Blood pressure lowering and prevention of dementia: an individual patient data meta-analysis
Open accessAbstract
Aims: Observational studies indicate U-shaped associations of blood pressure (BP) and incident dementia in older age, but randomized controlled trials of BP-lowering treatment show mixed results on this outcome in hypertensive patients. A pooled individual participant data analysis of five seminal randomized double-blind placebo-controlled trials was undertaken to better define the effects of BP-lowering treatment for the prevention of dementia. Methods and results: Multilevel logistic regression was used to evaluate the treatment effect on incident dementia. Effect modification was assessed for key population characteristics including age, baseline systolic BP, sex, and presence of prior stroke. Mediation analysis was used to quantify the contribution of trial medication and changes in systolic and diastolic BP on risk of dementia. The total sample included 28 008 individuals recruited from 20 countries. After a median follow-up of 4.3 years, there were 861 cases of incident dementia. Multilevel logistic regression reported an adjusted odds ratio 0.87 (95% confidence interval: 0.75, 0.99) in favour of antihypertensive treatment reducing risk of incident dementia with a mean BP lowering of 10/4 mmHg. Further multinomial regression taking account of death as a competing risk found similar results. There was no effect modification by age or sex. Mediation analysis confirmed the greater fall in BP in the actively treated group was associated with a greater reduction in dementia risk. Conclusion: The first single-stage individual patient data meta-analysis from randomized double-blind placebo-controlled clinical trials provides evidence to support benefits of antihypertensive treatment in late-mid and later life to lower the risk of dementia. Questions remain as to the potential for additional BP lowering in those with already well-controlled hypertension and of antihypertensive treatment commenced earlier in the life-course to reduce the long-term risk of dementia. Classification of evidence: Class I evidence in favour of antihypertensive treatment reducing risk of incident dementia compared with placebo.
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Obesity and high blood pressure represent risk factors in mid-life, often with earlier life origins, but in late-life may reduce if people are developing mild cognitive impairment and dementia.
“For example, obesity and high blood pressure (BP) represent risk factors in mid-life, often with earlier life origins, but in late-life may reduce if people are developing mild cognitive impairment (MCI) and dementia. (12-14)”
From Dementia prevention, intervention, and care: 2024 report of the Lancet standing Commission (2024) · cites this paper as [12]
The Introduction (p. 4) supports elevated blood pressure in mid-life as a risk factor for dementia and describes a different, U-shaped association in older adults. It does not address obesity or earlier-life origins, and it does not establish that obesity or blood pressure falls as people develop MCI or dementia. (LLM, conf=0.85)
Experimental — accuracy not yet measuredMR findings of high BP being protective are inconsistent with RCT findings and are likely influenced by survival bias.
“MR findings of high BP being protective (193-196) are inconsistent with RCTs findings and MR studies ' findings are likely to be influenced by survival bias. (12, 189, 197)”
From Dementia prevention, intervention, and care: 2024 report of the Lancet standing Commission (2024) · cites this paper as [12]
The Discussion (p. 13) reports that blood-pressure lowering reduced dementia risk, which is inconsistent with a protective effect of high blood pressure. The Discussion (p. 14) suggests that apparent protection at higher blood pressure in population studies may partly reflect survival, but it does not attribute that finding or survival bias specifically to Mendelian-randomisation studies. (LLM, conf=0.85)
Experimental — accuracy not yet measuredAntihypertensive treatment is associated with lower risk of dementia (OR 0.87, 95% CI 0.75-0.99).
“The second study used IPD from 5 RCTs (n=28,008) with placebo controls, three of which were in the first study, and found a lower risk of dementia in the treatment group (OR 0.87, 0.75-0.99). (12)”
From Dementia prevention, intervention, and care: 2024 report of the Lancet standing Commission (2024) · cites this paper as [12]
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- Authors
- Peters, R., Xu, Y., Fitzgerald, O., Aung, H. L., Beckett, N., Bulpitt, C., Chalmers, J., Forette, F., Gong, J., Harris, K., Humburg, P., Matthews, F. E., Staessen, J. A., Thijs, L., Tzourio, C., Warwick, J., Woodward, M., Anderson, C. S., & Dementia rIsk REduCTion (DIRECT) collaboration
- Affiliations
- UNSW Sydney (AU)
- Neuroscience Research Australia , Barker Street, Randwick, Sydney, New South Wales 2031 , Australia
- Neuroscience Research Australia (AU)
- Guy's and St Thomas' NHS Foundation Trust (GB)
- Imperial College London (GB)
- International Longevity Centre , 11 Rue Jean Mermoz, Paris 75008 , France
- Newcastle University (GB)
- KU Leuven (BE)
- Université de Bordeaux (FR)
- Independent University Banja Luka (BA)
- Corresponding author
- Peters, Ruth
- ORCID
- Venue
- European Heart Journal
- Publisher
- Oxford University Press (OUP)
- Published
- 2022-10-25
- Volume
- 43
- Issue
- 48
- Pages
- 4980-4990
- ISSN
- 0195-668X (ISSN-L)
- 1522-9645
- OpenAlex
- W4307216070
- Cited by
- 142
- References
- 47
- Citations by year
- 2026: 29 · 2025: 36 · 2024: 49 · 2023: 27 · 2022: 1
- FWCI
- 4.86
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- European Heart Journal (publishedVersion)
- PubMed (publishedVersion)
- Repository@Hull (Worktribe) (University of Hull) (submittedVersion, cc-by)
- Lirias (submittedVersion, other-oa)
- HAL (submittedVersion)
- Oskar-Bordeaux (Universite de Bordeaux) (submittedVersion)
- UNSWorks (UNSW Sydney) (submittedVersion, cc-by)
- Newcastle University ePrints (Newcastle Univesity)
- Funders
- Australian National Health and Medical Research Centre Australian Dementia Centre for Research Collaboration
- Neuroscience Research Australia
- NHMRC (APP1160373)
- Investigator Grants (APP1174120 and GNT1175861)
- Penumbra, Takeda, Credit, and Genesis
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Blood Pressure and Hypertension Studies
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Health and Disease Prevention
- Keywords
- blood pressure reduction, antihypertensive therapy, dementia prevention, incident dementia, hypertension, systolic blood pressure, diastolic blood pressure, mediation analysis, competing risk of death, older adults, effect modification
- MeSH terms
- Antihypertensive Agents, Blood Pressure, Dementia, Humans, Hypertension, Randomized Controlled Trials as Topic, Stroke
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