Evaluating the Causal Effects of Gestational Diabetes Mellitus, Heart Disease, and High Body Mass Index on Maternal Alzheimer’s Disease and Dementia: Multivariable Mendelian Randomization

Abstract

Introduction: Gestational diabetes mellitus (GDM), heart disease (HD) and high body mass index (BMI) are strongly related to Alzheimer’s disease (AD) dementia in pregnant women. Therefore, we aimed to determine the total effects of GDM, heart disease, and high BMI on maternal AD dementia.Methods: We used data from the genome-wide association studies of European populations including more than 30,000 participants. We performed two-sample Mendelian randomization (MR) and multivariable MR (MVMR) to systematically estimate the direct effects of GDM, HD, and high BMI on maternal AD and dementia. Multiple sensitivity analyses involving classical MR approaches and expanded MR-pleiotropy residual sum and outlier analysis.Results: In two-sample MR analysis, the inverse-variance weighted method in our study demonstrated no significant causality between GDM and maternal dementia (β = −0.006 ± 0.0026, p = 0.82). This method also revealed no significant causality between high BMI and maternal dementia (β = 0.0024 ± 0.0043, p = 0.57), and it was supported by the MR-Egger regression results, which showed no causal effect of high BMI on maternal Alzheimer’s disease and dementia (β = 0.0027 ± 0.0096, p = 0.78). The IVW method showed no significant causal relationship between maternal HD and maternal Alzheimer’s disease and dementia (β = −0.05 ± 0.0042, p = 0.117) and MR-Egger regression analysis gave a similar result (β = −0.12 ± 0.0060, p = 0.079). In MVMR analysis, we found no significant causal relationship between GDM, high BMI, or HD and maternal Alzheimer’s disease and dementia (p = 0.94, 0.82, and 0.13, respectively). Thus, the MVMR estimates were consistent with our results from the two-sample MR analysis. We confirmed that these results showed no horizontal pleiotropy and enhanced the robustness of our results through multiple sensitivity analyses.Conclusion: In two-sample MR analysis, we found no significant causal relationship between GDM, HD, high BMI and maternal AD and dementia. These results differed from previous observational studies showing HD is a significant predictor of dementia. MVMR analysis supported no significant causal relationship between GDM, HD, high BMI and maternal AD and dementia. Sensitivity analysis broadly increased the robustness of two-sample MR and MVMR analysis results.

The role of plasma cortisol in dementia, epilepsy, and multiple sclerosis: A Mendelian randomization study

“…AD data were derived from the UKB, and a GWAS summary database published by Neale Laboratories in 2017. This database covered 26,757 patients with AD and 283,086 controls, all of whom were of European ancestry ( 35 ). In those data, AD was characterized as an anamnestic syndrome of the hippocampal type, with decreased memory, executive function, attention and word finding ( 36 ).…”

Gestational diabetes mellitus is associated with greater incidence of dementia during long‐term post‐partum follow‐up

“…However, it is currently unclear whether cognitive impairment improves with the improvement of GDM after childbirth or whether it has delayed effects or even causes dementia later in life. In addition, no significant causal relationship between GDM and dementia was found in a two‐sample Mendelian randomization analysis [12]. Thus, the impact of GDM on long‐term cognition and dementia is ambiguous.…”

Causal associations between dietary factors and colorectal cancer risk: a Mendelian randomization study

“…SNPs follow the principle of being randomly allocated during the process of meiosis. This helps to eliminate the influence of confounding factors and the possibility of reverse causation, as genetic variants exist before the onset of the disease ( 17 , 18 ). Recent MR studies suggest that dietary habits have a significant effect on several cardiovascular diseases ( 16 ) and five major mental disorders ( 19 ).…”