Research on the potential protective benefits of angiotensin II receptor blockers (ARBs) in preventing Alzheimer’s disease and related dementias (AD/ADRD) as well as cognitive impairment has produced mixed and inconclusive results. This retrospective cohort study utilized Optum’s de-identified Clinformatics® Data Mart database and focused on hypertensive patients without any prior diagnosis of ADRD. Antihypertensive medication (AHM) categories were determined, and ARBs were further grouped according to their ability to cross the blood–brain barrier (BBB). Baseline patient characteristics were examined, while survival analyses relied on Kaplan–Meier (KM) survival curves together with multivariable-adjusted Cox proportional hazards (PH) models. The study population comprised 6,390,826 individuals diagnosed with hypertension, including 1,839,176 ARB users, 3,366,841 users of non-ARB antihypertensive agents, and 1,184,809 individuals not taking any AHM. Unadjusted KM curves showed a significantly lower cumulative incidence of ADRD among ARB users than among both other AHM users and non-users (P < 0.0001). Following adjustment in Cox PH models, ARB exposure was associated with a 20% reduction in the hazard of ADRD relative to angiotensin-converting enzyme inhibitor (ACEI) users, a 29% reduction compared with non-ARB/ACEI AHM users, and an 18% reduction versus AHM non-users (all P < 0.0001). Moreover, ARBs capable of crossing the BBB were linked to an 11% lower hazard than non-BBB-crossing ARBs, a 25% lower hazard than ARBs with undetermined permeability, and a 31% lower hazard than non-use of AHMs (all P < 0.0001).These findings indicate that, among patients with hypertension, ARBs provide superior protection against ADRD compared with ACEIs, other non-ARB/ACEI antihypertensive drugs, or the absence of antihypertensive treatment. Additionally, ARBs with enhanced BBB permeability were associated with a further reduction in ADRD risk. In view of the absence of effective curative therapies for AD, ADRD, or vascular dementia, the results highlight a valuable opportunity for prevention using widely available, cost-effective, and well-tolerated medications. Nevertheless, the constraints of administrative claims data must be acknowledged when considering these conclusions.
