Although polygenic Mendelian randomization analyses excluding variants from the APOE gene region have consistently given null results,78 a previous cis-Mendelian randomization analysis for LDL cholesterol and Alzheimer disease based solely on variants in the PCSK9 gene region gave an inverse estimate of OR 0.69 (95% CI: 0.59, 0.81) per standard deviation increase in genetically predicted LDL cholesterol, suggesting that lowering LDL cholesterol via PCSK9 inhibition may increase risk of Alzheimer disease.79 This evidence concerns the gene APOE and early-onset autosomal dominant Alzheimer disease.