Association of Angiotensin II-Stimulating Antihypertensive Use and Dementia Risk: Post Hoc Analysis of the PreDIVA Trial

Neurology. 2021 Jan 5;96(1):e67-e80. doi: 10.1212/WNL.0000000000010996. Epub 2020 Nov 5.


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

Methods: We performed Cox regression analyses of incident dementia (or mortality as competing risk) during 6-8 years of follow-up in a population sample of 1,909 community-dwelling individuals (54% women) without dementia, 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 1,870 (98%) and mortality for 1,904 (>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 (hazard ratio [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 nonsignificant 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 subanalyses suggest this did not influence results. If replicated, dementia prevention could become a compelling indication for older individuals receiving antihypertensive treatment.

Publication types

  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Aged
  • Angiotensin II / drug effects*
  • Angiotensin-Converting Enzyme Inhibitors / therapeutic use
  • Antihypertensive Agents / therapeutic use*
  • Dementia / epidemiology*
  • Female
  • Humans
  • Hypertension / drug therapy
  • Incidence
  • Male
  • Sodium Chloride Symporter Inhibitors / therapeutic use


  • Angiotensin-Converting Enzyme Inhibitors
  • Antihypertensive Agents
  • Sodium Chloride Symporter Inhibitors
  • Angiotensin II

Associated data

  • ISRCTN/ISRCTN29711771