all Danes above the age of 65 years (n = 784 434) combined with genetic consortia data on 213 370 individuals, we investigated the associations between type-2 diabetes and Alzheimer's disease, vascular dementia, unspecified dementia and all-cause dementia, and whether observational associations were of a causal nature by applying a two-sample Mendelian randomisation strategy. We addressed key biases inherent in Mendelian randomisation approaches.ResultsImportant confounders (age, ethnicity, size of community, region, civil status and education level) were captured on all 784 434 individuals and adjusted for in the models. Multifactorial adjusted hazard ratios were 1.13 (1.06-1.21) for Alzheimer's disease, 1.98 (1.83-2.14) for vascular dementia, 1.53 (1.48-1.59) for unspecified dementia and 1.48 (1.44-1.53) for all-cause dementia in persons with type-2 diabetes v. without. Results were similar for men and women. The two-sample Mendelian randomisation estimate for the association between the genetic instrument and Alzheimer's disease was 1.04 (0.98-1.10), consistent with sensitivity estimates, addressing pleiotropy, measurement bias and weak instrument bias.ConclusionsIn a nationwide study of all Danes above the age of 65 years, we show that type-2 diabetes is associated with major subtypes of dementia - with particularly strong associations for vascular dementia and unspecified dementia - the two types of dementia with the most obvious vascular pathologies. Although the present two-sample Mendelian randomisation approach using genetic consortia data suggests that type-2 diabetes is not a direct cause of Alzheimer's disease, we were unable to test the causal nature of type-2 diabetes for vascular dementia and unspecified dementia, because no publicly available genetic consortia data yet exist for these dementia endpoints. The causal nature of type-2 diabetes for dementia with vascular pathologies is pivotal questions to solve for future public health recommendations and therapeutic advice.

KW - Alzheimer's disease

KW - dementia

KW - Mendelian randomisation

KW - type-2 diabetes

KW - unspecified dementia

KW - vascular dementia

U2 - 10.1017/S2045796020000347

DO - 10.1017/S2045796020000347

M3 - Journal article

C2 - 32326995

AN - SCOPUS:85084030199

VL - 29

JO - Epidemiology and Psychiatric Sciences

JF - Epidemiology and Psychiatric Sciences

SN - 2045-7960

M1 - e118

ER -