| Title: | Cholesterol-lowering drug targets reduce risk of dementia: Mendelian randomization and meta-analyses of 1 million individuals |
| Journal: | Alzheimer's & Dementia |
| Published: | 8 Oct 2025 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/41059729/ |
| DOI: | https://doi.org/10.1002/alz.70638 |
Publication 19251
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Abstract
INTRODUCTION: We tested whether genetically proxied non-high-density lipoprotein cholesterol (non-HDL-C)-lowering drug targets reduce risk of all-cause dementia.</p>
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.</p>
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.</p>
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.</p>
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.</p>
11 Keywords
- Angiopoietin-Like Protein 4
- Anticholesteremic Agents
- Cholesterol
- Cholesterol Ester Transfer Proteins
- Dementia
- Humans
- Hydroxymethylglutaryl CoA Reductases
- Lipoprotein Lipase
- Membrane Transport Proteins
- Mendelian Randomization Analysis
- Proprotein Convertase 9
8 Authors
- Liv Tybjærg Nordestgaard
- Aimee Hanson
- Eleanor Sanderson
- Emma Anderson
- Venexia Walker
- Anne Tybjærg-Hansen
- George Davey Smith
- Børge G. Nordestgaard
1 Application
| Application ID | Title |
|---|---|
| 81499 | Using human genetics to develop insight into putative causal relationships between modifiable exposures and disease endpoints |
Enabling scientific discoveries that improve human health