Meta-Analysis

. 2024 Sep 10;103(5):e209715.

doi: 10.1212/WNL.0000000000209715. Epub 2024 Aug 14.

Blood Pressure, Antihypertensive Use, and Late-Life Alzheimer and Non-Alzheimer Dementia Risk: An Individual Participant Data Meta-Analysis

Matthew J Lennon¹, Darren M Lipnicki¹, Ben Chun Pan Lam¹, John D Crawford¹, Aletta E Schutte¹, Ruth Peters¹, Therese Rydberg-Sterner¹, Jenna Najar¹, Ingmar Skoog¹, Steffi G Riedel-Heller¹, Susanne Röhr¹, Alexander Pabst¹, Antonio Lobo¹, Concepción De-la-Cámara¹, Elena Lobo¹, Richard B Lipton¹, Mindy J Katz¹, Carol A Derby¹, Ki Woong Kim¹, Ji Won Han¹, Dae Jong Oh¹, Elena Rolandi¹, Annalisa Davin¹, Michele Rossi¹, Nikolaos Scarmeas¹, Mary Yannakoulia¹, Themis Dardiotis¹, Hugh C Hendrie¹, Sujuan Gao¹, Isabelle Carriere¹, Karen Ritchie¹, Kaarin J Anstey¹, Nicolas Cherbuin¹, Shifu Xiao¹, Ling Yue¹, Wei Li¹, Maëlenn Guerchet¹, Pierre-Marie Preux¹, Victor Aboyans¹, Mary N Haan¹, Allison Aiello¹, Marcia Scazufca¹, Perminder S Sachdev¹; as the Cohort Studies of Memory in an International Consortium (COSMIC) Group¹

Affiliations

Affiliation

¹ From the Faculty of Medicine and Health (M.J.L., D.M.L., B.C.P.L., J.D.C., P.S.S.), and Centre for Healthy Brain Aging (CHeBA) (M.J.L., D.M.L., B.C.P.L., J.D.C., P.S.S.), Discipline of Psychiatry & Mental Health, School of Clinical Medicine, University of New South Wales, Sydney; School of Psychology and Public Health (B.C.P.L.), La Trobe University, Melbourne; The George Institute for Global Health (A.E.S., R.P.), Barangaroo; School of Biomedical Sciences (R.P.), University of New South Wales, Sydney, Australia; School of Public Health (R.P.), Imperial College London, United Kingdom; School of Population Health (A.E.S.), University of New South Wales, Sydney, Australia; Neuropsychiatric Epidemiology Unit (T.R.-S., J.N., I.S.), Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy, Centre for Ageing and Health (AGECAP) at the University of Gothenburg; Aging Research Center (T.R.-S.), Department of Neurobiology, Care Sciences and Society, Karolinska Institutet and Stockholm University; Region Västra Götaland (J.N., I.S.), Sahlgrenska University Hospital, Psychiatry, Cognition and Old Age Psychiatry Clinic, Gothenburg, Sweden; Section Genomics of Neurodegenerative Diseases and Aging (J.N.), Department of Clinical Genetics, Vrije Universiteit Amsterdam, Amsterdam UMC, the Netherlands; Institute of Social Medicine (S.G.R.-H., S.R., A.P.), Occupational Health and Public Health (ISAP), Medical Faculty, University of Leipzig, Germany; School of Psychology (S.R.), Massey University, Albany Campus, Auckland, New Zealand; Global Brain Health Institute (GBHI) (S.R.), Trinity College Dublin, Ireland; Department of Medicine and Psychiatry (A.L., C.D.-l-C.), Universidad de Zaragoza; Instituto de Investigación Sanitaria Aragón (IIS Aragón) (A.L., C.D.-l-C., E.L.), Zaragoza; CIBERSAM (A.L., C.D.-l-C., E.L.), Madrid, Spain; Department of Preventive Medicine and Public Health (E.L.), Universidad de Zaragoza, Spain; Department of Neurology (R.B.L., M.J.K., C.A.D.), and Department of Epidemiology and Population Health (R.B.L., C.A.D.), Albert Einstein College of Medicine, Bronx, NY; Department of Neuropsychiatry (K.W.K., J.W.H.), Seoul National University Bundang Hospital, Seongnam; Department of Psychiatry (K.W.K., J.W.H.), Seoul National University College of Medicine; Department of Brain and Cognitive Sciences (K.W.K.), Seoul National University College of Natural Sciences; Workplace Mental Health Institute (D.J.O.), Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, South Korea; Golgi Cenci Foundation (E.R., A.D., M.R.), Abbiategrasso, Milan; Department of Brain and Behavioural Sciences (E.R.), University of Pavia, Italy; 1st Department of Neurology (N.S.), Aiginition Hospital, National and Kapodistrian University of Athens, Greece; Department of Neurology (N.S.), Columbia University, New York, NY; School of Health Sciences and Education (M.Y.), Department of Nutrition and Dietetics, Harokopio University; Department of Neurology (T.D.), University Hospital of Larissa; Faculty of Medicine (T.D.), School of Health Sciences, University of Thessaly, Larissa, Greece; Department of Psychiatry (H.C.H.), Indiana University School of Medicine; Indiana Alzheimer Disease Research Center (H.C.H., S.G.), Indiana Alzheimer Disease Research Center; Department of Biostatistics and Health Data Science (S.G.), Indiana University School of Medicine, Indianapolis; Institut for Neurosciences of Montpellier INM (I.C., K.R.), University Montpellier, INSERM; Institut du Cerveau Trocadéro (K.R.), Paris, France; School of Psychology (K.J.A.), and Ageing Futures Institute (K.J.A.), University of New South Wales; Neuroscience Research Australia (K.J.A.), Sydney; National Centre for Epidemiology and Population Health (N.C.), Australian National University, Canberra, Australia; Department of Geriatric Psychiatry (S.X., L.Y., W.L.), Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine; Alzheimer's Disease and Related Disorders Center (S.X., L.Y., W.L.), Shanghai Jiao Tong University, China; Inserm U1094 (M.G., P.-M.P., V.A.), IRD UMR270, Univ. Limoges, CHU Limoges, EpiMaCT-Epidemiology of Chronic Diseases in Tropical Zone, Institute of Epidemiology and Tropical Neurology, OmegaHealth, France; Laboratory of Chronic and Neurological Diseases Epidemiology (LEMACEN) (M.G.), Faculty of Health Sciences, University of Abomey-Calavi, Cotonou, Benin; Department of Cardiology (V.A.), Dupuytren 2 University Hospital, Limoges, France; School of Medicine (M.N.H.), University of California, San Francisco; Robert N. Butler Columbia Aging Center (A.A.), Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY; Departamento de Psiquiatria (M.S.), Faculdade de Medicina FMUSP, Universidade de Sao Paulo, Brazil; and Neuropsychiatric Institute (P.S.S.), Prince of Wales Hospital, Sydney, Australia.

PMID: 39141884
PMCID: PMC11329294
DOI: 10.1212/WNL.0000000000209715

Meta-Analysis

Blood Pressure, Antihypertensive Use, and Late-Life Alzheimer and Non-Alzheimer Dementia Risk: An Individual Participant Data Meta-Analysis

Matthew J Lennon et al. Neurology. 2024.

. 2024 Sep 10;103(5):e209715.

doi: 10.1212/WNL.0000000000209715. Epub 2024 Aug 14.

Authors

Affiliation

¹ From the Faculty of Medicine and Health (M.J.L., D.M.L., B.C.P.L., J.D.C., P.S.S.), and Centre for Healthy Brain Aging (CHeBA) (M.J.L., D.M.L., B.C.P.L., J.D.C., P.S.S.), Discipline of Psychiatry & Mental Health, School of Clinical Medicine, University of New South Wales, Sydney; School of Psychology and Public Health (B.C.P.L.), La Trobe University, Melbourne; The George Institute for Global Health (A.E.S., R.P.), Barangaroo; School of Biomedical Sciences (R.P.), University of New South Wales, Sydney, Australia; School of Public Health (R.P.), Imperial College London, United Kingdom; School of Population Health (A.E.S.), University of New South Wales, Sydney, Australia; Neuropsychiatric Epidemiology Unit (T.R.-S., J.N., I.S.), Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy, Centre for Ageing and Health (AGECAP) at the University of Gothenburg; Aging Research Center (T.R.-S.), Department of Neurobiology, Care Sciences and Society, Karolinska Institutet and Stockholm University; Region Västra Götaland (J.N., I.S.), Sahlgrenska University Hospital, Psychiatry, Cognition and Old Age Psychiatry Clinic, Gothenburg, Sweden; Section Genomics of Neurodegenerative Diseases and Aging (J.N.), Department of Clinical Genetics, Vrije Universiteit Amsterdam, Amsterdam UMC, the Netherlands; Institute of Social Medicine (S.G.R.-H., S.R., A.P.), Occupational Health and Public Health (ISAP), Medical Faculty, University of Leipzig, Germany; School of Psychology (S.R.), Massey University, Albany Campus, Auckland, New Zealand; Global Brain Health Institute (GBHI) (S.R.), Trinity College Dublin, Ireland; Department of Medicine and Psychiatry (A.L., C.D.-l-C.), Universidad de Zaragoza; Instituto de Investigación Sanitaria Aragón (IIS Aragón) (A.L., C.D.-l-C., E.L.), Zaragoza; CIBERSAM (A.L., C.D.-l-C., E.L.), Madrid, Spain; Department of Preventive Medicine and Public Health (E.L.), Universidad de Zaragoza, Spain; Department of Neurology (R.B.L., M.J.K., C.A.D.), and Department of Epidemiology and Population Health (R.B.L., C.A.D.), Albert Einstein College of Medicine, Bronx, NY; Department of Neuropsychiatry (K.W.K., J.W.H.), Seoul National University Bundang Hospital, Seongnam; Department of Psychiatry (K.W.K., J.W.H.), Seoul National University College of Medicine; Department of Brain and Cognitive Sciences (K.W.K.), Seoul National University College of Natural Sciences; Workplace Mental Health Institute (D.J.O.), Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, South Korea; Golgi Cenci Foundation (E.R., A.D., M.R.), Abbiategrasso, Milan; Department of Brain and Behavioural Sciences (E.R.), University of Pavia, Italy; 1st Department of Neurology (N.S.), Aiginition Hospital, National and Kapodistrian University of Athens, Greece; Department of Neurology (N.S.), Columbia University, New York, NY; School of Health Sciences and Education (M.Y.), Department of Nutrition and Dietetics, Harokopio University; Department of Neurology (T.D.), University Hospital of Larissa; Faculty of Medicine (T.D.), School of Health Sciences, University of Thessaly, Larissa, Greece; Department of Psychiatry (H.C.H.), Indiana University School of Medicine; Indiana Alzheimer Disease Research Center (H.C.H., S.G.), Indiana Alzheimer Disease Research Center; Department of Biostatistics and Health Data Science (S.G.), Indiana University School of Medicine, Indianapolis; Institut for Neurosciences of Montpellier INM (I.C., K.R.), University Montpellier, INSERM; Institut du Cerveau Trocadéro (K.R.), Paris, France; School of Psychology (K.J.A.), and Ageing Futures Institute (K.J.A.), University of New South Wales; Neuroscience Research Australia (K.J.A.), Sydney; National Centre for Epidemiology and Population Health (N.C.), Australian National University, Canberra, Australia; Department of Geriatric Psychiatry (S.X., L.Y., W.L.), Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine; Alzheimer's Disease and Related Disorders Center (S.X., L.Y., W.L.), Shanghai Jiao Tong University, China; Inserm U1094 (M.G., P.-M.P., V.A.), IRD UMR270, Univ. Limoges, CHU Limoges, EpiMaCT-Epidemiology of Chronic Diseases in Tropical Zone, Institute of Epidemiology and Tropical Neurology, OmegaHealth, France; Laboratory of Chronic and Neurological Diseases Epidemiology (LEMACEN) (M.G.), Faculty of Health Sciences, University of Abomey-Calavi, Cotonou, Benin; Department of Cardiology (V.A.), Dupuytren 2 University Hospital, Limoges, France; School of Medicine (M.N.H.), University of California, San Francisco; Robert N. Butler Columbia Aging Center (A.A.), Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY; Departamento de Psiquiatria (M.S.), Faculdade de Medicina FMUSP, Universidade de Sao Paulo, Brazil; and Neuropsychiatric Institute (P.S.S.), Prince of Wales Hospital, Sydney, Australia.

PMID: 39141884
PMCID: PMC11329294
DOI: 10.1212/WNL.0000000000209715

Abstract

Background and objectives: Previous randomized controlled trials and longitudinal studies have indicated that ongoing antihypertensive use in late life reduces all-cause dementia risk, but the specific impact on Alzheimer dementia (AD) and non-AD risk remains unclear. This study investigates whether previous hypertension or antihypertensive use modifies AD or non-AD risk in late life and the ideal blood pressure (BP) for risk reduction in a diverse consortium of cohort studies.

Methods: This individual participant data meta-analysis included community-based longitudinal studies of aging from a preexisting consortium. The main outcomes were risk of developing AD and non-AD. The main exposures were hypertension history/antihypertensive use and baseline systolic BP/diastolic BP. Mixed-effects Cox proportional hazards models were used to assess risk and natural splines were applied to model the relationship between BP and the dementia outcomes. The main model controlled for age, age², sex, education, ethnoracial group, and study cohort. Supplementary analyses included a fully adjusted model, an analysis restricting to those with >5 years of follow-up and models that examined the moderating effect of age, sex, and ethnoracial group.

Results: There were 31,250 participants from 14 nations in the analysis (41% male) with a mean baseline age of 72 (SD 7.5, range 60-110) years. Participants with untreated hypertension had a 36% (hazard ratio [HR] 1.36, 95% CI 1.01-1.83, p = 0.0406) and 42% (HR 1.42, 95% CI 1.08-1.87, p = 0.0135) increased risk of AD compared with "healthy controls" and those with treated hypertension, respectively. Compared with "healthy controls" both those with treated (HR 1.29, 95% CI 1.03-1.60, p = 0.0267) and untreated hypertension (HR 1.69, 95% CI 1.19-2.40, p = 0.0032) had greater non-AD risk, but there was no difference between the treated and untreated groups. Baseline diastolic BP had a significant U-shaped relationship (p = 0.0227) with non-AD risk in an analysis restricted to those with 5-year follow-up, but otherwise there was no significant relationship between baseline BP and either AD or non-AD risk.

Discussion: Antihypertensive use was associated with decreased AD but not non-AD risk throughout late life. This suggests that treating hypertension throughout late life continues to be crucial in AD risk mitigation. A single measure of BP was not associated with AD risk, but DBP may have a U-shaped relationship with non-AD risk over longer periods in late life.

PubMed Disclaimer

Conflict of interest statement

A.E. Schutte is funded by an Investigator Grant of the National Health and Medical Research Council of Australia (GNT2017504), and received speaker honoraria from Servier, Novartis, Abbott, Medtronic, Omron, and Aktiia. J. Najar was funded by Alzheimersfonden (AF-967865), the ALF-agreement (72660), and Stiftelsens Hjalmar Svenssons forskningsfond (HJSV2022059, HJSV2023023). A. Lobo had a consultancy with Janssen and received financial support to attend scientific meetings from Eli Lilly, Bial, and Janssen. C. De-la-Cámara received financial support to attend scientific meetings from Janssen, Almirall, Lilly, Lundbeck, Rovi, Esteve, Novartis, AstraZeneca, Pfizer, and Casen Recordati. E. Lobo has received an honorarium from the University of Granada. K.J. Anstey is supported by ARC Laureate Fellowship FL190100011, and received a speaker honoraria from Roche. The other authors report no relevant disclosures. Go to Neurology.org/N for full disclosures.

Figures

**Figure 1. Association of HTN/AHT Status With AD and Non-AD Risk**
The association of HTN/AHT status with the risk of AD and non-AD dementia (x-axis in log2 scale). The main analysis (partially adjusted) included covariates of age, age², sex, education, ethnoracial group, and a random effect for study. The fully adjusted analysis included additional covariates of BMI, smoking status, history of hypercholesterolemia, and diabetes mellitus. Each of the other analyses applied the partially adjusted model. The p-values show the size of the interaction effect for age, sex, and ethnoracial group with treated hypertension (compared with “healthy controls”) and untreated hypertension (compared with “healthy controls”). Age was treated as a continuous variable, sex as a categorical variable, and ethnoracial group as a categorical variable with 3 major groups (White, Asian, and Black). The numbers and brackets on the right are the hazard ratios and 95% confidence intervals. The p-values show the significance of the interaction term. The interaction p-values used White participants as the main comparison group in the ethnoracial analysis (as this was the largest group included). AD = Alzheimer dementia; BMI = body mass index; HTN/AHT = hypertension history-antihypertensive use.

**Figure 2. Association Between Continuous SBP/DBP and Both AD and Non-AD Risk Using Nonlinear Natural Splines**
The relationship between SBP, DBP, and AD/non-AD risk with 95% CIs (shaded areas). In all models, SBP and DBP was grand-mean centered (at 140 mm Hg and 80 mm Hg, respectively) and all HRs represent within-group risk relative to this grand-mean. A restricted cubic splines model was applied. (A and B) The main analysis (partially adjusted) which included the covariates of age, age², sex, education, ethnoracial group and a random effect for study. (C and D) The fully adjusted analysis which included additional covariates of BMI, smoking status, history of hypercholesterolemia, and diabetes mellitus. AD = Alzheimer dementia; BMI = body mass index; DBP = diastolic blood pressure; HR = hazard ratio; SBP = systolic blood pressure.

**Figure 3. Association Between Continuous SBP/DBP and Both AD and Non-AD Risk Restricted to Participants With Over 5-Year Follow-Up**
The relationship between SBP, DBP, and AD/non-AD risk with 95% CIs (shaded areas) in participants with over 5 years of follow-up. In all models SBP and DBP was grand-mean centered (at 140 mm Hg and 80 mm Hg, respectively), and all HRs represent within-group risk relative to this grand-mean. A restricted cubic splines model was applied. (A and B) SBP and DBP, respectively, are shown. AD = Alzheimer dementia; BMI = body mass index; DBP = diastolic blood pressure; HR = hazard ratio; SBP = systolic blood pressure.

**Figure 4. Moderating Effect of Age on the Association Between Continuous SBP/DBP and Both AD and Non-AD Risk**
The relationship between SBP, DBP, and AD/non-AD risk with 95% CIs (shaded areas) showing the changing relationship with increasing age. In all models SBP and DBP was grand-mean centered (at 140 mm Hg and 80 mm Hg, respectively), and all HRs represent within-group risk relative to this grand-mean. These models were partially adjusted and included covariates of age, age², sex, education, ethnoracial group, and a random effect for study. A restricted cubic splines model was applied. (A) The significant moderating effect of age on the relationship between baseline SBP and non-AD risk. (B) The significant moderating effect of age on the relationship between baseline DBP and AD risk. AD = Alzheimer dementia; BMI = body mass index; DBP = diastolic blood pressure; HR = hazard ratio; SBP = systolic blood pressure.

See this image and copyright information in PMC

References

1. World Health Organization. Global Report on Hypertension. WHO; 2023.
1. Murray CJL, Aravkin AY, Zheng P, et al. Global burden of 87 risk factors in 204 countries and territories, 1990-2019: a systematic analysis for the Global Burden of Disease Study 2019. Lancet. 2020;396(10258):1223-1249. doi: 10.1016/s0140-6736(20)30752-2 - DOI - PMC - PubMed
1. Emdin CA, Rothwell PM, Salimi-Khorshidi G, et al. Blood pressure and risk of vascular dementia: evidence from a primary care registry and a cohort study of transient ischemic attack and stroke. Stroke. 2016;47(6):1429-1435. doi: 10.1161/STROKEAHA.116.012658 - DOI - PMC - PubMed
1. Guan JW, Huang CQ, Li YH, et al. No association between hypertension and risk for Alzheimer's disease: a meta-analysis of longitudinal studies. J Alzheimers Dis. 2011;27(4):799-807. doi: 10.3233/JAD-2011-111160 - DOI - PubMed
1. Power MC, Weuve J, Gagne JJ, McQueen MB, Viswanathan A, Blacker D. The association between blood pressure and incident Alzheimer disease: a systematic review and meta-analysis. Epidemiology. 2011;22(5):646-659. doi: 10.1097/EDE.0b013e31822708b5 - DOI - PMC - PubMed

Publication types

Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Substances

Actions

Grants and funding

P01 AG003949/AG/NIA NIH HHS/United States

LinkOut - more resources

Full Text Sources
Medical
- MedlinePlus Health Information

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

Blood Pressure, Antihypertensive Use, and Late-Life Alzheimer and Non-Alzheimer Dementia Risk: An Individual Participant Data Meta-Analysis

Affiliation

Blood Pressure, Antihypertensive Use, and Late-Life Alzheimer and Non-Alzheimer Dementia Risk: An Individual Participant Data Meta-Analysis

Authors

Affiliation

Abstract

Conflict of interest statement

Figures

References

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Medical