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.

Alzheimer's disease (AD) is a neurodegenerative disease, in which an accumulation of toxic amyloid beta in the brain precedes the emergence of clinical symptoms. AD spectrum consists of presymptomatic, early symptomatic, and symptomatic phase of dementia. At present, no pharmacotherapy exists to modify or reverse a course of AD, and only symptomatic treatments are available. Many elderly patients, diagnosed with multiple medical conditions (such as cardiovascular diseases, Type 2 diabetes mellitus, and cerebrovascular diseases) are at increased risk of the development of mild cognitive impairment (MCI), AD, and vascular dementia. Studies have revealed reduced rates of cognitive decline, in elderly patients, who were treated with centrally active angiotensin-converting enzyme inhibitors (ACE-Is) (that have an ability to cross the blood-brain barrier). This article reviews recently published literature, focused on possible protective influence of the centrally active ACE-Is, in the elderly population, at risk for cognitive decline.

Introduction

Alzheimer's disease (AD) is a neurodegenerative disease, in which an accumulation of toxic amyloid beta in the brain precedes the emergence of clinical symptoms by 10–20 years, and its spectrum consists of different phases of dementia, such as presymptomatic, early symptomatic, and symptomatic (mild, moderate, and severe). Many individuals, who begin to display symptoms of cognitive decline can be categorized as having mild cognitive impairment (MCI), including its amnestic or nonamnestic form. MCI represents the earliest stage, during which a person's most complex mental abilities are compromised, but his/her activities of daily living (ADL) or instrumental ADL can still be spared.[1] MCI often “sets the stage” for AD or vascular dementia, and typically patients with an amnestic type of MCI are almost seven times more likely to develop AD.[1] Although the role of amyloid beta in the progression of AD pathophysiologic changes has been well documented, the exact influence of amyloid beta load on the mental and functional performance of the afflicted patients, and their other AD biomarkers, is still not precisely determined.[2] Furthermore, many elderly patients, who have been diagnosed with multiple chronic medical conditions, have a greater risk of the development of MCI or vascular dementia. It has been shown that in the elderly, inadequately controlled common comorbid conditions (such as arterial hypertension, Type 2 diabetes mellitus, cardiovascular diseases [CVDs], and cerebrovascular diseases), as well as an inactive lifestyle, inappropriate nutrition, and multiple medication use play a significant role in progressive cognitive decline that may lead to the development of AD or vascular dementia.[3] Vascular cognitive impairment is relevant to the impact of cerebrovascular diseases (e.g., stroke) on cognition, leading to vascular dementia.[4] A meta-analysis by Valenti et al. showed evidence suggesting that the vascular risk factors play an important role in the pathogenesis of AD, and epidemiological studies have also confirmed the association.[5] Arterial hypertension represents an important risk factor for dementia, and it has been noted that certain antihypertensive medications, such as angiotensin-converting enzyme inhibitors (ACE-Is), independently from blood pressure regulation, might be protective against dementia, and thus, could lead to improved cognitive outcomes.[6] These include centrally active ACE-Is (a subclass of ACE-Is), such as captopril, fosinopril, lisinopril, perindopril, ramipril, and trandolapril, which are lipid soluble and have an ability to cross the blood–brain barrier and penetrate cerebral tissues. They thus exert an effect on cognition via possible anti-inflammatory mechanisms independent of their blood pressure-lowering action.[6] In contrast, noncentrally active ACE-Is (without these cerebral properties), including benazepril, enalapril, moexipril, and quinapril, which work mainly by lowering blood pressure, do not have such an effect on cognitive functions.[6] Since AD has been associated with chronic inflammation in the brain, the centrally active ACE-Is may likely target the inflammatory processes, and in this way, impact cognitive decline.[6] In addition, the brain renin-angiotensin system (RAS) regulates cerebral blood flow (independently from the peripheral RAS), and plays a key role in linking arterial hypertension to cognitive functions.[7] It thus appears that the central actions of angiotensins are beyond their “traditional” physiologic roles and can be related to learning and memory processes. It is conceivable that some pharmacological manipulation of angiotensin ligands may translate to the possible management of cognitive deterioration in AD.[7] In the brain, angiotensin II activates two types of receptors: Type 1 that leads to vasoconstriction, endothelial dysfunction, and vascular remodeling and Type 2 that leads to vasodilatation, neuronal differentiation, decreased inflammation, and axonal regeneration.[8] Angiotensin receptor blockers (ARBs) block the Type 1, but not Type 2, whereas centrally active ACE-Is decrease activation of both receptors.[8] A study by Ohrui et al. has shown that the adequate blood pressure control, achieved by pharmacotherapy, based on brain-penetrating ACE-Is, has been associated with protection against cognitive decline and slowing down the progression of AD.[9] However, it is still unknown which treatment regimen: Centrally active ACE-Is or ARBs would have a superior impact on cerebral hemodynamics and cognitive or executive brain functions. At present, for AD, only symptomatic treatments that consist mostly of acetyl-cholinesterase inhibitors (including donepezil, galantamine, and rivastigmine) and the N-methyl-D-aspartate receptor antagonist memantine are available.[10] Although the above medications might exert some modest effects on the disease course, they do not prevent the AD progression, and thus, additional approaches aimed at slowing cognitive decline have been investigated.

This article reviews published literature (over the last 15 years) on the antihypertensive medications, associated with a possible influence on cognitive status, focusing on the role of centrally active ACE-Is in the reduction of the cognitive decline in early AD stages and MCI. In preparing of this review, a PubMed search of English language medical literature was performed using the keywords: “Alzheimer's disease,” “mild cognitive impairment,” “angiotensin-converting enzyme inhibitors,” and “renin-angiotensin system.” The main search timeframe was set up for the last 10 years, in relevance to the elderly patient population, with common comorbidities, including arterial hypertension. This search was supplemented with some data from cross references, addressing the effects of centrally active ACE-Is on cognitive status (beyond their blood pressure controlling actions), in patients with early stages of AD.

Antihypertensive medications and their possible beneficial impact on cognitive functions in elderly patients – insights from research studies

According to research evidence [Table 1], the antihypertensive medications associated with reduced risk of developing cognitive decline or dementia include: centrally active ACE-Is, for example, perindopril;[61113] calcium channel blockers (CCBs), for example, nilvadipine;[12] diuretics, for example, indapamide;[13] and ARBs, for example, candesartan.[14] In general, the results of studies related to the potential role of antihypertensive agents (in particular brain-penetrating ACE-Is) in older individuals with prodromal AD or MCI appear promising. Evidence from the Perindopril Protection against Recurrent Stroke Study demonstrated that a combination of perindopril (a centrally active ACE-I) and indapamide (adiuretic) was associated with a significant reduction in the incidence of stroke and cognitive decline, compared to placebo, among patients with cerebrovascular disease.[13] Concurrently, the antihypertensives and vascular, endothelial, and cognitive function trial, conducted in elderly hypertensives with early cognitive impairment, supported the notion that the centrally active ACE-Is and ARBs might lower dementia risk, independently of their blood pressure lowering properties.[14] Likewise, the Systolic Hypertension in Europe study has found that the combination of nitrendipine (CCB), enalapril (ACE-I), and/or hydrochlorothiazide (diuretic) reduced the incidence of dementia by 55% compared with placebo.[15] Similarly, in the Study on Cognition and Prognosis in the Elderly, a monotherapy with the ARB, candesartan, showed modest cognitive effects.[16] It should be highlighted that in the Cardiovascular Health Study cognition trial, a large group of elderly patients with hypertension (treated pharmacologically) was followed to determine whether the cumulative exposure to ACE-Is (as a class and by central activity), compared with other antihypertensive agents, was associated with a lower risk of incident dementia, cognitive decline, or incident disability.[6] Although the observational data from the Cardiovascular Health Study have revealed that the centrally active ACE-Is were associated with 65% less cognitive decline per year of exposure (this effect was mostly related to their properties of cerebral tissues penetration), these findings would have to be confirmed by further large-scale, randomized controlled, clinical trials (RCTs).[6] In addition, it has been considered that the difference in the impact on cognitive status between centrally active ACE-Is and noncentrally active ACE-Is is not due to their antihypertensive mechanism of action but rather to their effect on the brain's intrinsic RAS, which is involved in memory and cognition.[6] In addition, the results of an observational study that involved patients with AD, vascular dementia, or mixed dementia have suggested that the centrally active ACE-Is may reduce the rate of cognitive decline in patients with dementia, regardless of blood pressure levels.[17] Based on this study reports, the cognitive improvement had been most evident in the initial 6 months, during which the patients with dementia had been started on therapy with one of the centrally active ACE-Is (e.g., captopril, fosinopril, lisinopril, prinivil, perindopril, ramipril, or trandolapril).[17] There is a growing body of research showing that the centrally active ACE-Is slow down the cognitive deterioration in patients with AD, by almost 30% a year, compared with the other antihypertensive agents or with the ACE-Is that do not exhibit the central mechanism of action.[1718] Furthermore, centrally active ACE-Is may also improve exercise tolerance in functionally impaired older adults with normal cognition.[18] In agreement with the above findings, in the French cohort study, involving older adults with AD, it has been reported that the use of centrally active ACE-Is was associated with a slower cognitive decline, independent from the antihypertensive effect.[19] Moreover, an analysis of a large, prospective US cohort, involving mostly elderly male patients, has revealed that the ARBs alone or in combination with ACE-Is were associated with a significant reduction in the incidence, and progression of AD or other types of dementia, compared with ACE-Is alone, or other antihypertensive medications.[20] However, not all studies have shown cognitive benefits with the RAS-related antihypertensive agents. In particular, two large-scale parallel studies, the Ongoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial and Telmisartan Randomized Assessment Study in ACE Intolerant Subjects with CVD, have found that the centrally active ACE-Is did not reveal measurable effects on cognition.[21]

Table 1

Research studies evaluating the effects of antihypertensive medications on cognition in elderly patients with hypertension, Alzheimer’s disease, or risk factors for dementia

Author, year of publication Trial acronym (if available)	Sample size (n) diagnosis Length of treatment or follow-up	Antihypertensive medications used in the study	Brief study findings	Clinical relevance or implications for practice
Rozzini et al., 2006[11]	74 patientsAmnestic MCI 1 year	ACE-Is	ACE-Is were independently associated with the stability of cognitive function	ACE-Is can be protective against cognitive decline in elderly patients with MCI
Kennelly et al., 2012[12]	55 patients treated compared with 30 nontreated AD 6 weeks	CCB-nilvadipine	Apolipoprotein E genotype-specific short-term cognitive benefits of treatment with nilvadipine	Potential therapeutic efficacy of nilvadipine in treating AD
Tzourio et al., 2003[13] PROGRESS (a double-blind, placebo-controlled RCT)	6105 patients cerebrovascular disease (stroke or TIA) 3.9 years	Active treatment arm: ACEI - perindopril and diuretic - indapamide versus placebo	Active treatment was associated with reduced risks of dementia and cognitive decline associated with recurrent stroke	Reduction of blood pressure with perindopril and indapamide should be considered for patients with cerebrovascular disease
Hajjar et al., 2009[14] AVEC trial (a double-blind RCT)	100 patients hypertension and early cognitive decline 1 year	3-arm RCT with ACEI-lisinopril, ARB-candesartan, or diuretic-hydrochlorothiazide	Improvement in cognitive function scores and cerebral blood flow on antihypertensive treatment	The first trial exploring impact of antihypertensives in patients with early phase of cognitive decline (without dementia)
Forette et al., 2002[15] Syst-Eur study (a double-blind, placebo-controlled RCT)	1485 patients - active treatment 1417 controls Hypertension, no dementia 3.9 years	CCB - nitrendipine, combined with ACE-I - enalapril, or diuretic-hydrochlorothiazide	Antihypertensive therapy with CCB-nitrendipine protects against dementia in older patients with systolic hypertension	Prevention of dementia with CCB, ACEI, or diuretic is effective in hypertensive, elderly patients
Lithell et al., 2003[16] SCOPE (a double-blind RCT)	4964 patients hypertension 3.7 years	ARB - candesartan or placebo	In elderly hypertensive patients, a more effective blood pressure reduction with candesartan was associated with a decrease in major CV events, including nonfatal stroke	Cognitive function was maintained when blood pressure was substantially reduced
Sink et al., 2009[6] The Cardiovascular Health Study	1054 patients hypertension 6 years	ACE-Is inhibitors	ACE-Is as a class are not associated with cognitive decline/dementia risk in older hypertensives but within-class differences are present	Further RCTs of centrally active ACE-Is on the prevention of cognitive decline or dementia should be conducted
Gao et al., 2013[17]	817 patients AD, vascular, or mixed dementia 6 months	Centrally active ACE-Is (perindopril) versus noncentrally acting ACE-Is	Cognitive scores may improve in the first 6 months after treatment with centrally active ACE-Is	Therapy with centrally active ACE-Is is associated with a decreased rate of cognitive decline in patients with dementia
O’Caoimh et al., 2014[18]	406 patients mild to moderate AD 12-month	Centrally active ACE-Is (perindopril) versus noncentrally acting ACE-Is	Centrally active ACE-Is are associated with a decreased rate of functional decline in AD patients	Centrally active ACE-Is may slow disease progression in AD
Soto et al., 2013[19] A prospective multicenter cohort study	616 patients AD 4 years	ACE-Is versus other antihypertensives or no therapy	The use of ACE-Is in AD patients is related with slower cognitive decline, independent of hypertension therapy	The role of ACE-Is in AD progression needs to be further explored
Li et al., 2010[20] A prospective cohort analysis	819 491 - male patients CVD 4 years	ARBs alone or a combination of ARB and ACE-I versus ACE-I	ARBs are associated with lower incidence and progression of AD in older males with CVD	ARBs alone or in combination with ACE-Is may offer a superior protection against AD and dementia compared with other antihypertensive medications
Teo et al., 2004[21] ONTARGET/TRANSCEND trials (2 randomized, double-blind RCT)	ONTARGET n=25,620 TRANSCEND n=5776 patients (high risk) Hypertension 3.5-5.5 years	ONTARGET: A combination of ARB-telmisartan and ACE-I-ramipril versus ramipril alone TRANSCEND: ARB-telmisartan versus placebo in patients intolerant of ACE-Is	Centrally active ACE-Is did not reveal measurable effects on cognition	Further trials need to investigate the role of centrally active ACE-Is on cognition, long-term, in various clinical contexts

AD: Alzheimer’s disease, ACE-Is: Angiotensin-converting enzyme inhibitors, ARBs: Angiotensin receptor blockers, CCB: Calcium channel blockers, CV: Cardiovascular, CVD: Cardiovascular disease, MCI: Mild cognitive impairment, RCTs: Randomized controlled clinical trials, TIA: Transient ischemic attack, ONTARGET/TRANSCEND: The Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial/Telmisartan Randomized Assessment Study in ACE Intolerant Subjects with Cardiovascular Disease, PROGRESS: The Perindopril Protection Against Recurrent Stroke Study, AVEC: The antihypertensives and vascular, endothelial and cognitive, Syst-Eur: The Systolic Hypertension in Europe, SCOPE: The Study on Cognition and Prognosis in the Elderly

Relations between angiotensin-converting enzyme, the accumulation of amyloid beta, and inflammatory process in the brain of patients with Alzheimer's disease – “setting the stage” for angiotensin-converting enzyme inhibitors

According to the AD amyloid hypothesis, patients with AD have abnormal cleavage of amyloid precursor protein resulting in a pathological accumulation of amyloid beta in the brain.[22] The relationship between ACE and the accumulation of amyloid beta in the brain is very complex and not fully explained.[22] The results of the large meta-analysis by Lehmann et al. suggest that the ACE insertion-deletion polymorphism can be considered a marker of AD, indicating the elevated risk of developing AD.[23] Since ACE plays a central role in the regulation of blood pressure, this enzyme is commonly targeted by medications such as ACE-Is, especially in elderly patients, suffering from arterial hypertension. It should be noted that based on a long-term retrospective survey of neuropathological reports, ACE-Is had been one of the first antihypertensives studied in AD.[24] In addition, genetic, pathological, and biochemical studies have also associated ACE with AD and suggested that the ACE activity is increased in AD, proportionally to the cerebral load of amyloid beta.[25] It appears that the RAS might also contribute to a possible connection between the blood vessel functional condition and AD pathology. This concept has been supported by a higher ACE activity (a component of the intrinsic cerebral RAS) in the cortical areas, including hippocampus, parahippocampal gyrus, frontal cortex, and caudate nucleus that are particularly responsible for memory, cognitive, and executive functions, which are primarily affected in patients with AD.[26] Furthermore, higher ACE levels were also documented in autopsies of the AD brain tissue in direct relation to the parenchymal amyloid beta load.[27] A recent meta-analysis by Ye et al. evaluated the exact role of RAS-targeting antihypertensive agents (such as centrally active ACE-Is) in terms of slowing down cognitive decline in patients with AD.[28] It has been indicated that the RAS-targeting antihypertensive medications might serve as a potential treatment for reducing the incidence and progression of AD beyond just blood pressure controlling properties.[28] Moreover, a meta-analysis by Ligthart et al.[29] provided evidence that the adequate management of cardiovascular risk factors, in particular, blood pressure control, with centrally active antihypertensive medications, might not only optimize cerebral perfusion but also decrease inflammatory processes and reduce amyloid beta accumulation in the brain. This is convergent with some reports concerning the effects of antihypertensive therapy on the reduction of cognitive decline rate in AD.[30] It should be emphasized that the recommendations from the National Institute on Aging-Alzheimer's Association include antihypertensive therapies in the preclinical stages of AD.[31]

Potential risks of centrally active angiotensin-converting enzyme inhibitors

There is a concern that in some patients, centrally active ACE-Is can interfere with degradation of amyloid beta that in turn might contribute to its higher accumulation in the brain. Since AD is a very heterogeneous disease, it is possible that in certain patients, the accumulation of the amyloid plaques plays a more prominent role in the AD pathology than the inflammatory process.[17] It appears that beneficial effects of the centrally active ACE-Is (in particular perindopril, which has a strong ability of cerebral tissue penetration) are related to their lipophilic properties rather than to their hypotensive mechanism of action.[17] At present, it remains unclear how the centrally active ACE-Is slow down the cognitive decline in AD patients. One possible suggestion relates to the concept that AD represents a chronic inflammatory process in the brain. Since centrally active ACE-Is can possibly exert some anti-inflammatory effects, they may counteract this cerebral proinflammatory state.[17] On the other hand, a stimulation of the cerebral RAS can potentially mediate activation of proinflammatory cytokines, which could influence neurodegenerative processes, leading to dementia. Evidence from the AD Centers’ Uniform Data Set revealed that the treatment with RAS-acting antihypertensive medications decreased AD incidence, among individuals without dementia,[32] and also improved cognitive performance, among the ones with AD,[9] in comparison to the therapy with non-RAS-acting medications or RAS-acting medications that do not cross the blood–brain barrier. These benefits have been reported independently from changes in blood pressure.[32] However, more clinical trials are needed to fully explain whether the RAS-acting medications (such as the centrally active ACE-Is) can effectively impact cognitive functions or influence the disease conversion from its prodromal stage or MCI to more advanced AD stages. Answers to these questions are important for a possible further implementation of targeted therapies with the centrally active ACE-Is, early in the disease process to reduce the amyloid beta toxicity and in consequence to slow down the development of AD pathology in the brain.

Predictors of conversion from mild cognitive impairment to Alzheimer's disease

The main factors that are helpful in predicting the likelihood of progression from MCI to AD include: (1) whole brain and hippocampal volume on magnetic resonance imaging (MRI) and computed tomography (CT) (at present, CT and MRI scans are mostly used to rule out coexisting cerebral pathologies),[33] (2) apolipoprotein E (APOE) status-the APOE epsilon4 allele is associated with incident MCI among community-dwelling older persons (this genetic test it is highly informative in providing AD risk evaluation; however, it is not recommended for routine clinical use [34]), and (3) the severity of memory impairment (evaluated via psychometric tests and neuropsychological testing).[35] It should be highlighted that emerging technologies of amyloid imaging scans have a tremendous impact on the early diagnosis of AD; however, they are not yet accessible in clinical practice. For instance, the positron emission tomography (PET) scan, using a radioactive glucose tracer, reveals some findings characteristic for early-stage AD, and the amyloid-based PET scan reflects a relative amyloid load in the brain that is also associated with the early, often asymptomatic AD stage.[36]

Future research directions for angiotensin-converting enzyme inhibitors in patients with elevated Alzheimer's disease risk

In the future, clinical trials examining the impact of blood–brain barrier crossing RAS-acting medications on the biomarkers of AD, in prodromal and mild AD stages, or MCI are merited. In particular, this includes trials using neuroimaging, and cerebrospinal fluid analysis, since they could elucidate the relation between AD and RAS, especially among patients in early AD stages.[37] Further clinical studies in patient groups with or without hypertension, and with elevated risk of AD (due to genetic predispositions, early onset of cognitive impairment, cardiovascular comorbidities, or ethnicity) should be conducted to explore whether the RAS-modifying medications, including centrally acting ACE-Is, should be considered for repurposing for AD indications in high-risk for dementia older patient populations.[37] It should be highlighted that outside of the large-scale clinical trials, there are only limited reports on the effects of centrally active ACE-Is on the rate of cognitive decline in elderly patients with dementia or its risk factors. Therefore, further prospective, long-term trials, conducted in a “real world” setting would be helpful for medical providers managing such patients. Finally, to test the hypothesis that the centrally active ACE-Is has protective effects on cognition (beyond the effects of blood-pressure control) it would be necessary to conduct a large-scale RCT, randomizing older adults with hypertension to centrally active ACE-Is versus noncentrally active ACE-Is. In addition, further prospective RCTs, in elderly patients with early AD stage or MCI, naive to ACE-Is, with one arm receiving centrally active ACE-Is and the other arm receiving standard medical treatment (not containing centrally active ACE-Is), followed for at least a year, would be helpful to address whether this treatment could be another potential therapeutic option for prevention of cognitive decline in a growing population of geriatric patients suffering from AD or MCI (often associated with cardiovascular, cerebral, and metabolic comorbidities).

Conclusion

Treatment options for AD are limited, and therefore the potential approaches to intervene at the earliest possible AD stage are necessary to fulfill the unmet needs of a growing population of elderly patients, who are at risk of cognitive decline. Identifying such patients, establishing an early diagnosis of AD or MCI, and designing an individualized therapy plan, including the safe and effective treatment for comorbidities (that often accompany MCI and AD), represent important priorities for physicians involved in the management of elderly patients. 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.

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Conflicts of interest

There are no conflicts of interest.