Key PointsQuestionWhat are the genetic associations between modifiable risk factors and Alzheimer disease (AD)?FindingsIn this genetic association study using a mendelian randomization framework with the largest genomic data sets to date, including 39 106 participants with clinically diagnosed AD and 401 577 control participants without AD, genetically determined increased high-density lipoprotein cholesterol and increased systolic blood pressure were associated with higher risk of AD.MeaningThese findings suggest that genetically determined increased high-density lipoprotein cholesterol and systolic blood pressure may be involved in AD pathogenesis, which may thus inspire new drug targeting and improved early dementia prevention.