The angiotensin-converting enzyme is an amyloid-ß-degrading enzyme. While angiotensin-converting enzyme inhibitors could increase amyloid-ß accumulation, they might also slow cognitive decline by way of cholinergic effects, by increasing brain substance P and boosting the activity of neprilysin, and by modulating glucose homeostasis and augmenting the secretion of adipokines to enhance insulin sensitivity in patients with Alzheimer's disease dementia. In this study from São Paulo, Brazil, we aimed to investigate whether ACE polymorphisms rs1800764 and rs4291 are associated with cognitive and functional change in patients with Alzheimer's disease dementia, while also taking APOE haplotypes and anti-hypertensive treatment with angiotensin-converting enzyme inhibitors into account for stratification. Overall, 193 consecutive patients with late-onset Alzheimer's disease dementia were screened with cognitive tests, while their caregivers were queried for functional and caregiver burden scores. Prospective pharmacogenetic correlations were estimated for one year, considering APOE and ACE genotypes and haplotypes, and treatment with angiotensin-converting enzyme inhibitors. Almost 94% of all patients used cholinesterase inhibitors, whereas 155 had arterial hypertension, and 124 used angiotensin-converting enzyme inhibitors. No functional impacts were found regarding any genotypes or pharmacological treatment. Either for carriers of ACE haplotypes that included rs1800764 -- T and rs4291 -- A, or for APOE4- carriers of rs1800764 -- T or rs4291 -- T, angiotensin-converting enzyme inhibitors slowed cognitive decline independently of blood pressure variations, possibly by way of central and peripheral effects. APOE4+ carriers were not responsive to treatment with angiotensin-converting enzyme inhibitors. In conclusion, angiotensin-converting enzyme inhibitors may slow cognitive decline for patients with Alzheimer's disease dementia, more remarkably for APOE4- carriers of specific ACE genotypes. Future trials should prospectively compare angiotensin-converting enzyme inhibitors according to their brain-penetrating properties since the start of anti-hypertensive therapy, with measurements of cerebrospinal fluid and serum levels and activity of the angiotensin-converting enzyme, as well as genetic profiles and neuroimaging parameters.
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