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

Importance 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. Objective 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. Data sources MR studies identified by systematic search of Web of Science, OVID and Scopus. Study selection 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 extraction and synthesis 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 2 and Cochrane Q values using fixed-effect model. Main outcomes and measures Odds ratio (OR) of developing dementia per standardized unit increase in the risk factor of interest. 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 2 increase, one study, p = 0.00285). Overall estimates from MR studies showed a smaller number of associations than those from meta-analyses of observational studies. Conclusion and relevance Genetically predicted body mass index was associated with an increase in risk of dementia. Key points Question Are genetically predicted modifiable risk factors associated with dementia? Findings Genetically predicted higher body mass index was associated with a higher odds of dementia. No evidence was found to support an association between genetically predicted type 2 diabetes mellitus, low density lipoprotein (LDL) cholesterol, high density lipoprotein (HDL) cholesterol, total cholesterol, triglycerides, systolic blood pressure, diastolic blood pressure, plasma glucose and dementia risk. Meaning Many modifiable risk factors associated with dementia in observational studies may not play a causative role.