Pharmacogenetics of angiotensin modulators according to APOE-4 alleles and the ACE insertion/deletion polymorphism in Alzheimer's disease

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-beta by suppressing effects of the angiotensin-converting enzyme 1, an amyloid-beta-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)-epsilon 4 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-epsilon 4 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-epsilon 4 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-epsilon 4 carriers concerning caregiver burden variations, cognitive and functional decline. ACEis benefitted APOE-epsilon 4 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.