The causal role of lipids in dementia: A Mendelian randomization study.

Background: Increasing evidence suggests that abnormal lipid metabolism is one of the pathogeneses of dementia. It is necessary to reveal the relationship between lipids and dementia.

Objective: This study used bidirectional two-sample Mendelian randomization to explore the causal relationship between 179 lipid species and the risk of dementia.

Methods: We assessed the causal effects of 179 lipid species and four subtypes of dementia including Alzheimer's disease (AD), vascular dementia (VaD), frontotemporal dementia (FTD), and dementia with Lewy bodies (DLB). Inverse variance weighting, MR-Egger method, weighted median, simple mode, and weighted mode were used to analyze the relationship between lipids and dementia. Cochran's Q, MR-Egger intercept test, and MR-PRESSO test were used to test the heterogeneity and pleiotropy of the results. In addition, we performed an inverse MR analysis testing the causal effects of dementia on lipids.

Results: Our study revealed causal effects of glycerophospholipid, glycerolipid, and sterol on the risk of dementia. Phosphatidylcholine, phosphatidylinositol, and triglycerides play significant roles in AD. Notably, phosphatidylcholine played a protective role in both FTD and DLB. However, this study did not observe a significant effect of phosphatidylinositol on FTD. In the case of VaD, not only glycerophospholipid, but also glycerolipid, exerted an influence, but sterol was also a risk factor.

Conclusions: Our study provided new evidence supporting the causal role of genetically predicted lipid species in dementia. Future clinical trials are necessary to evaluate the potential role of lipid levels in dementia prevention.