Objective: To assess whether angiotensin-II stimulating antihypertensives (thiazides, dihydropyridine calcium channel blockers, and angiotensin-1 receptor blockers) convey a lower risk of incident dementia compared to angiotensin-II inhibiting antihypertensives (angiotensin-converting enzyme inhibitors, beta blockers, and non-dihydropyridine calcium channel blockers), in accordance with the ‘angiotensin hypothesis’.

Methods: Cox regression analyses of incident dementia (and/or mortality as competing risk) during 6-8 years of follow-up, in a population sample of 1909 non-demented community-dwelling individuals (54% women), aged 70-78 (mean: 74.5 ±2.5) years.

Results: After a median of 6.7 years of follow-up, dementia status was available for 1870 (98%) and mortality for 1904 (>99%) participants. Dementia incidence was 5.6% (27/480) in angiotensin-II stimulating, 8.2% (59/721) in angiotensin-II inhibiting, and 6.9% (46/669) in both antihypertensive type users. Adjusted for dementia risk factors including blood pressure and medical history, angiotensin-II stimulating antihypertensive users had a 45% lower incident dementia rate (HR=0.55, 95%CI=0.34-0.89) without excess mortality (HR=0.86, 95%CI=0.64-1.16), and individuals using both types had a non-significant 20% lower dementia rate (HR=0.80, 95%CI=0.53-1.20) without excess mortality (HR=0.97, 95%CI=0.76-1.24), compared to angiotensin-II inhibiting antihypertensive users. Results were consistent for subgroups based on diabetes and stroke history, but may be specific for individuals without a history of cardiovascular disease.

Conclusions: Users of angiotensin-II stimulating antihypertensives had lower dementia rates compared to angiotensin-II inhibiting antihypertensive users, supporting the ‘angiotensin hypothesis’. Confounding by indication must be examined further, although sub-analyses suggest this did not influence results. If replicated, dementia prevention could become a compelling indication for older individuals receiving antihypertensive treatment.