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.
https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/alz.70638
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