| Title: | The heterogeneous treatment effects of statins on dementia: a target trial emulation with causal machine learning using integrated genetic and real-world data |
| Journal: | Alzheimer's & Dementia |
| Published: | 26 Feb 2026 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/41748529/ |
| DOI: | https://doi.org/10.1002/alz.71178 |
Publication 17606
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Abstract
INTRODUCTION: Given the complexity of dementia, the inconsistent evidence on statins and dementia highlights the need for robust methods to assess heterogeneous treatment effects (HTEs).</p>
METHODS: We emulated a target trial using UK Biobank comparing statin initiators and non-initiators aged ≥55 years. Marginal structural models were fitted to estimate 5-year adjusted risk difference (aRD). We used iterative causal forest, a causal machine learning subgrouping algorithm, to identify subgroups with HTEs.</p>
RESULTS: Among 18,366 participants, the overall aRD for all-cause dementia was -1.0‰ (95% CI: -4.2‰ to 2.3‰). We identified subgroups by polygenic risk score for Alzheimer's disease (AD) excluding apolipoprotein E (APOE) genotype ("non-APOE PRS"). Participants with high non-APOE PRS showed cognitive benefit (all-cause dementia: aRD -5.9‰, 95% CI: -8.1‰ to 1.2‰; AD: aRD -5.0‰, 95% CI: -8.2‰ to -0.2‰).</p>
DISCUSSION: Participants with high non-APOE PRS may benefit from statins, suggesting genetic susceptibility beyond APOE could modify statins' cognitive effects.</p>
13 Keywords
- Aged
- Alzheimer Disease
- Apolipoproteins E
- Dementia
- Female
- Genotype
- Humans
- Hydroxymethylglutaryl-CoA Reductase Inhibitors
- Machine Learning
- Male
- Middle Aged
- Treatment Effect Heterogeneity
- Treatment Outcome
11 Authors
- Yongjie Lai
- Qoua L Her
- Yue Zhang
- Hong Xu
- Anna Kucharska-Newton
- Dongze Ji
- Guorong Wu
- Gwenn Garden
- Til Stürmer
- Tiansheng Wang
- Yang Xu
1 Application
| Application ID | Title |
|---|---|
| 89514 | Integrating analyses of multidimensional exposures on complex diseases |
Enabling scientific discoveries that improve human health