Association between centrally active angiotensin‐converting enzyme inhibitors with dementia risk

Abstract Background Hypertension is a well‐established risk factor for dementia and antihypertensive treatments could be important for disease prevention. Observational and animal studies suggest Angiotensin‐Converting Enzyme Inhibitors (ACEIs) are associated with reduced dementia risk whereas genetic studies show these drugs increase risk. One plausible explanation of this heterogeneity is that not all ACEIs cross the blood–brain barrier (BBB) and their association with disease risk may depend on whether or not the specific molecule crosses the blood brain barrier. We investigated the association of centrally vs non‐centrally active ACEIs with incident dementia compared using medical records from the USA (OPTUM). Methods This is a retrospective new‐user comparative cohort study using patients ≥50 years old with hypertension who were new users of centrally active ACEIs (captopril, fosinopril, lisinopril, perindopril, ramipril, trandolapril; n = 327,663 or non‐centrally active ACEIs (n = 30,867) (benazepril, enalapril, moexipril, quinapril). Patients were followed for up to 10 years (2006‐2018) during which 11,422 dementia cases were diagnosed. Stratified Cox proportional hazards models were used to estimate the hazard ratio (HR) of incidence all‐cause dementia and sub types over the follow up period, controlling for age, demographics such as geographic location and other comorbidities such as stroke, myocardial infarction and diabetes. Results In unadjusted and adjusted models, new users of centrally active ACEIs had a slightly greater risk for all cause dementia and vascular dementia but not for Alzheimer’s disease. HR for unadjusted models were 1.08 (95% CI 1.01‐1.15), 1.34 (95% CI 1.13‐1.60) and 1.00 (95% CI 0.90‐1.12) for all cause dementia, vascular dementia and Alzheimer’s disease respectively. Whereas HR for adjusted models for all cause dementia, vascular dementia and Alzheimer’s disease were 1.16 (95% CI 1.09‐1.24), 1.35 (95% CI 1.12‐1.62) and 1.10 (95% CI 0.98‐1.23) respectively. Conclusions Our results potentially indicate centrally active ACEIs are associated with a slightly higher risk of all‐cause dementia compared to non‐centrally active ACEIs. This work supports causal genetics studies which indicate links between ACE inhibitors in the brain with increased dementia risk. Future work will investigate whether other antihypertensive drug classes differ in risk based on blood brain barrier penetrating ability.