What is the clinical evidence from this study?

Study design: Cohort. Population: Ischemic heart disease (n=57420). Intervention: Blood-brain barrier-crossing angiotensin II receptor blockers (ARBs) vs. Non-users of renin-angiotensin system inhibitors. Primary outcome: Incidence of Alzheimer's disease (aHR 0.83, 95% CI 0.78-0.88).

March 6, 2023Frontiers in Aging Neuroscience45 citationsOpen Access

Neuroprotective effect of angiotensin II receptor blockers on the risk of incident Alzheimer’s disease: A nationwide population-based cohort study

HLHyun Woo LeeSeoul National University SKSeung Yeon KimInternational Vaccine Institute YJYoungkwon JoYonsei University

Key Result

Blood-brain barrier-crossing angiotensin II receptor blockers significantly reduced the risk of incident Alzheimer's disease by 17% compared to non-users in patients with ischemic heart disease.

Study Design

Type

Cohort (n=57,420)

Structured PICO

Does the use of angiotensin II receptor blockers reduce the risk of incident Alzheimer's disease in patients with ischemic heart disease?

Population

57,420 propensity score-matched individuals diagnosed with ischemic heart disease between January 2009 and June 2009 in South Korea.

Intervention

Angiotensin II receptor blockers (ARBs), including blood-brain barrier (BBB)-crossing ARBs

Comparator

Non-users of renin-angiotensin system (RAS) inhibitors

Outcome

Incident Alzheimer's diseasehard clinical

Long-term use of blood-brain barrier-crossing ARBs is associated with a significantly reduced risk of incident Alzheimer's disease in patients with ischemic heart disease.

Main Result

Effect estimate: aHR 0.83 (95% CI 0.78-0.88)

Absolute Event Rate: 12.96% vs 15.07%

Limitations

Use of a secondary claims database lacking detailed clinical information such as symptoms, body weight, blood pressure, smoking, and APOE ε4 status
Reliance on ICD-10 diagnostic codes for identifying incident Alzheimer's disease
Potential selection bias due to a short 6-month identification period
Inability to use active comparators (e.g., beta-blockers, calcium channel blockers) for direct comparison
Limited generalizability as the study population consisted exclusively of patients with ischemic heart disease
Inability to account for the duration or cumulative doses of concomitant medications

Abstract

Background Recent studies on renin-angiotensin system (RAS) inhibitors have reported a reduced risk of Alzheimer’s disease (AD). Nevertheless, the effect of RAS inhibitor type and blood–brain barrier (BBB) permeability on the risk of AD is still unknown. Objectives To assess the effects of RAS inhibitors on the risk of AD based on the type and BBB permeability and investigate the cumulative duration-response relationship. Methods This was a population-based retrospective cohort study using the Korean Health Insurance Review and Assessment database records from 2008 to 2019. The data of patients diagnosed with ischemic heart disease between January 2009 and June 2009 were identified for inclusion in the analyses. Propensity score matching was used to balance RAS inhibitor users with non-users. The association between the use of RAS inhibitors and incident AD was evaluated using a multivariate Cox proportional hazard regression model. The results are presented in adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs). Results Among the 57,420 matched individuals, 7,303 developed AD within the follow-up period. While the use of angiotensin-converting enzyme inhibitors (ACEIs) was not significantly associated with AD risk, the use of angiotensin II receptor blockers (ARBs) showed a significant association with reduced risk of incident AD (aHR = 0.94; 95% CI = 0.90–0.99). Furthermore, the use of BBB-crossing ARBs was associated with a lower risk of AD (aHR = 0.83; 95% CI = 0.78–0.88) with a cumulative duration-response relationship. A higher cumulative dose or duration of BBB-crossing ARBs was associated with a gradual decrease in AD risk ( P for trend 0.001 ). No significant association between the use of ACEIs and the risk of AD was observed regardless of BBB permeability. Conclusion Long-term use of BBB-crossing ARBs significantly reduced the risk of AD development. The finding may provide valuable insight into disease-modifying drug options for preventing AD in patients with cardiovascular diseases.

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