Use of Antihypertensives, Blood Pressure, and Estimated Risk of Dementia in Late Life: An Individual Participant Data Meta-Analysis

doi:10.1001/jamanetworkopen.2023.33353

Meta-Analysis

. 2023 Sep 5;6(9):e2333353.

doi: 10.1001/jamanetworkopen.2023.33353.

Use of Antihypertensives, Blood Pressure, and Estimated Risk of Dementia in Late Life: An Individual Participant Data Meta-Analysis

Matthew J Lennon^{1

2}, Ben Chun Pan Lam^{1

2

3}, Darren M Lipnicki^{1

2}, John D Crawford^{1

2}, Ruth Peters^{4

5

6}, Aletta E Schutte^{4

7}, Henry Brodaty^{1

2

8}, Anbupalam Thalamuthu^{1

2}, Therese Rydberg-Sterner^{9

10}, Jenna Najar^{9

11}, Ingmar Skoog^{9

11}, Steffi G Riedel-Heller¹², Susanne Röhr^{12

13

14}, Alexander Pabst¹², Antonio Lobo^{15

16

17}, Concepción De-la-Cámara^{15

16

17}, Elena Lobo^{15

16

17}, Toyin Bello¹⁸, Oye Gureje¹⁸, Akin Ojagbemi¹⁸, Richard B Lipton^{19

20}, Mindy J Katz¹⁹, Carol A Derby^{19

20}, Ki Woong Kim^{21

22

23}, Ji Won Han^{21

22}, Dae Jong Oh²⁴, Elena Rolandi^{25

26}, Annalisa Davin²⁵, Michele Rossi²⁵, Nikolaos Scarmeas^{27

28}, Mary Yannakoulia²⁹, Themis Dardiotis^{30

31}, Hugh C Hendrie^{32

33}, Sujuan Gao^{33

34}, Isabelle Carrière³⁵, Karen Ritchie^{35

36}, Kaarin J Anstey^{37

38

39}, Nicolas Cherbuin⁴⁰, Shifu Xiao^{41

42}, Ling Yue^{41

42}, Wei Li^{41

42}, Maëlenn M Guerchet⁴³, Pierre-Marie Preux⁴³, Victor Aboyans^{43

44}, Mary N Haan⁴⁵, Allison E Aiello⁴⁶, Tze Pin Ng^{47

48}, Ma Shwe Zin Nyunt⁴⁷, Qi Gao⁴⁷, Marcia Scazufca⁴⁹, Perminder S S Sachdev^{1

2

50}

Affiliations

¹ Faculty of Medicine, University of New South Wales, Sydney, Australia.
² Centre for Healthy Brain Aging, Discipline of Psychiatry & Mental Health, School of Clinical Medicine, University of New South Wales, Sydney, Australia.
³ School of Psychology and Public Health, La Trobe University, Melbourne, Australia.
⁴ The George Institute for Global Health, Sydney, Australia.
⁵ School of Biomedical Sciences, University of New South Wales, Sydney, Australia.
⁶ School of Public Health, Imperial College London, London, United Kingdom.
⁷ School of Population Health, University of New South Wales, Sydney, Australia.
⁸ Eastern Suburbs Older Persons' Mental Health Service, Sydney, Australia.
⁹ Neuropsychiatric Epidemiology Unit, Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, Centre for Ageing and Health at the University of Gothenburg, Gothenburg, Sweden.
¹⁰ Aging Research Center, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet and Stockholm University, Stockholm, Sweden.
¹¹ Psychiatry, Cognition and Old Age Psychiatry Clinic, Region Västra Götaland, Sahlgrenska University Hospital, Gothenburg, Sweden.
¹² Institute of Social Medicine, Occupational Health and Public Health, Medical Faculty, University of Leipzig, Leipzig, Germany.
¹³ School of Psychology, Manawatu Campus, Massey University, Palmerston North, New Zealand.
¹⁴ Global Brain Health Institute, Trinity College Dublin, Dublin, Ireland.
¹⁵ Department of Medicine and Psychiatry, Universidad de Zaragoza, Zaragoza, Spain.
¹⁶ Instituto de Investigación Sanitaria Aragón, Zaragoza, Spain.
¹⁷ Centro de Investigación Biomédica en Red de Salud Mental, Madrid, Spain.
¹⁸ World Health Organization Collaborating Centre for Research and Training in Mental Health, Neuroscience, and Substance Abuse, Department of Psychiatry, College of Medicine, University of Ibadan, Ibadan, Nigeria.
¹⁹ Department of Neurology, Albert Einstein College of Medicine, Bronx, New York.
²⁰ Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, New York.
²¹ Department of Neuropsychiatry, Seoul National University Bundang Hospital, Seongnam, Korea.
²² Department of Psychiatry, Seoul National University College of Medicine, Seoul, Korea.
²³ Department of Brain and Cognitive Sciences, Seoul National University College of Natural Sciences, Seoul, Korea.
²⁴ Workplace Mental Health Institute, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea.
²⁵ Golgi Cenci Foundation, Abbiategrasso, Italy.
²⁶ Department of Brain and Behavioural Sciences, University of Pavia, Pavia, Italy.
²⁷ First Department of Neurology, Aiginition Hospital, National and Kapodistrian University of Athens, Athens, Greece.
²⁸ Department of Neurology, Columbia University, New York, New York.
²⁹ Department of Nutrition and Dietetics, School of Health Sciences and Education, Harokopio University, Athens, Greece.
³⁰ Department of Neurology, University Hospital of Larissa, Larissa, Greece.
³¹ Faculty of Medicine, School of Health Sciences, University of Thessaly, Larissa, Greece.
³² Department of Psychiatry, Indiana University School of Medicine, Indianapolis.
³³ Indiana Alzheimer Disease Research Center, Indiana Alzheimer Disease Research Center, Indianapolis.
³⁴ Department of Biostatistics and Health Data Science, Indiana University School of Medicine, Indianapolis.
³⁵ Institut for Neurosciences of Montpellier, University Montpellier, National Institute for Health and Medical Research, Montpellier, France.
³⁶ Institut du Cerveau Trocadéro, Paris, France.
³⁷ University of New South Wales, School of Psychology, Sydney, Australia.
³⁸ Ageing Futures Institute, University of New South Wales, Sydney, Australia.
³⁹ Neuroscience Research Australia, Sydney, Australia.
⁴⁰ National Centre for Epidemiology and Population Health, Australian National University, Canberra, Australia.
⁴¹ Department of Geriatric Psychiatry, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
⁴² Alzheimer's Disease and Related Disorders Center, Shanghai Jiao Tong University, Shanghai, China.
⁴³ National Institute for Health and Medical Research U1094, Institut de Recherche pour le Developpement UMR270, Epidemiology of Chronic Diseases in Tropical Zone, Institute of Epidemiology and Tropical Neurology, OmegaHealth, University Limoges, Centre Hospitalier et Universitaire Limoges, Limoges, France.
⁴⁴ Department of Cardiology, Dupuytren 2 University Hospital, Limoges, France.
⁴⁵ School of Medicine, University of California, San Francisco.
⁴⁶ Robert N. Butler Columbia Aging Center, Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, New York.
⁴⁷ Department of Psychological Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
⁴⁸ Geriatric Education and Research Institute, Ministry of Health, Singapore, Singapore.
⁴⁹ Departamento de Psiquiatria, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, Brazil.
⁵⁰ Neuropsychiatric Institute, Prince of Wales Hospital, Sydney, Australia.

PMID: 37698858
PMCID: PMC10498335
DOI: 10.1001/jamanetworkopen.2023.33353

Meta-Analysis

Use of Antihypertensives, Blood Pressure, and Estimated Risk of Dementia in Late Life: An Individual Participant Data Meta-Analysis

Matthew J Lennon et al. JAMA Netw Open. 2023.

. 2023 Sep 5;6(9):e2333353.

doi: 10.1001/jamanetworkopen.2023.33353.

Authors

Affiliations

¹ Faculty of Medicine, University of New South Wales, Sydney, Australia.
² Centre for Healthy Brain Aging, Discipline of Psychiatry & Mental Health, School of Clinical Medicine, University of New South Wales, Sydney, Australia.
³ School of Psychology and Public Health, La Trobe University, Melbourne, Australia.
⁴ The George Institute for Global Health, Sydney, Australia.
⁵ School of Biomedical Sciences, University of New South Wales, Sydney, Australia.
⁶ School of Public Health, Imperial College London, London, United Kingdom.
⁷ School of Population Health, University of New South Wales, Sydney, Australia.
⁸ Eastern Suburbs Older Persons' Mental Health Service, Sydney, Australia.
⁹ Neuropsychiatric Epidemiology Unit, Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, Centre for Ageing and Health at the University of Gothenburg, Gothenburg, Sweden.
¹⁰ Aging Research Center, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet and Stockholm University, Stockholm, Sweden.
¹¹ Psychiatry, Cognition and Old Age Psychiatry Clinic, Region Västra Götaland, Sahlgrenska University Hospital, Gothenburg, Sweden.
¹² Institute of Social Medicine, Occupational Health and Public Health, Medical Faculty, University of Leipzig, Leipzig, Germany.
¹³ School of Psychology, Manawatu Campus, Massey University, Palmerston North, New Zealand.
¹⁴ Global Brain Health Institute, Trinity College Dublin, Dublin, Ireland.
¹⁵ Department of Medicine and Psychiatry, Universidad de Zaragoza, Zaragoza, Spain.
¹⁶ Instituto de Investigación Sanitaria Aragón, Zaragoza, Spain.
¹⁷ Centro de Investigación Biomédica en Red de Salud Mental, Madrid, Spain.
¹⁸ World Health Organization Collaborating Centre for Research and Training in Mental Health, Neuroscience, and Substance Abuse, Department of Psychiatry, College of Medicine, University of Ibadan, Ibadan, Nigeria.
¹⁹ Department of Neurology, Albert Einstein College of Medicine, Bronx, New York.
²⁰ Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, New York.
²¹ Department of Neuropsychiatry, Seoul National University Bundang Hospital, Seongnam, Korea.
²² Department of Psychiatry, Seoul National University College of Medicine, Seoul, Korea.
²³ Department of Brain and Cognitive Sciences, Seoul National University College of Natural Sciences, Seoul, Korea.
²⁴ Workplace Mental Health Institute, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea.
²⁵ Golgi Cenci Foundation, Abbiategrasso, Italy.
²⁶ Department of Brain and Behavioural Sciences, University of Pavia, Pavia, Italy.
²⁷ First Department of Neurology, Aiginition Hospital, National and Kapodistrian University of Athens, Athens, Greece.
²⁸ Department of Neurology, Columbia University, New York, New York.
²⁹ Department of Nutrition and Dietetics, School of Health Sciences and Education, Harokopio University, Athens, Greece.
³⁰ Department of Neurology, University Hospital of Larissa, Larissa, Greece.
³¹ Faculty of Medicine, School of Health Sciences, University of Thessaly, Larissa, Greece.
³² Department of Psychiatry, Indiana University School of Medicine, Indianapolis.
³³ Indiana Alzheimer Disease Research Center, Indiana Alzheimer Disease Research Center, Indianapolis.
³⁴ Department of Biostatistics and Health Data Science, Indiana University School of Medicine, Indianapolis.
³⁵ Institut for Neurosciences of Montpellier, University Montpellier, National Institute for Health and Medical Research, Montpellier, France.
³⁶ Institut du Cerveau Trocadéro, Paris, France.
³⁷ University of New South Wales, School of Psychology, Sydney, Australia.
³⁸ Ageing Futures Institute, University of New South Wales, Sydney, Australia.
³⁹ Neuroscience Research Australia, Sydney, Australia.
⁴⁰ National Centre for Epidemiology and Population Health, Australian National University, Canberra, Australia.
⁴¹ Department of Geriatric Psychiatry, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
⁴² Alzheimer's Disease and Related Disorders Center, Shanghai Jiao Tong University, Shanghai, China.
⁴³ National Institute for Health and Medical Research U1094, Institut de Recherche pour le Developpement UMR270, Epidemiology of Chronic Diseases in Tropical Zone, Institute of Epidemiology and Tropical Neurology, OmegaHealth, University Limoges, Centre Hospitalier et Universitaire Limoges, Limoges, France.
⁴⁴ Department of Cardiology, Dupuytren 2 University Hospital, Limoges, France.
⁴⁵ School of Medicine, University of California, San Francisco.
⁴⁶ Robert N. Butler Columbia Aging Center, Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, New York.
⁴⁷ Department of Psychological Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
⁴⁸ Geriatric Education and Research Institute, Ministry of Health, Singapore, Singapore.
⁴⁹ Departamento de Psiquiatria, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, Brazil.
⁵⁰ Neuropsychiatric Institute, Prince of Wales Hospital, Sydney, Australia.

PMID: 37698858
PMCID: PMC10498335
DOI: 10.1001/jamanetworkopen.2023.33353

Abstract

Importance: The utility of antihypertensives and ideal blood pressure (BP) for dementia prevention in late life remains unclear and highly contested.

Objectives: To assess the associations of hypertension history, antihypertensive use, and baseline measured BP in late life (age >60 years) with dementia and the moderating factors of age, sex, and racial group.

Data source and study selection: Longitudinal, population-based studies of aging participating in the Cohort Studies of Memory in an International Consortium (COSMIC) group were included. Participants were individuals without dementia at baseline aged 60 to 110 years and were based in 15 different countries (US, Brazil, Australia, China, Korea, Singapore, Central African Republic, Republic of Congo, Nigeria, Germany, Spain, Italy, France, Sweden, and Greece).

Data extraction and synthesis: Participants were grouped in 3 categories based on previous diagnosis of hypertension and baseline antihypertensive use: healthy controls, treated hypertension, and untreated hypertension. Baseline systolic BP (SBP) and diastolic BP (DBP) were treated as continuous variables. Reporting followed the Preferred Reporting Items for Systematic Review and Meta-Analyses of Individual Participant Data reporting guidelines.

Main outcomes and measures: The key outcome was all-cause dementia. Mixed-effects Cox proportional hazards models were used to assess the associations between the exposures and the key outcome variable. The association between dementia and baseline BP was modeled using nonlinear natural splines. The main analysis was a partially adjusted Cox proportional hazards model controlling for age, age squared, sex, education, racial group, and a random effect for study. Sensitivity analyses included a fully adjusted analysis, a restricted analysis of those individuals with more than 5 years of follow-up data, and models examining the moderating factors of age, sex, and racial group.

Results: The analysis included 17 studies with 34 519 community dwelling older adults (20 160 [58.4%] female) with a mean (SD) age of 72.5 (7.5) years and a mean (SD) follow-up of 4.3 (4.3) years. In the main, partially adjusted analysis including 14 studies, individuals with untreated hypertension had a 42% increased risk of dementia compared with healthy controls (hazard ratio [HR], 1.42; 95% CI 1.15-1.76; P = .001) and 26% increased risk compared with individuals with treated hypertension (HR, 1.26; 95% CI, 1.03-1.53; P = .02). Individuals with treated hypertension had no significant increased dementia risk compared with healthy controls (HR, 1.13; 95% CI, 0.99-1.28; P = .07). The association of antihypertensive use or hypertension status with dementia did not vary with baseline BP. There was no significant association of baseline SBP or DBP with dementia risk in any of the analyses. There were no significant interactions with age, sex, or racial group for any of the analyses.

Conclusions and relevance: This individual patient data meta-analysis of longitudinal cohort studies found that antihypertensive use was associated with decreased dementia risk compared with individuals with untreated hypertension through all ages in late life. Individuals with treated hypertension had no increased risk of dementia compared with healthy controls.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Peters reported receiving grants from the Australian National Health and Medical Research Council (NHMRC) and Mindgardens Neuroscience Network outside the submitted work. Dr Schutte reported receiving personal fees from Omron Healthcare, Servier, Abbott, and Sanofi outside the submitted work. Dr Brodaty reported receiving personal fees from Biogen, Eli Lilly, Eisai, Roche, Skin2Neuron, and Cranbrook Care and grants from the NHMRC (paid to institution) outside the submitted work. Dr A. Lobo reported receiving personal fees from Janssen. Dr Scarmeas reported receiving grants from Novo Nordisc and the National Institutes of Health outside the submitted work. Dr Aboyans reported receiving personal fees from Bayer Healthcare and Novo Nordisk outside the submitted work. Dr Sachdev reported serving as a consultant for Biogen and Roche. No other disclosures were reported.

Figures

**Figure 1.. Association of Hypertension (HTN) and Antihypertensive Status With the Risk of All-Cause Dementia**
The x-axis is in log2 scale. The main analysis (partially adjusted) included covariates of age, age squared, sex, education, and racial group. The fully adjusted analysis included additional covariates of body mass index, smoking status, history of hypercholesterolemia, and diabetes. Each of the other analyses applied the partially adjusted model. The P values show the size of the interaction effect for age, sex, and racial group with treated HTN (compared with healthy controls) and untreated HTN (compared with healthy controls). Age was treated as a continuous variable, sex as a categorical variable, and racial group as a categorical variable with 3 major groups (Asian, Black, and White). The P values show the significance of the interaction term. The interaction P values used White participants as the main comparison group in the racial analysis (as this was the largest group included). HR indicates hazard ratio.

**Figure 2.. The Associations of Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) With Dementia Risk**
In all models, SBP and DBP were centered at the overall mean (SBP: 140 mm Hg; DBP: 80 mm Hg), and all hazard ratios (HRs) represent within-group risk relative to this overall mean; shading indicates 95% CI. A restricted cubic splines model was applied. The partially adjusted analysis included the covariates of age, age squared, sex, education, racial group, and a random effect for study. The fully adjusted analysis included additional covariates of body mass index, smoking status, history of hypercholesterolemia, and diabetes.

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References

1. Bloch MJ. Worldwide prevalence of hypertension exceeds 1.3 billion. J Am Soc Hypertens. 2016;10(10):753-754. doi:10.1016/j.jash.2016.08.006 - DOI - PubMed
1. Livingston G, Huntley J, Sommerlad A, et al. . Dementia prevention, intervention, and care: 2020 report of the Lancet Commission. Lancet. 2020;396(10248):413-446. doi:10.1016/S0140-6736(20)30367-6 - DOI - PMC - PubMed
1. Lennon MJ, Makkar SR, Crawford JD, Sachdev PS. Midlife hypertension and Alzheimer’s disease: a systematic review and meta-analysis. J Alzheimers Dis. 2019;71(1):307-316. doi:10.3233/JAD-190474 - DOI - PubMed
1. Forte G, De Pascalis V, Favieri F, Casagrande M. Effects of blood pressure on cognitive performance: a systematic review. J Clin Med. 2019;9(1):34. doi:10.3390/jcm9010034 - DOI - PMC - PubMed
1. van Dalen JW, Brayne C, Crane PK, et al. . Association of systolic blood pressure with dementia risk and the role of age, U-shaped associations, and mortality. JAMA Intern Med. 2022;182(2):142-152. doi:10.1001/jamainternmed.2021.7009 - DOI - PMC - PubMed

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[1] Bloch MJ. Worldwide prevalence of hypertension exceeds 1.3 billion. J Am Soc Hypertens. 2016;10(10):753-754. doi:10.1016/j.jash.2016.08.006 - DOI - PubMed

[2] Bloch MJ. Worldwide prevalence of hypertension exceeds 1.3 billion. J Am Soc Hypertens. 2016;10(10):753-754. doi:10.1016/j.jash.2016.08.006 - DOI - PubMed

[3] Livingston G, Huntley J, Sommerlad A, et al. . Dementia prevention, intervention, and care: 2020 report of the Lancet Commission. Lancet. 2020;396(10248):413-446. doi:10.1016/S0140-6736(20)30367-6 - DOI - PMC - PubMed

[4] Livingston G, Huntley J, Sommerlad A, et al. . Dementia prevention, intervention, and care: 2020 report of the Lancet Commission. Lancet. 2020;396(10248):413-446. doi:10.1016/S0140-6736(20)30367-6 - DOI - PMC - PubMed

[5] Lennon MJ, Makkar SR, Crawford JD, Sachdev PS. Midlife hypertension and Alzheimer’s disease: a systematic review and meta-analysis. J Alzheimers Dis. 2019;71(1):307-316. doi:10.3233/JAD-190474 - DOI - PubMed

[6] Lennon MJ, Makkar SR, Crawford JD, Sachdev PS. Midlife hypertension and Alzheimer’s disease: a systematic review and meta-analysis. J Alzheimers Dis. 2019;71(1):307-316. doi:10.3233/JAD-190474 - DOI - PubMed

[7] Forte G, De Pascalis V, Favieri F, Casagrande M. Effects of blood pressure on cognitive performance: a systematic review. J Clin Med. 2019;9(1):34. doi:10.3390/jcm9010034 - DOI - PMC - PubMed

[8] Forte G, De Pascalis V, Favieri F, Casagrande M. Effects of blood pressure on cognitive performance: a systematic review. J Clin Med. 2019;9(1):34. doi:10.3390/jcm9010034 - DOI - PMC - PubMed

[9] van Dalen JW, Brayne C, Crane PK, et al. . Association of systolic blood pressure with dementia risk and the role of age, U-shaped associations, and mortality. JAMA Intern Med. 2022;182(2):142-152. doi:10.1001/jamainternmed.2021.7009 - DOI - PMC - PubMed

[10] van Dalen JW, Brayne C, Crane PK, et al. . Association of systolic blood pressure with dementia risk and the role of age, U-shaped associations, and mortality. JAMA Intern Med. 2022;182(2):142-152. doi:10.1001/jamainternmed.2021.7009 - DOI - PMC - PubMed

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Use of Antihypertensives, Blood Pressure, and Estimated Risk of Dementia in Late Life: An Individual Participant Data Meta-Analysis

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Use of Antihypertensives, Blood Pressure, and Estimated Risk of Dementia in Late Life: An Individual Participant Data Meta-Analysis

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