Evidence map›Paper›PMID 41059729›Full record

SynthesisAlzheimer's & dementia : the journal of the Alzheimer's Association2025

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

Abstract readMeta-Analysis
PubMed Full text at PMC Publisher
In one paragraph

Synthesis in Alzheimer's & dementia : the journal of the Alzheimer's Association, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers, 1 of them a synthesis that pooled it.

0numbers the graph read from it
0cells of the map it votes in
6citing papers in PubMed, 1 pooled it
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

6 citing papers in PubMed, 1 synthesis or guideline pooled it.

  1. Pooled it
  2. Article
  3. Review
  4. Review
  5. CETP Renaissance with Obicetrapib.Current atherosclerosis reports · 2026
    Review
  6. Review
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

8 authors.

Liv Tybjærg NordestgaardDepartment of Clinical Biochemistry, Copenhagen University Hospital - Herlev and Gentofte, Herlev, Denmark.ORCID 0000-0002-5490-0034
Aimee HansonMedical Research Council Integrative Epidemiology Unit, Population Health Sciences, University of Bristol, Bristol, UK.
Eleanor SandersonMedical Research Council Integrative Epidemiology Unit, Population Health Sciences, University of Bristol, Bristol, UK.
Emma AndersonDivision of Psychiatry, University College London, London, UK.
Venexia WalkerMedical Research Council Integrative Epidemiology Unit, Population Health Sciences, University of Bristol, Bristol, UK.
Anne Tybjærg-HansenDepartment of Clinical Biochemistry, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark.
George Davey SmithMedical Research Council Integrative Epidemiology Unit, Population Health Sciences, University of Bristol, Bristol, UK.
Børge G NordestgaardDepartment of Clinical Biochemistry, Copenhagen University Hospital - Herlev and Gentofte, Herlev, Denmark.

Funding

Independent Research Fund Denmark 10.46540/3100-00007BMedical Research Council MC_UU_00032/1Research Council at the Capital Region of Denmark
6 · The paper itself

Abstract

introductionWe tested whether genetically proxied non-high-density lipoprotein cholesterol (non-HDL-C)-lowering drug targets reduce risk of all-cause dementia.

methodsWe 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.

resultsMeta-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.

Indexed as

Anticholesteremic AgentsCholesterolDementiaAngiopoietin-Like Protein 4Cholesterol Ester Transfer ProteinsHumansHydroxymethylglutaryl CoA ReductasesLipoprotein LipaseMembrane Transport ProteinsMendelian Randomization AnalysisProprotein Convertase 9Angiopoietin-Like Protein 4ANGPTL4 protein, humanAnticholesteremic AgentsCETP protein, humanCholesterolCholesterol Ester Transfer ProteinsHMGCR protein, humanHydroxymethylglutaryl CoA ReductasesLipoprotein LipaseMembrane Transport ProteinsNPC1L1 protein, humanPCSK9 protein, humanProprotein Convertase 9atherosclerosischolesterolcholesteryl ester transfer proteindementiageneticslipid loweringlipoproteinsMendelian randomizationNiemann‐Pick C1‐like 1β‐hydroxy β‐methylglutaryl‐CoA reductase

Identifiers

PMID41059729
PMCPMC12505197

What Socratic holds

Textmetadata
LicenceCC BY
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Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.