Assessing the role of vascular risk factors in dementia: Mendelian randomization meta-analysis and comparison with observational estimates

<ns4:p> Background Although observational studies demonstrate that higher levels of vascular risk factors are associated with an increased risk of dementia, these associations might be explained by confounding or other biases. Mendelian randomization (MR) uses genetic instruments to test causal relationships in observational data. We sought to determine if genetically predicted modifiable risk factors (type 2 diabetes mellitus, low density lipoprotein cholesterol, high density lipoprotein cholesterol, total cholesterol, triglycerides, systolic blood pressure, diastolic blood pressure, body mass index, and circulating glucose) are associated with dementia by meta-analysing published MR studies. Secondary objectives were to identify heterogeneity in effect estimates across primary MR studies and to compare meta-analysis results with observational studies. Methods MR studies were identified by systematic search of Web of Science, OVID and Scopus. We selected primary MR studies investigating the modifiable risk factors of interest. Only one study from each cohort per risk factor was included. A quality assessment tool was developed to primarily assess the three assumptions of MR for each MR study. Data were extracted on study characteristics, exposure and outcome, effect estimates per unit increase, and measures of variation. Effect estimates were pooled to generate an overall estimate, I <ns4:sup>2</ns4:sup> and Cochrane Q values using fixed-effect model. Results We screened 5211 studies and included 12 primary MR studies after applying inclusion and exclusion criteria. Higher genetically predicted body mass index was associated with a higher odds of dementia (OR 1.03 [1.01, 1.05] per 5 kg/m <ns4:sup>2</ns4:sup> increase, one study, p=0.00285). Fewer hypothesized vascular risk factors were supported by estimates from MR studies than estimates from meta-analyses of observational studies. Conclusion Genetically predicted body mass index was associated with an increase in risk of dementia. </ns4:p>