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Pharmacogenetics of angiotensin modulators according to APOE-ϵ4 alleles and the ACE insertion/deletion polymorphism in Alzheimer’s disease

Published online by Cambridge University Press:  22 August 2023

Fabricio Ferreira de Oliveira Open the ORCID record for Fabricio Ferreira de Oliveira [Opens in a new window] ,
Sandro Soares de Almeida ,
Elizabeth Suchi Chen ,
Marilia Cardoso Smith  and
Paulo Henrique Ferreira Bertolucci
Fabricio Ferreira de Oliveira*
Affiliation:
Department of Neurology and Neurosurgery, Escola Paulista de Medicina, Federal University of São Paulo (UNIFESP), São Paulo, SP, Brazil
Sandro Soares de Almeida
Affiliation:
Department of Biophysics, Escola Paulista de Medicina, Federal University of São Paulo (UNIFESP), São Paulo, SP, Brazil
Elizabeth Suchi Chen
Affiliation:
Department of Morphology and Genetics, Escola Paulista de Medicina, Federal University of São Paulo (UNIFESP), São Paulo, SP, Brazil
Marilia Cardoso Smith
Affiliation:
Department of Morphology and Genetics, Escola Paulista de Medicina, Federal University of São Paulo (UNIFESP), São Paulo, SP, Brazil
Paulo Henrique Ferreira Bertolucci
Affiliation:
Department of Neurology and Neurosurgery, Escola Paulista de Medicina, Federal University of São Paulo (UNIFESP), São Paulo, SP, Brazil
*
Corresponding author: Fabricio Ferreira de Oliveira; Email: fabricioferreiradeoliveira@hotmail.com
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Abstract

Objective:

In Alzheimer’s disease (AD), angiotensin II receptor blockers (ARBs) could reduce cerebrovascular dysfunction, while angiotensin-converting enzyme inhibitors (ACEis) might increase brain amyloid-β by suppressing effects of the angiotensin-converting enzyme 1, an amyloid-β-degrading enzyme. However, ACEis could benefit patients with AD by reducing the amyloidogenic processing of the amyloid precursor protein, by central cholinergic and anti-inflammatory mechanisms, and by peripheral modulation of glucose homeostasis. We aimed to investigate whether the ACE insertion/deletion polymorphism is associated with clinical changes in patients with AD, while considering apolipoprotein E (APOE)-ϵ4 carrier status and blood pressure response to angiotensin modulators.

Methods:

Consecutive outpatients with late-onset AD were screened with cognitive tests and anthropometric measurements, while their caregivers were queried for functional and caregiver burden scores. Prospective pharmacogenetic associations were estimated for 1 year, taking APOE-ϵ4 carrier status and genotypes of the ACE insertion/deletion polymorphism into account, along with treatment with ACEis or ARBs.

Results:

For 193 patients (67.4% women, 53.4% APOE-ϵ4 carriers), the ACE insertion/deletion polymorphism was in Hardy–Weinberg equilibrium (p = 0.281), while arterial hypertension was prevalent in 80.3% (n = 124 used an ACEi, n = 21 used an ARB). ARBs benefitted mostly APOE-ϵ4 carriers concerning caregiver burden variations, cognitive and functional decline. ACEis benefitted APOE-ϵ4 non-carriers concerning cognitive and functional decline due to improved blood pressure control in addition to possible central mechanisms. The ACE insertion/deletion polymorphism led to variable response to angiotensin modulators concerning neurological outcomes and blood pressure variations.

Conclusion:

Angiotensin modulators may be disease-modifiers in AD, while genetic stratification of samples is recommended in clinical studies.

Keywords

Alzheimer diseasedrug therapyneurodegenerative diseasespharmacogeneticsrenin-angiotensin system
Type
Original Article
Information
Acta Neuropsychiatrica , Volume 35 , Issue 6 , December 2023 , pp. 346 - 361
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Copyright
© The Author(s), 2023. Published by Cambridge University Press on behalf of Scandinavian College of Neuropsychopharmacology

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