Brain-Penetrating Angiotensin-Converting Enzyme Inhibitors and Cognitive Change in Patients with Dementia due to Alzheimer's Disease

Abstract

Controversy over benefits of angiotensin-converting enzyme inhibitors (ACEIs) for treatment of dementia due to Alzheimer's disease (AD) led to this alternative investigational approach by the employment of pharmacogenetic methods, correlating the cognitive change of patients with late-onset AD with the presence of common ACE gene promoter polymorphisms, and stratifying the sample in groups of patients who responded or not to the brain-penetrating ACEIs Captopril or Perindopril. A trend was found for treatment with brain-penetrating ACEIs to slow cognitive decline in AD patients with the haplotype rs1800764 (CC): rs4291 (TT) (p = 0.024), and also non-significantly for independent carriers of rs1800764 or rs4291.

Predictors of Cognitive and Functional Decline in Patients With Alzheimer Disease Dementia From Brazil

“…27 Brain-penetrating angiotensin-converting enzyme inhibitors captopril and perindopril are neuroprotective for patients with AD, whereas their cognitive effects seem to be genetically mediated. 28 Randomized controlled trials would be required to confirm that therapy of cerebrovascular risk factors actually impacts cognitive decline in AD, but ethical considerations may prevent such trials from being carried out.…”

Associations of cerebrovascular metabolism genotypes with neuropsychiatric symptoms and age at onset of Alzheimer’s disease dementia

“…To the best of our knowledge, these are all previously unreported associations, while only the T allele of rs4291 was reported as a susceptibility factor for unipolar major depression and hypothalamic-hypophyseal-adrenocortical axis hyperactivity in an earlier study of subjects without dementia. 34 Given that angiotensin-converting enzyme degrades amyloid-b 35 and is overexpressed in a compensatory manner in the hippocampus, frontal cortex, and caudate nucleus of both hemispheres of patients with AD, 12 suppression of frontally mediated behaviors could occur by boosted enzyme levels and activity. Functional studies are needed to confirm these associations.…”

“…The two functional variants of the angiotensin-converting enzyme gene (ACE) with the most significant effects for higher activity and boosted serum levels of the angiotensinconverting enzyme (ACE) are the promoter polymorphisms rs1800764 and rs4291, affecting risk and age at onset of the amnestic phenotype of AD, 11 as well as cognitive decline and incidence of early-onset hypertension. 12 The LDLR mediates increased astrocytic expression of APOE induced by amyloid-b, 4 whereas storage and release of cholesterol depend on the expression of the low-density lipoprotein receptor gene (LDLR), which resides within a region linked to AD in 19p13.3; rs11669576 7 and rs5930 13 are two of the most important genetic variants of the epidermal growth factor precursor homology domain of LDLR to be associated with disrupted cholesterol metabolism and variability in the risk of AD. Cholesterol governs synaptogenesis and myelin biosynthesis, 14 while the cholesteryl ester transfer protein (CETP) is associated with reverse cholesterol transport (from tissues to the liver) 5 ; protective cholesteryl ester transfer protein gene (CETP) variants lead to lower serum CETP levels and healthier lipid profiles, 15 though not all studies have shown genetically mediated lifetime cognitive effects.…”

Can angiotensin-converting enzyme inhibitors impact cognitive decline in early stages of Alzheimer's disease? An overview of research evidence in the elderly patient population

“…In conclusion, it should be emphasized that the centrally active ACE-Is (in contrast, noncentrally active ones) can impact cognitive functions (e.g., reduce risk for cognitive decline or dementia) via a possible anti-inflammatory or cerebral RAS-related actions and not by a blood pressure-lowering. [3738] Unquestionably, long-term prospective RCTs of centrally-active ACE-Is versus a noncentrally active ACE-Is would be warranted to establish further recommendations for centrally active ACE-Is as possible additional options to be adopted in the therapy of early AD stages or MCI. However, such evidence is not available yet and in the meantime, possible practical implications for many older patients at risk for dementia who have medical indications for the ACE-Is use (due to comorbidities, such as arterial hypertension, congestive heart failure, status post myocardial infarction, diabetes mellitus, or chronic kidney disease) might include a preferred choice of a centrally active ACE-I (e.g., captopril, fosinopril, lisinopril, perindopril, ramipril, or trandolapril) rather than a noncentrally active one.…”