Cited by 212Dementia and Cognitive Impairment ResearchAlzheimer's disease research and treatmentsBlood Pressure and Hypertension Studies

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Associations of Anti-Hypertensive Treatments with Alzheimer's Disease, Vascular Dementia, and Other Dementias

Davies, Neil M., Kehoe, Patrick G, Ben-Shlomo, Yoav, Martin, Richard M.·2011·Journal of Alzheimer’s Disease

DOI 10.3233/jad-2011-110347

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Abstract

We investigated whether angiotensin II receptor blockers (ARBs) and angiotensin converting enzyme inhibitors (ACE-Is) are more strongly associated with Alzheimer's disease (AD), vascular dementia (VaD), and other dementias, than other anti-hypertensive drugs. We conducted a nested case-control analysis within the UK general practice research database, with prospectively recorded anti-hypertensive prescribing data. We sampled cases aged ≥60 years and diagnosed between 1997–2008 (5,797 with AD, 2,186 with VaD, 1,214 with unspecified/other dementia) which were matched to up to four controls by age, general practice and gender. We computed odds-ratios and dose response effects for AD, vascular and unspecified/other dementia, comparing those prescribed ARBs or ACE-Is for at least six months with patients prescribed other anti-hypertensives. We controlled for matching factors, co-morbidities, smoking status, an area measure of socioeconomic status, consultation rate and blood pressure and accounted for reverse causality by introducing time-lags of up to eight years prior to diagnosis/index date. Patients diagnosed with AD, vascular and unspecified/other dementia had fewer prescriptions for ARBs and ACE-Is. Inverse associations with AD were strongest for ARBs (odds-ratio; 0.47, 95%CI, 0.37–0.58) compared with ACE-Is (odds-ratio; 0.76, 95%CI, 0.69–0.84) (p difference < 0.001). Associations of ARBs with AD were stronger than for vascular dementia (p difference = 0.01) and unspecified/other dementia (p difference = 0.23). There were inverse dose-response relationships between ARBs and ACE-Is with AD (both p trend < 0.01). The inverse association of ACE-Is with AD diminished when using longer time lags but the ARB-AD association persisted. Patients with AD were around half as likely to be prescribed ARBs. Further randomized controlled trial evidence is required to rigorously test these findings.

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“Recently several large clinical studies [158, 183] have reported that antihypertensive drugs that modulate the RAS, that is, RAS blockers, such as angiotensin receptor blockers [ARBs] or angiotensin-converting enzyme [ACE] inhibitors, are associated with a decreased incidence of AD and reduced rates of cognitive decli…”
Background
Inhibition of central angiotensin converting enzyme ameliorates scopolamine induced memory impairment in mice: Role of cholinergic neurotransmission, cerebral blood flow and brain energy metabolism
Tota, S., Nath, C., Najmi, A. K., Shukla, R., & Hanif, K. (2012) · Behavioural Brain Research · doi:10.1016/j.bbr.2012.03.015 · Cited by 57
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“Anti-hypertensive therapies targeting RAAS function (ACE-Is and ARBs -- not DRIs, since there is limited evidence most likely due to the short time they have been in use) are associated with lower incidence of AD in UK-based [37] and US-based patients [38].”
BackgroundResultSelf-citation
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Neuroprotective effect of angiotensin II receptor blockers on the risk of incident Alzheimer’s disease: A nationwide population-based cohort study
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“This result is consistent with some clinical studies that have shown the advantageous effect of ARBs over ACEIs in reducing AD risk (Li et al., 2010; Davies et al., 2011; Barthold et al., 2018; Marcum et al., 2022).”
BackgroundResult
Angiotensin Receptor Blockers and Cognition: a Scoping Review
Zhou, Z., Orchard, S. G., Nelson, M. R., Fravel, M. A., & Ernst, M. E. (2023) · Current Hypertension Reports · doi:10.1007/s11906-023-01266-0 · Cited by 47
“…age 82 years) with good adherence to anti-hypertensive therapy, the use of either ARBs or ACEis was associated with a reduced risk of AD compared with the use of other classes, and a stronger inverse association was observed with ARBs than ACEis (odds ratios, 0.47 and 0.76, respectively) [32].”
Influential
Hypertension exacerbates predisposition to neurodegeneration and memory impairment in the presence of a neuroinflammatory stimulus: Protection by angiotensin converting enzyme inhibition
Goel, R., Bhat, S. A., Rajasekar, N., Hanif, K., Nath, C., & Shukla, R. (2015) · Pharmacology Biochemistry and Behavior · doi:10.1016/j.pbb.2015.04.002 · Cited by 47
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Antihypertensive and neuroprotective effects of catestatin in spontaneously hypertensive rats: Interaction with GABAergic transmission in amygdala and brainstem
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“These risks seem to be tightly correlated with the incidence of dementia (Qiu et al., 2005; Igase et al., 2012), Alzheimer’s disease (AD; Davies et al., 2011), and diminished cognitive abilities (Wysocki et al., 2012); yet, only the former two mental defects proved to be altered in middle-aged…”
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“based on previously validated algorithms [24].”
An integrative genome-wide transcriptome reveals that candesartan is neuroprotective and a candidate therapeutic for Alzheimer’s disease
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“are not associated with risk of AD [6, 7], we think that”
Direct angiotensin II type 2 receptor stimulation by compound 21 prevents vascular dementia
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“Similar results were reported by Davies et al, who conducted a nested case–control analysis within the UK general practice research database.(4) Fuentes et al reported that patients taking antihypertensive drugs at stroke onset had a lower rate of poor outcome than those not on antihypertensive treatment, and those ta…”
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“Data from large retrospective clinical studies (Li et al., 2010; Davies et al., 2011) and secondary explorations of clinical trial studies (Gao et al., 2013; O’Caoimh et al., 2014) suggest that use of ARBs may be protective against the development and progression of AD (reviewed in Ashby and Kehoe,…”
MethodSelf-citation
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“In addition, two RCTs [7, 18], two cohort studies [14, 17] and one case-control study [4] analyzed the impact of ARBs use on the incidence of dementia.”
Influential
COVID-19 as a Risk Factor for Alzheimer’s Disease
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“To ameliorate the cognitive symptoms of AD, ACE2 therapeutics have been suggested despite their consequence of increasing levels of ACE2 [109].”
Background
Intracerebroventricular Infusion of Angiotensin-(1–7) Ameliorates Cognitive Impairment and Memory Dysfunction in a Mouse Model of Alzheimer’s Disease
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“Interestingly, treatment with RAS blockers of hypertensive patients is associated with slowing of cognitive impairment and AD progression [1, 4–8].”
Impact of renin-angiotensin system-targeting antihypertensive drugs on treatment of Alzheimer's disease: a meta-analysis
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The Rationale and Design of the Reducing Pathology in Alzheimer’s Disease through Angiotensin TaRgeting (RADAR) Trial
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“Recently, we [9] and others [10] observed that angiotensin II (AngII) targeting drugs (AngII type 1 receptor antagonists (AT1RAs) and angiotensin converting enzyme inhibitors (ACEIs) had lower incidence of AD compared with other types of anti-hypertensive drugs.”
Self-citation
Renin Angiotensin Aldosterone System Inhibition in Controlling Dementia-Related Cognitive Decline
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“Those treated with ARBs also have a significant reduction in the incidence and progression of AD compared to those taking ACE-Is or other cardiovascular drugs [15], although further analysis to adjust for protopathic bias reduced the overall protective effect [62].”
ResultSelf-citation
Chronic Renin-Angiotensin System Activation Induced Neuroinflammation: Common Mechanisms Underlying Hypertension and Dementia?
Tran, S., Kuruppu, S., & Rajapakse, N. W. (2021) · Journal of Alzheimer s Disease · doi:10.3233/jad-215231 · Cited by 35
“…had no previous dementia [77, 80] or were diagnosed with dementia [78] also demonstrated decreased incidence of AD and dementia, however to a much lesser degree than patients using ARBs [77, 78], while other studies found that ACE-Is as a drug class had no inﬂuence on the risk of AD [81, 82].”
Angiotensin type 1a receptor deficiency decreases amyloid β-protein generation and ameliorates brain amyloid pathology
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In silico Structure-based Identification of Novel Acetylcholinesterase Inhibitors Against Alzheimer’s Disease
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The Brain AT2R—a Potential Target for Therapy in Alzheimer’s Disease and Vascular Cognitive Impairment: a Comprehensive Review of Clinical and Experimental Therapeutics
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Antihypertensive Agents and Incident Alzheimer's Disease: A Systematic Review and Meta-Analysis of Observational Studies
Adesuyan, M., Jani, Y. H., Alsugeir, D. M., Cheung, E. C. L., Chui, C. S. L., Howard, R. J., Wong, I. C. K., & Brauer, R. (2022) · The Journal of Prevention of Alzheimer s Disease · doi:10.14283/jpad.2022.77 · Cited by 33

Authors: Davies, N. M., Kehoe, P. G., Ben-Shlomo, Y., & Martin, R. M.
Affiliations: University of Bristol (GB)
Frenchay Hospital (GB)
School of Social and Community Medicine, Faculty of Medicine and Dentistry, University of Bristol, Canynge Hall, Bristol, UK
Corresponding author: Kehoe, Patrick G
ORCID: Davies, Neil M.
Kehoe, Patrick G
Martin, Richard M.
Venue: Journal of Alzheimer’s Disease
Publisher: SAGE Publications
Published: 2011-10-04
Volume: 26
Issue: 4
Pages: 699-708
ISSN: 1387-2877 (ISSN-L)
1875-8908
DOI: 10.3233/jad-2011-110347
OpenAlex: W1828947725
Cited by: 212
References: 41
Citations by year: 2026: 3 · 2025: 3 · 2024: 12 · 2023: 9 · 2022: 9 · 2021: 16 · 2020: 17 · 2019: 8 · 2018: 14 · 2017: 12 · 2016: 28 · 2015: 15 · 2014: 18 · 2013: 24 · 2012: 19
FWCI: 14.44
Type: journal article
Language: en
Open access: closed
Licence: journals.sagepub.com/page/policies/text-and-data-mining-license (tdm)
Locations: Journal of Alzheimer s Disease (publishedVersion)
PubMed (publishedVersion)
Explore Bristol Research (publishedVersion)
Bristol Research (University of Bristol) (submittedVersion)
Funders: North Bristol NHS Trust
Medical Research Council
Topics: Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Blood Pressure and Hypertension Studies
Keywords: angiotensin receptor blockers, ACE inhibitors
MeSH terms: Aged, Aged, 80 and over, Alzheimer Disease, Angiotensin-Converting Enzyme Inhibitors, Antihypertensive Agents, Blood Pressure, Data Interpretation, Statistical, Dementia, Dose-Response Relationship, Drug, Female, United Kingdom, Humans, Male, Socioeconomic Factors, Dementia, Vascular, Case-Control Studies, Databases, Factual, Angiotensin II Type 1 Receptor Blockers

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Associations of Anti-Hypertensive Treatments with Alzheimer's Disease, Vascular Dementia, and Other Dementias

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