Background: Considering that the angiotensin-converting enzyme is an amyloid-β-degrading enzyme, brain-penetrating angiotensin-converting enzyme inhibitors (bpACEis) might increase amyloid-β concentrations. Contrariwise, bpACEis may improve cognitive function by affecting the angiotensin-2-mediated inhibition of acetylcholine release, and also by increasing brain substance P (normally degraded by the angiotensin-converting enzyme), which has been reported to enhance the activity of neprilysin. Likewise, angiotensin receptor blockers and bpACEis have been implicated in the modulation of glucose homeostasis and in the boosted secretion of adipocytokines such as adiponectin and leptin, thus improving insulin sensitivity and potentially slowing cognitive decline in patients with dementia due to Alzheimer's disease (AD). Methods: In this pharmacogenetic study, participants with late-onset AD according to National Institute on Aging - Alzheimer's Association criteria were screened with Mini-Mental State Examination (MMSE) and Clinical Dementia Rating Sum-of-Boxes (CDR-SB) and followed for one year. Genotyping was undertaken with TaqMan® Real-Time PCR technology for ACE gene polymorphisms rs1800764 and rs4291, and also for APOE. Presence of each polymorphism was correlated with APOE haplotypes and treatment using bpACEis Captopril or Perindopril. Mann-Whitney test and two-way ANOVA were employed for statistics, significance at ρ<0.05. Results: A total of 184 consecutive patients were included, with minor allele frequencies of 0.49 (rs1800764 - C) and 0.33 (rs4291 - T). Overall 175 patients (95.1%) used cholinesterase inhibitors, whereas 149 (80.9%) had systemic hypertension, and 112 (60.8%) used bpACEis. Patients with the APOE -ε4/ε4 haplotype had earlier onset of AD (ρ<0.007), while rs1800764 and rs4291 genotypes had no influence over age of dementia onset (ρ>0.08), even after controlling for APOE haplotypes (ρ>0.09). All patients who used bpACEis had slower cognitive decline according to the MMSE (ρ=0.004), but only those who were APOE4- had slower cognitive decline according to CDR-SB scores (ρ=0.025). Carriers of the rs1800764 - TT genotype had slower worsening of CDR-SB scores (ρ=0.049), particularly when they were APOE4+ (ρ=0.041). Treatment with bpACEis was particularly effective for slowing the worsening of CDR-SB scores (ρ=0.017) for carriers of the haplotype rs1800764 - CC : rs4291 - TT. Conclusions: Captopril and Perindopril may slow the cognitive decline of patients with AD, more remarkably for carriers of specific ACE gene polymorphisms.