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Blood pressure reduction and all-cause dementia in people with uncontrolled hypertension: an open-label, blinded-endpoint, cluster-randomized trial

Nature Medicine volume 31, pages 2054–2061 (2025)Cite this article

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Abstract

Dementia is a leading cause of death and disability worldwide. Here we tested the effectiveness of blood pressure (BP) reduction on the risk of all-cause dementia among 33,995 individuals aged ≥40 years with uncontrolled hypertension in rural China. We randomly assigned 163 villages to a non-physician community healthcare provider-led intervention and 163 villages to usual care. In the intervention group, trained non-physician community healthcare providers initiated and titrated antihypertensive medications according to a simple stepped-care protocol to achieve a systolic BP goal of <130 mm Hg and a diastolic BP goal of <80 mm Hg, with supervision from primary care physicians. Over 48 months, the net reduction in systolic BP was 22.0 mm Hg (95% confidence interval (CI) 20.6 to 23.4; P < 0.0001) and that in diastolic BP was 9.3 mm Hg (95% CI 8.7 to 10.0; P < 0.0001) in the intervention group compared to usual care. The primary outcome of all-cause dementia was significantly lower in the intervention group than in the usual care group (risk ratio: 0.85; 95% CI 0.76 to 0.95; P = 0.0035). Additionally, serious adverse events occurred less frequently in the intervention group (risk ratio: 0.94; 95% CI 0.91 to 0.98; P = 0.0006). This cluster-randomized trial indicates that intensive BP reduction is effective in lowering the risk of all-cause dementia in patients with hypertension. ClinicalTrials.gov: NCT03527719.

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Fig. 1: Flowchart of recruitment, randomization and follow-up.
Fig. 2: SBP and DBP in the intervention and usual care groups over the 48 months of follow-up.
Fig. 3: Forest plot of the primary and main secondary outcomes according to subgroups.

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Data availability

Since patients have not explicitly consented to data sharing, we are not allowed to post individual participant data in a public data repository for legal reasons. However, researchers with a valuable research question can request study data from the corresponding authors. If the proposal is approved by the CRHCP Study Steering Committee, deidentified individual data may be shared after consultation with the data protection officers and legal representatives of the participating institutions and after signing a data-sharing agreement. All data sharing will abide by the rules and policies defined by the sponsor, relevant ethics committees, and government laws and regulations. A response to requests for data access can be expected within 4 weeks. Source data are provided with this paper.

Code availability

The modified Poisson regression analysis and generalized estimating equation linear model were implemented using Proc GENMOD in SAS v.9.4.

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Acknowledgements

This work was supported by the National Key Research and Development Program of the Ministry of Science and Technology of China (grant no. 2017YFC1307600, Y.S.), Chinese Society of Cardiology Foundation (grant no. CSCF2022B02, Y.S.), and the Science and Technology Program of Liaoning Province, China (grant no. 2020JH1/10300002, Y.S.). The funder of the study had no role in study design, data collection, data analysis, data interpretation or writing of the report. The US investigators did not receive any financial support from this study. We are grateful to the NPCHPs, primary care physicians, hypertension specialists and research staff at all participating institutes for their support throughout the study. A full list of the committee members and study group members of the China Rural Hypertension Control Project is provided in Supplementary Information. We acknowledge C. Li from the Alzheimerʼs Disease Research Center at the Icahn School of Medicine at Mount Sinai and J. S.-Lemus from the Department of Psychology at Montclair State University for their advice and recommendations on cognitive and functional status screening tools and diagnostic guidelines for dementia and CIND. We thank C. Li and X. Zeng for providing training and certification on cognitive and functional status assessment to the key investigators. Furthermore, we express our gratitude to H. He and S. Geng from the Tulane University Translational Science Institute for their advice and assistance in statistical analyses.

Author information

Author notes

  1. These authors contributed equally: Jiang He, Chuansheng Zhao, Shanshan Zhong, Nanxiang Ouyang, Guozhe Sun, Lixia Qiao.

Authors and Affiliations

  1. Department of Epidemiology, Peter O’Donnell Jr. School of Public Health, UT Southwestern Medical Center, Dallas, TX, USA

    Jiang He

  2. Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX, USA

    Jiang He

  3. Department of Neurology, UT Southwestern Medical Center, Dallas, TX, USA

    Jiang He

  4. Peter O’Donnell Jr. Brain Institute, UT Southwestern Medical Center, Dallas, TX, USA

    Jiang He

  5. Department of Neurology, First Hospital of China Medical University, Shenyang, China

    Chuansheng Zhao, Shanshan Zhong, Huayan Liu, Weiyu Teng & Xu Liu

  6. Department of Cardiology, First Hospital of China Medical University, Shenyang, China

    Nanxiang Ouyang, Guozhe Sun, Lixia Qiao, Chang Wang, Songyue Liu & Yingxian Sun

  7. Hanzhong People’s Hospital, Hanzhong, China

    Ruihai Yang

  8. Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China

    Chunxia Zhao

  9. Tulane University Translational Science Institute, New Orleans, LA, USA

    Chung-Shiuan Chen

  10. Sticht Center for Healthy Aging and Alzheimer’s Prevention, Department of Internal Medicine, Section on Geriatric Medicine, Wake Forest University School of Medicine, Winston-Salem, NC, USA

    Jeff D. Williamson

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Contributions

J.H., Chuansheng Zhao, S.Z., N.O., G.S., J.D.W. and Y.S. conceived and designed the study. J.H., Chuansheng Zhao, S.Z., N.O., G.S., L.Q., R.Y., Chunxia Zhao, H.L., W.T., X.L., C.W., S.L. and Y.S. supervised the data collection. J.H., Chuansheng Zhao, S.Z., N.O., G.S., L.Q., C.-S.C., J.D.W. and Y.S. analyzed and interpreted the data. J.H. drafted the paper. All authors revised the paper for important intellectual content and approved the final submitted version. J.H., Chuansheng Zhao, S.Z., N.O., G.S., C.-S.C. and Y.S. accessed and verified the data. J.H. and Y.S. had full access to all the data in the study and had final responsibility for the decision to submit for publication. All authors vouch for the completeness and accuracy of the data and for the fidelity of the trial to the protocol.

Corresponding authors

Correspondence to Jiang He or Yingxian Sun.

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Nature Medicine thanks Josef Coresh, Ruth Peters and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary Handling Editor: Jerome Staal, in collaboration with the Nature Medicine team.

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Supplementary information

Supplementary Information (download PDF )

List of CRHCP committee members and study group members, eligibility criteria, definition of study outcomes, and Supplementary Tables 1–8 and Fig. 1.

Reporting Summary (download PDF )

Source data

Source Data Fig. 2 (download XLSX )

Systolic and diastolic blood pressure in the intervention and usual care groups over the 48 months of follow-up.

Source Data Fig. 3 (download XLSX )

Forest plot of the primary and main secondary outcomes according to subgroups.

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He, J., Zhao, C., Zhong, S. et al. Blood pressure reduction and all-cause dementia in people with uncontrolled hypertension: an open-label, blinded-endpoint, cluster-randomized trial. Nat Med 31, 2054–2061 (2025). https://doi.org/10.1038/s41591-025-03616-8

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