(096) N-Domain vs. C-Domain Angiotensin Converting Enzyme-inhibitors and the risk of Alzheimer's disease: A cohort study

Publication Number: 757

Background: There are conflicting reports of the association between angiotensin converting enzyme (ACE) inhibitors and the risk of incident Alzheimer’s disease (AD). However, not all ACE-inhibitors are the same. The ACE has two catalytic active binding sites; N-domain and C-domain. Studies have shown that N-domain site cleavage is responsible for amyloid-beta (Aβ) degradation. Therefore, it can be hypothesised that ACE-inhibitors with a preference for the N-domain may increase the risk of AD due to reduced Aβ clearance.

Objectives: To examine the association between ACE-inhibitors with N-domain affinity compared to ACE-inhibitors with C-domain affinity and the risk of incident AD.

Methods: Primary care electronic health records from IQVIA Medical Research Data-UK, previously known as THIN were used to conduct a new user, active-comparator population-based cohort study in adults aged ≥40 years between 2000-2021. The exposure group were individuals newly prescribed ACE-inhibitors with evidence for affinity to the N-domain (captopril and enalapril). Comparator group were newly prescribed ACE-inhibitors with evidence for affinity to the C-domain (lisinopril). Diagnostic Read-codes linked to clinical diagnoses were used to measure the primary outcome of AD and secondary outcome of combined AD and ≥1 prescription for symptomatic treatment of AD. Potential confounders including comorbidities, lifestyle factors, co-medications and socioeconomic status were adjusted for using a multivariable Cox proportional hazard model to estimate the adjusted hazard ratio (HR) with 95% confidence intervals (CI).

Results: The cohort included 144,875 new ACE-inhibitor users, with 2,139 newly diagnosed with AD during a median follow up of 7.9 (IQR 4.0-12.0) years and mean age 64 (12) in N-domain and 63 (12) in C-domain users. The crude incidence rate (IR) for users of N-domain ACE-inhibitors was 21.7 per 10,000 person-years at risk (PYAR) (95%CI 19.3-24.3) and 19.1 per 10,000 PYAR (95%CI 18.3-20.0) in C-domain ACE-inhibitor users. The adjusted HR of incident AD in N-domain compared to C-domain ACE-inhibitor users was 1.10 (95%CI, 0.97-1.25). For the secondary outcome, the adjusted HR was 1.18 (95%CI, 1.01-1.38).

Conclusions: ACE-inhibitors with greater affinity for the N-domain binding site may be associated with an increased risk of AD compared to ACE-inhibitors with preferential affinity for the C-domain binding site. This effect was modest but strengthened when we applied a specific outcome definition. Examining the relationship between ACE-inhibitors and AD based on pharmacological binding site activity is a novel feature of this study. However, more research is needed to corroborate the observed relationship, taking into consideration the site of enzymatic cleavage.