Central‐acting vs. Peripheral‐acting Angiotensin Converting Enzyme‐inhibitors and the risk of Alzheimer’s disease: A cohort study
Matthew Adesuyan, Ruth Brauer, Yogini Jani- Psychiatry and Mental health
- Cellular and Molecular Neuroscience
- Geriatrics and Gerontology
- Neurology (clinical)
- Developmental Neuroscience
- Health Policy
- Epidemiology
Abstract
Background
Cerebral Angiotensin converting enzyme (ACE) has been shown to cleave amyloid‐beta (Aβ) and its expression may have a protective effect on the risk of Alzheimer’s disease (AD). However, there are conflicting reports of the association between ACE‐inhibitors (ACEi) and AD. ACE‐i drugs differ in their ability to cross the blood brain barrier and inhibit cerebral ACE activity. No previous study has investigated the effect of ACE‐i on the risk of AD based on their different pharmacological properties.
Method
A population based cohort study was performed using real‐world data from the IQVIA Medical Research Database (IMRD‐UK). Adults aged ≥40 years initiating ACEi therapy were followed from 2000‐2021. Based on previous studies of tissue‐specific ACE‐activity and radio‐labelled imaging after administration of ACEi, we classified ACEi as either central (CA) or non‐central (NC) acting. New users of CA‐ACEi were compared with new users of NC‐ACEi. Diagnostic read codes linked to clinical diagnoses were used to measure the primary outcome of incident AD. Potential confounders including, laboratory results, socioeconomic status, comorbidities, co‐prescriptions, smoking, alcohol and body mass index were adjusted for using multivariable Cox proportional hazard regression to estimate adjusted hazard ratios (HR) with 95% confidence intervals (CI).
Result
The cohort included 808,180 new ACEi initiators, with 7,356 newly diagnosed with AD during a median follow up of 8 (IQR 4‐12) years. The crude incidence rate (IR) for users of CA‐ACEi was 18.6 per 10,000 PYAR (95% CI 18.2‐19.1) and 21.6 per 10,000 PYAR (95% CI 19.3‐24.2) in NC‐ACEi initiators. The adjusted HR for the associated risk of AD in CA‐ACEi compared to NC‐ACEi was 0.83 (95% CI, 0.74‐0.94; p = 0.002). Primary results were robust to sensitivity analysis that required the outcome of AD to include both a clinical diagnosis and prescription for symptomatic treatment of AD; HR 0.80 (95% CI 0.69‐0.92; p = 0.002).
Conclusion
Conversely, CA‐ACEi with penetrative blood‐brain‐barrier properties were associated with a lower risk of AD compared to NC‐ACEi. This may be due to improved cerebral blood flow and the prevention of angiotensin II‐mediated inhibition of acetylcholine. Our results question the significant contribution of ACE mediated Aβ degradation.