Abstract
Because dementia is associated with both deterioration in the quality of life and poor prognosis, the prevention of cognitive impairment (CI) is a critical problem in public health promotion. Hypertension is a risk factor for the aggravation of CI, and the renin–angiotensin–aldosterone system (RAAS) is a key player in the increased incidence and development of hypertension. Therefore, the RAAS is considered to be a promoting factor for CI development. Conversely, recent studies have shown that lowering blood pressure with RAAS inhibitors decreases the incidence of CI, dementia and cardiovascular disease. Blood–brain barrier-penetrating RAAS inhibitors appear to have advantages in preventing cognitive decline because they can suppress the RAAS in the hippocampus, which has an important role in cognition. Thus, RAAS blockage is a notable strategy for preventing CI.
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Introduction
Due to the aging of the population, the number of elderly patients with dementia is increasing. Dementia is associated with both deterioration in the quality of life and poor prognosis; the prevention of dementia is therefore important for promoting public health and reducing national medical expenses.1 Dementia includes Alzheimer’s disease (AD) and vascular dementia; the major causes of these two types of dementia are hypothesized to be amyloid β (Aβ) deposition due to a disorder of cholinergic neurons and vascular injury, respectively. Recent studies have shown that the manifestation of dementia can be delayed by several pharmacological agents, including cholinesterase inhibitors;2 however, sufficient treatment for patients with dementia has not yet been established. Because it is difficult to remove deposits of Aβ at an advanced stage, the early detection of cognitive impairment (CI) by screening and identifying high-risk patients are important issues.
Hypertension is hypothesized to be one of the most critical risk factors for CI, and the renin–angiotensin–aldosterone system (RAAS) is a key player for hypertension in a blood pressure (BP)-dependent/independent manner. Therefore, the RAAS is a crucial target for preventing CI (Figure 1). In this review, we focus on effects of the RAAS on CI leading to dementia.
Renin–angiotensin–aldosterone system (RAAS) is a critical target for preventing cognitive impairment and cardiovascular/cerebrovascular events. A full color version of this figure is available at the Hypertension Research journal online.
Hypertension is a risk factor for dementia and cognitive impairment
It is unclear whether there is an association between hypertension and cognitive decline; however, some longitudinal cohort studies have revealed there is a positive association between these conditions.3, 4, 5
Dementia can be classified into two types based on the pathogenesis: AD and vascular dementia. AD is a neurodegenerative disease caused by damage to cholinergic neurons, which leads to Aβ peptide deposition, especially in the cerebral limbic system, including the hippocampus. On the other hand, vascular dementia is caused by neural damage from a single stroke or multiple strokes, interrupting brain circulation for memory and cognition. Vascular dementia also results from damage to subcortical small vessels of the medullary arteries due to exposure to highly pulsatile pressure and flow, which causes white matter damage, lacunae and loss of cortical connections.
In some cases, these two types of dementia overlap. Accumulating evidence suggests associations among AD, cardiovascular risk factors and atherosclerosis. Neuroimaging and postmortem histopathological studies have indicated that up to one third of AD patients have some degree of vascular pathology; AD lesions are also present in a similar proportion of vascular dementia patients.6, 7 Moreover, decreased cerebral blood flow is a common and early observation in people with AD, implying that Aβ induces vascular dysfunction.8, 9
Hypertension is associated with increased risk for CI, leading to AD in addition to vascular dementia, suggesting that lowering BP would reduce the incidence of dementia. Petrovitch et al.10 showed that elevated systolic BP in midlife was associated with low brain weight and greater numbers of neurofibrillary tangles of hyperphosphorylated tau proteins, known as a primary marker of AD, in both the neocortex and hippocampus. In addition, diastolic BP elevation has been shown to be associated with greater numbers of neurofibrillary tangles in the hippocampus. Kivipelto et al.11, 12, 13 showed that high systolic BP is also a risk factor for AD in later life. Posner et al.14 showed that a history of hypertension is not associated with AD incidence, but is associated with an increased risk of vascular dementia, particularly in the presence of heart disease or diabetes. These studies indicate high BP is a risk for both vascular dementia and AD.
Moreover, high BP is associated with not only dementia but also with cognitive dysfunction, an early manifestation of dementia, especially in the elderly. Cross-sectional studies have shown that systolic and/or diastolic BP were associated with declined cognitive function.15, 16, 17, 18, 19, 20, 21 Longitudinal studies have shown that high BP was significantly associated with the decline in visualization/fluid abilities in both younger and older age groups.22 On the other hand, some studies have shown that a certain BP level, particularly a systolic pressure of at least 130 mm Hg, is important for the maintenance of cognitive functioning in the elderly.23, 24 Thus, lowering BP at an old age does not prevent dementia and lowering BP beginning in the midlife period therefore appears to be an important strategy for preserving cognitive function.
Lowering BP ameliorates dementia and cognitive impairment
Several studies have shown that lowering BP is associated with a decline of cognitive dysfunction or incidence of dementia,25 although other studies have failed to show a relationship between BP lowering and cognitive function.26, 27 The Syst-Eur study demonstrated that antihypertensive treatment with nitrendipine, a calcium channel blocker, in elderly patients reduced the incidence of dementia; the reduction in AD was greater than that of vascular dementia.28 The hypertension in the Very Elderly Trial cognitive function assessment (HYVET-COG) trial showed that antihypertensive treatment with indapamide, a diuretic, in elderly patients did not significantly reduce the incidence of dementia;29 however, significant favorable effects of antihypertensive treatment were observed when these data were combined in a meta-analysis with data from other placebo-controlled trials of antihypertensive treatment, and the combined risk ratio favored treatment.29 Therefore, lowering BP appears to have a role in preventing dementia and in preventing cardiovascular events. Conversely, dementia per se could be an independent cardiovascular risk factor: patients with dementia have lifestyle-related problems, such as inappropriate food or alcohol intake, sedentary activity levels and psychosocial stress, including depression.30 Therefore, preventing dementia might lead to the suppression of cardiovascular events.
RAAS is involved in cognitive decline
Several animal studies have shown that RAAS activation is associated with CI. RAAS-activated model mice showed declined cognitive function compared with wild-type mice, and the declined cognitive function was associated with a decrease in cerebral surface blood flow and an increase in oxidative stress.31, 32
Systemic RAAS activation occurs when angiotensinogen is cleaved in circulation by renin, which is secreted by the kidney, to form angiotensin (Ang) I. Ang I is then converted to Ang II by angiotensin-converting enzyme (ACE) in the pulmonary circulation. Ang II activates Ang II type 1 receptors on vascular smooth muscle cells to induce vasoconstriction. Ang II also stimulates the release of aldosterone from the adrenal cortex into circulation. In addition, the local RAAS is believed to have a pivotal role in organ damage. Components of the RAAS have been detected in various organs, such as the heart, kidney and brain. Indeed, the brain expresses genes that encode all components of the RAAS.33, 34, 35 The local RAAS can be activated independently of the systemic RAAS, indicating that end-organ damage may occur even though the systemic RAAS is attenuated.
Therefore, local RAAS blockage is necessary to prevent CI in addition to a systemic RAAS blockage; however, controversy remains regarding, which drugs are useful for blocking the brain RAAS. Recent studies have indicated that a drug’s ability to prevent CI depends on blood–brain barrier (BBB) penetration, and is independent of BP-lowering effects (Table 1). Of note, although there is no evidence of penetration through the BBB, some RAAS inhibitors have clinical benefits for preventing CI, suggesting that RAAS inhibitors might pass through the damaged BBB caused by the accumulation of cardiorenal risk factors.
In addition, diabetes is an independent risk factor for dementia and hypertension because the RAAS is also activated in diabetic patients. Blockage of the RAAS in diabetic patients might therefore be effective for preventing dementia, even in patients without hypertension.36
ACE inhibitors
The Syst-Eur study demonstrated that active treatment with an ACE inhibitor (ACE-I) (perindopril) with possible addition of a diuretic (indapamide) was associated with reduced risks of dementia and cognitive decline associated with recurrent stroke.37 It has been shown that brain-penetrating ACE-Is suppress cognitive decline compared with non-brain-penetrating ACE-Is or calcium channel blockers,38, 39 which is consistent with other observational studies.40 Therefore, blockage of the brain RAAS with brain-penetrating drugs is important to cognitive function and systemic blockage of the RAAS.
The PROGRESS (Perindopril Protection Against Recurrent Stroke study) study showed that an ACE-I (perindopril) with possible addition of a diuretic (indapamide) reduced the risks of dementia and cognitive decline associated with recurrent stroke.31 The HOPE (Heart Outcomes Prevention Evaluation) trial showed that an ACE-I (ramipril) reduced the incidence of stroke and the rate of CI in patients at high risk, despite only a modest reduction in BP.41
An increase in ACE activity has been shown in AD, indicating that ACE-Is are effective for preventing AD. ACE has been detected in the cerebral parenchyma, including microglia, astrocytes and vasculature of the brain, especially in the endothelium.42 BBB-penetrating ACE-Is can inhibit the activity of hippocampal ACE and prevent cognitive decline.43 There appear to be some possible mechanisms by which ACE-Is prevent CI. ACE-Is reduce oxidative stress, which can cause neuron damage.44 Inhibition of ACE activity in the brain also enhances the release of acetylcholine from neurons. Moreover, ACE inhibition decreases deposition of Aβ through an increase in substance P, which can activate neutral endopeptidase, an enzyme that degrades Aβ in the brain.45, 46 ACE-Is, especially BBB-penetrating ACE-Is, are able to prevent cognitive decline.
Angiotensin II receptor blockers
In addition, an angiotensin II receptor blocker (ARB) improved CI through a decrease in hippocampal long-term potentiation and improvement in functional blood flow compared with a calcium channel blocker.47
Some studies have shown that inhibition of the RAAS improves not only vascular function but also the accumulation of Aβ. Wang et al.48 reported that certain ARBs reduced Aβ accumulation and attenuated the development of Aβ-mediated cognitive deterioration through a possible efflux of Aβ from the brain into circulation. Hajjar et al.49 showed in an autopsy study that treatment with ARBs is associated with less Aβ accumulation and AD-related pathology independent of other AD risk factors.
The OSCAR (OlmeSartan and Calcium Antagonists Randomized) study demonstrated that significant systolic BP reduction with an ARB (eprosartan) had a negative association with cognitive decline.50 Fogari et al.51 reported that a group of patients treated with an ARB (telmisartan) and diuretic (hydrochlorothiazide) showed significantly improved cognitive function compared with a group treated with an ACE-I (lisinopril) and a diuretic (hydrochlorothiazide). Li et al.12 reported that treatments with ARBs were associated with a significant reduction in the incidence and progression of AD and dementia compared with treatments with ACE-Is or other cardiovascular drugs in a predominantly male population.
There appear to be some mechanisms involved in the ability of ARBs to prevent CI in addition to reducing oxidative stress. Mogi et al.52 showed that the angiotensin II type-2 (AT2) receptor has an important role in brain protection because cognitive function was significantly impaired in AT2 receptor-null mice compared with that in wild-type mice, and direct stimulation of the AT2 receptor by a newly generated direct AT2 receptor agonist, Compound 21, enhanced cognitive function in wild-type mice, which was not observed in AT2 receptor-deficient mice.53 Ang IV, a degradation product of Ang II, might have a role in CI prevention because the Ang IV receptor has an important role in memory in the hippocampus.44 AT receptors, including AT1, AT2 and AT4, have been detected in the hippocampus; therefore, blockage of AT1 and enhancement of AT2 and AT4 signaling by an ARB might be a reasonable strategy for preventing CI (Figure 2).54
Protective effects of renin–angiotensin–aldosterone system (RAAS) inhibitors on hippocampal neuron and vascular damage. Ang, angiotensin; Ald, aldosterone; MR, mineralocorticoid receptor; I, inhibitors; ARB, angiotensin II receptor blockers. A full color version of this figure is available at the Hypertension Research journal online.
Mineralocorticoid receptor blockers
It is well known that an increased plasma aldosterone level is a risk factor for the development of cardiovascular diseases.55 In addition, the incidence of cerebrovascular disease was shown to be significantly higher in patients with primary aldosteronism than in an essential hypertension group.56 A number of previous studies have shown that blockage of the mineralocorticoid receptor (MR) prevents cerebrovascular events, and that MR blockers improve cognitive function and prognosis in a BP-independent manner.57, 58, 59 The Cache County cohort study in Utah, USA, showed that potassium-sparing diuretics are associated with reduced incidence of AD compared with other antihypertensive drugs, suggesting that potassium-sparing diuretics, including spironolactone, have additive effects on dementia prevention.60
Iwanami et al.61 showed that MR blockage by eplerenone has a protective effect on ischemic brain damage through improved cerebral blood flow in the penumbra and reduction of oxidative stress in wild-type mice. MR blockers reduce the size of cerebral infarcts via a reduction in the expression of epidermal growth factor receptor mRNA, leading to reduced remodeling in stroke-prone, spontaneously hypertensive rats.59 We previously showed that a high plasma aldosterone level is a risk factor for CI, and that the administration of an MR blocker prevents further CI in patients with hypertension.62 Sakata et al.63 demonstrated that MR blockage with spironolactone improved impaired cognitive function observed in diabetic female mice in a BP-independent manner.
The MR has been identified not only in blood vessels but also in the brain, especially in the hippocampus. Moreover, aldosterone is synthesized in the brain and enters the brain from circulation. Therefore, blockage of aldosterone in the brain is critical to prevent CI in addition to systemic RAAS inhibition. Activation of the RAAS or low potassium concentration has been suggested to be involved in CI through possible contributions to CI pathogenesis, including oxidative stress, inflammation, platelet aggregation and vasoconstriction.64
Renin inhibitor
Aliskiren, a direct renin inhibitor, ameliorated brain damage and working memory deficits in a model of chronic cerebral ischemia through oxidative stress attenuation.65 Inhibition of upstream RAAS components could prevent the synthesis of all types of angiotensins, and might be a strategy to prevent cognitive decline; however, more evidence is needed to confirm aliskiren’s ability to prevent CI.
Conclusion
Activation of the RAAS is associated with cognitive decline and the development of hypertension. The RAAS in the brain might be an important target for the prevention of CI.
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Yagi, S., Akaike, M., Ise, T. et al. Renin–angiotensin–aldosterone system has a pivotal role in cognitive impairment. Hypertens Res 36, 753–758 (2013). https://doi.org/10.1038/hr.2013.51
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DOI: https://doi.org/10.1038/hr.2013.51
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