Blood pressure, antihypertensive use, and late-life alzheimer and non-alzheimer dementia risk : An individual participant data meta-analysis

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.

© 2024 American Academy of Neurology.

n Australia, the project is funded by a National Health and Medical Research Council grant (grant number APP1169489). Research reported in this publication was supported by the National Institute on Aging of the NIH under Award Number R01AG057531. The EPIDEMCA study was funded by the French National Research Agency (ANR-09-MNPS-009–01), the AXA Research Fund (grant 2012–Project Public Health Institute [Inserm]–PREUX Pierre-Marie), and the Limoges University Hospital through its Appel à Projet des Equipes Émergentes et Labellisées scheme The HELIAD cohort was funded by the Alzheimer's Association, European Social Fund, and Greek Ministry of Health. Alzheimer's Association under grant IIRG-09-133014; National Strategic Reference Framework (NSRF)-EU program Excellence Grant (ARISTEIA), which is cofunded by the European Social Fund and Greek financial resources under grant 189 10276/8/9/2011; and the Greek Ministry for Health and Social Solidarity under grant DY2b/oik.51657/14.4.2009. The LEILA75+ study was funded by the Interdisciplinary Centre for Clinical Research at the University of Leipzig (grant 01KS9504). The MAS study was funded by the National Health and Medical Research Council (grant numbers APP350833, APP568969, and APP1093083) in Australia. Funding for the CLAS study was from the Ministry of Science and Technology, National Pillar Program 2009BAI77B03 and the National Key Clinical Disciplines at Shanghai Mental Health Center (Office of Medical Affairs, Ministry of Health, 2011-873). The H70 study was supported by AgeCap-Center for Aging and Health, Riksbankens Jubileumsfond, FORTE, and the Swedish Brain Power. The H70 study data collection was supported by The Swedish Research Council, Swedish Research Council for Health, Working Life and Welfare, Epilife, Swedish Brain Power, The Alzheimer's Association Zenith Award, The Alzheimer's Association Stephanie B Overstreet Scholars, The Bank of Sweden Tercentenary Foundation, Stiftelsen Söderström-Königska Sjukhemmet, Stiftelsen för Gamla Tjänarinnor, Handlanden Hjalmar Svenssons Forskningsfond, and Stiftelsen Professor Bror Gadelius' Minnesfond. KLOSCAD was supported by a grant from the Korean Health Technology R&D Project, Ministry of Health and Welfare, South Korea (grant number HI09C1379 [A092077]). PATH is funded by NHMRC Grants 973302, 179805, 418039, 1002160. SLAS was supported by a research grant (number 03/1/21/17/214) from the Biomedical Research Council, Agency for Science, Technology and Research, Singapore. ZARADEMP Study was supported by grants from the Fondo de Investigación Sanitaria, Instituto de Salud Carlos III, Spanish Ministry of Economy and Competitiveness, Madrid, Spain (grants 94/1562, 97/1321E, 98/0103, 01/0255, 03/0815, 06/0617, G03/128, 12/02254, 16/00896, 19/01874), and the Fondo Europeo de Desarrollo Regional (FEDER) of the European Union and Gobierno de Aragón (grant B15_17R). The ESPRIT project is financed by the regional government of Languedoc-Roussillon, the Agence National de Recherche (ANR) Project 07 LVIE 004, and an unconditional grant from Novartis. The Einstein Aging Study (EAS) is supported by the NIA (P01AG03949), the Czap Foundation, and the Max and Sylvia Marx Foundation. SPAH was funded by the Wellcome Trust (GR066133MA), UK and FAPESP (grant number 1998/12727-0), São Paulo, Brazil; Marcia Scazufca is supported by CNPq-Brazil (307579/2019-0). Funding for COSMIC comes from the NIA–NIH (award number 1RF1AG057531–01). The funder approved the initial plan for the consortium but had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; or decision to submit the manuscript for publication.