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

• Published in: Acta neuropsychiatrica 2023-12, Vol.35 (6), p.346-361
• Main Authors: Oliveira, Fabricio Ferreira de, Almeida, Sandro Soares de, Chen, Elizabeth Suchi, Smith, Marilia Cardoso, Bertolucci, Paulo Henrique Ferreira
• Format: Article
• Language: English
• Subjects: Alleles; Alzheimer Disease - complications; Alzheimer Disease - drug therapy; Alzheimer Disease - genetics; Angiotensin Receptor Antagonists - therapeutic use; Angiotensin-Converting Enzyme Inhibitors - pharmacology; Angiotensin-Converting Enzyme Inhibitors - therapeutic use; Angiotensins - genetics; Angiotensins - therapeutic use; Apolipoproteins E - genetics; Apolipoproteins E - therapeutic use; Female; Humans; Male; Pharmacogenetics; Prospective Studies
• ISSN: 0924-2708; 1601-5215
• DOI: 10.1017/neu.2023.38

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 insertion/deletion polymorphism is associated with clinical changes in patients with AD, while considering apolipoprotein E ( )-ϵ4 carrier status and blood pressure response to angiotensin modulators. 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 -ϵ4 carrier status and genotypes of the insertion/deletion polymorphism into account, along with treatment with ACEis or ARBs. For 193 patients (67.4% women, 53.4% -ϵ4 carriers), the insertion/deletion polymorphism was in Hardy-Weinberg equilibrium ( = 0.281), while arterial hypertension was prevalent in 80.3% ( = 124 used an ACEi, = 21 used an ARB). ARBs benefitted mostly -ϵ4 carriers concerning caregiver burden variations, cognitive and functional decline. ACEis benefitted -ϵ4 non-carriers concerning cognitive and functional decline due to improved blood pressure control in addition to possible central mechanisms. The insertion/deletion polymorphism led to variable response to angiotensin modulators concerning neurological outcomes and blood pressure variations. Angiotensin modulators may be disease-modifiers in AD, while genetic stratification of samples is recommended in clinical studies.