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

Liv Tybjærg Nordestgaard, Aimee Hanson, Eleanor Sanderson, Emma Anderson, Venexia Walker, Anne Tybjærg-Hansen, George Davey Smith, Børge G Nordestgaard

Journal: Alzheimer's & dementia : the journal of the Alzheimer's Association 2025;21(10):e70638

PMID: 41059729

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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.

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.

Address: Department of Clinical Biochemistry, Copenhagen University Hospital - Herlev and Gentofte, Herlev, Denmark.; Medical Research Council Integrative Epidemiology Unit, Population Health Sciences, University of Bristol, Bristol, UK.; Medical Research Council Integrative Epidemiology Unit, Population Health Sciences, University of Bristol, Bristol, UK.; Division of Psychiatry, University College London, London, UK.; Department of Clinical Biochemistry, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark.; The Copenhagen General Population Study, Copenhagen University Hospital - Herlev and Gentofte, Herlev, Denmark.; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.; The Copenhagen City Heart Study, Copenhagen University Hospital - Bispebjerg and Frederiksberg, Frederiksberg, Denmark.; Department of Clinical Biochemistry, Copenhagen University Hospital - Herlev and Gentofte, Herlev, Denmark.; The Copenhagen General Population Study, Copenhagen University Hospital - Herlev and Gentofte, Herlev, Denmark.; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.; The Copenhagen City Heart Study, Copenhagen University Hospital - Bispebjerg and Frederiksberg, Frederiksberg, Denmark.

DOI: 10.1002/alz.70638

MeSH Terms: Humans, Mendelian Randomization Analysis, Dementia, Cholesterol Ester Transfer Proteins, Angiopoietin-Like Protein 4, Anticholesteremic Agents, Proprotein Convertase 9, Hydroxymethylglutaryl CoA Reductases, Cholesterol, Lipoprotein Lipase, Membrane Transport Proteins