Cholesterol‐lowering drug targets reduce risk of dementia: Mendelian randomization and meta‐analyses of 1 million individuals

INTRODUCTION We tested whether genetically proxied non‐high‐density lipoprotein cholesterol (non‐HDL‐C)–lowering drug targets reduce risk of all‐cause dementia. METHODS We included 1,091,775 individuals from three prospective general population cohorts with individual‐level data and two consortia with summary‐level data. We selected genetic variants within HMGCR, NPC1L1, PCSK9, ANGPTL4, LPL , and CETP associated with non‐HDL‐C. These variants were used as exposures in Cox regression and one‐ and two‐sample Mendelian randomization. Results were meta‐analyzed. RESULTS Meta‐analysis of one‐sample Mendelian randomization odds ratios per 1 mmol/L (39 mg/dL) lower non‐HDL‐C was 0.24 (0.18–0.31) for HMGCR , 0.18 (0.12–0.25) for NPC1L1 , 0.97 (0.70–1.35) for PCSK9 , 1.66 (0.52–5.36) for ANGPTL4 , 1.41 (0.63–3.16) for LPL , and 0.30 (0.26–0.34) for CETP . Cox regression and two‐sample Mendelian randomization results were mostly directionally consistent. DISCUSSION Genetic lowering of non‐HDL cholesterol via HMGCR, NPC1L1 , and CETP reduces the risk of dementia. This reflects the effect of lifelong differences in non‐HDL cholesterol on risk of dementia. Highlights Variants in HMGCR, NPC1L1 , and CETP reduce the risk of dementia via non‐high‐density lipoprotein cholesterol (non‐HDL‐C). An effect of PCSK9, ANGPTL4 , and LPL variants on dementia risk cannot be excluded. This reflects the effect of lifelong lower non‐HDL‐C on risk of dementia.