The use of angiotensin receptor blockers in dementia prevention

Müller, Jordana de Araujo; Giacobe, Laura Jacques; Grassi, Vanise; Palmeira, André Luiz Rodrigues

doi:10.1590/1980-5764-DN-2023-3006

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Dementia & Neuropsychologia

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View & Review • Dement. neuropsychol. 17 • 2023 • https://doi.org/10.1590/1980-5764-DN-2023-3006 copy

The use of angiotensin receptor blockers in dementia prevention

O uso de bloqueadores de receptor de angiotensina na prevenção de demência

Authorship SCIMAGO INSTITUTIONS RANKINGS

Abstract

Alzheimer’s disease (AD) and dementia are preventable and highly prevalent diseases, as is systemic arterial hypertension. Thus, it is speculated that angiotensin receptor blockers (ARBs) may be neuroprotective against AD.

Objective:

The aim of this study was to evaluate if the use of ARBs confers a neuroprotective effect on AD, through a systematic review.

Methods:

Studies published on Embase, LILACS, SciELO, and PubMed were evaluated. The selection of the studies included those that evaluated the use of antihypertensive drugs in individuals with a previous diagnosis of mild cognitive impairment. The data were extracted with the Cochrane Effective Practice and Organization of Care (EPOC) form. The risk of bias was evaluated by the EPOC “Risk of bias tool.”

Results:

A total of 12 articles were identified, and 3 articles were selected. Two of them analyzed the use of ARB/ACEI versus other antihypertensives and the development of dementia.

Conclusion:

There is a tendency for ARBs to be superior to other antihypertensives in preventing dementia.

Keywords:
Dementia; Alzheimer Disease; Hypertension; Angiotensin Receptor Antagonists

Article	Population	Intervention	Outcomes	Conclusion
Wharton et al.⁸8. Wharton W, Goldstein FC, Zhao L, Steenland K, Levey AI, Hajjar I. Modulation of renin-angiotensin system may slow conversion from mild cognitive impairment to Alzheimer’s disease. J Am Geriatr Soc. 2015;63(9):1749-56. https://doi.org/10.1111/jgs.13627 https://doi.org/10.1111/jgs.13627...	83 individuals with MCI who were taking an antihypertensive at baseline. 38 RAS users. Age: 82.6±7.2 years. Sex: 45% male. Black: 13.9%. 45 RAS non-users. Age: 83.7±5.9 years. Sex: 20% male. Black: 4.4%.	38 participants were allocated in the RAS (renin-angiotensin system) users. They received ACEI (angiotensin converting enzyme inhibitors) or ARB (angiotensin receptor blockers). 45 participants were allocated in the non-RAS users. They received beta blocker, diuretics or calcium channel blockers. Both groups were accompanied for 4 years.	Progression from MCI to AD (Alzheimer’s disease: RAS users=3 (7.9%). Non-RAS users=11 (24.4%). Neuropathological changes: Absolute numbers of plaques in hippocampus CA1 and entorhinal cortex were significantly lower in non-RAS-AHM group. In the fully adjusted model, RAS users had significantly fewer overall neurofibrillary tangles (NFTs) (p<0.01) and fewer tangles in all prespecified regions of interest including the hippocampal CA1 region (p<0.01), the entorhinal cortex (p<0.01), and the average number of NFT in brain regions, including the angular gyrus, inferior temporal, mid-frontal cortex, and superior frontal (p=0.06). RAS users also had higher brain weight (p=0.03) and fewer diffuse plaques (p=0.02). RAS-AHM and non-RAS-AHM users did not differ on neuropathological indices of NIA Reagan, amyloid burden, arteriolosclerosis, Lewy body disease, chronic, micro, or gross infarcts, Braak, or CERAD scores.	The association between use of RAS-AHM and conversion to AD remains significant (p=0.0285). RAS users had significantly fewer overall NFTs (p<0.01) and fewer tangles in all prespecified regions of interest.
Wharton et al.¹⁰10. Wharton W, Zhao L, Steenland K, Goldstein FC, Schneider JA, Barnes LL, et al. Neurofibrillary tangles and conversion to mild cognitive impairment with certain antihypertensives. J Alzheimers Dis. 2019;70(1):153-61. https://doi.org/10.3233/JAD-190011 https://doi.org/10.3233/JAD-190011...	RAS acting: 488 (312 were taking BBB-crossing medications and 124 were taking non-BBB-crossing formulations). African-American: 90; Caucasians: 398. Age: 74.6±8 years. Male: 46%. Non RAS: 296 (113 were taking a calcium channel blocker, 174 a beta-blocker, and 108 a diuretic). African-American: 117; Caucasians: 552. Age: 75.5±8.8 years. Male: 49%.	488 were allocated in the RAS-acting group, taking ACEI or ARB. 296 were allocated in the non RAS group, taking calcium channel blockers, diuretics, or beta-blockers. Both groups had a follow-up of 3 years.	Conversion rates to AD as a function of RAS-acting medication use: 280 of the 784 participants taking an antihypertensive medication converted to AD. 161 were RAS-acting medication users (33.0%), 119 non-users (40.2%), 98 centrally acting medication users (30.7%), and 48 non-centrally acting medication users (40.0%) converted to AD.	Participants taking BBB-crossing RAS-acting medications would have greater cognitive protection than those taking non-centrally acting medications. Results regarding the rate of decline showed beneficial cognitive and functional effects on the Boston Naming Test (p<0.01), MMSE (p<0.01), and Clinical Dementia Rating-Sum of Boxes (CDR-SOB p<0.01).
Peters et al.⁹9. Peters R, Beckett N, Fagard R, Thijs L, Wang JG, Forette F, et al. Increased pulse pressure linked to dementia: further results from the Hypertension in the Very Elderly Trial - HYVET. J Hypertens. 2013;31(9):1868-75. https://doi.org/10.1097/HJH.0b013e3283622cc6 https://doi.org/10.1097/HJH.0b013e328362...	Participants were recruited from Eastern European countries and from China. 60% woman. Age 83.5 years (3.1). Active group n=1,623. Placebo group n=1,580.	Placebo-controlled trial comparing indapamide SR 1.5 mg or matching placebo with the optional addition of 2 or 4 mg perindopril, or matching placebo to reach a goal BP of less than 150/80 mmHg.	There were 263 cases of incident dementia (3.8/100 patient-years in the placebo compared with 3.3/100 in the actively treated group). Placebo: For SBP and DBP, there was no significant relationship with later dementia (p=0.13 and p=0.43, respectively). For PP, higher PP was associated with increased risk (p=0.032). Intervention: There was no significant relationship between SBP and later dementia (p=0.36). Diastolic pressure showed a clearer and statistically significant U-shaped relationship with later dementia with a calculated nadir of 87.5 mmHg (p=0.0195). Higher PP was associated with increased risk (p=0.0046).	The HYVET trial also collected data relating to incident dementia and found no difference between the active and placebo groups with regard to this endpoint, although there were 8% fewer cases in the actively treated group. That SBP shows no clear relationship with dementia (…)

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[1] Correspondence: Laura Jacques Giacobe; Email: laura.giacobe@universo.univates.br.