2022 Volume 8 Pages 5-8
The number of the elderly with dementia is increasing as the number aging people is increasing. The increase of dementia has been social problem, because the most majority cause of bedridden in the elderly is dementia replaced by cerebrovascular disease. Hypertension is associated with increased risk for dementia both in Alzheimer’s disease and vascular dementia. However, interventional studies failed to establish the relationship between blood pressure lowering and dementia. Antihypertensive treatment with renin-angiotensin-aldosterone system (RAAS) blocker may be an additional strategy for preventing dementia because systemic or local RAAS activation exacerbate neurovascular damage through enhancement of oxidative stress. Especially aldosterone, the most downstream component of RAAS, plays a pivotal role on progression of dementia. Thus, mineralocorticoid receptor blockade might be beneficial for preventing dementia.
The number of the elderly with dementia is increasing as the number aging people is increasing. The increase of dementia has been social problem, because the most majority cause of bedridden in the elderly is dementia replaced by cerebrovascular disease. Dementia is related to bedridden and deterioration in the quality of life as well as survival rate, and prevention of dementia is thus crucial in terms of promoting public health and decreasing national medical expenses1,2). Several studies showed that onset of dementia could be delayed by pharmacological agents such as cholinesterase inhibitors and antibody for amyloid β3); however, strategy of the treatment of dementia has not been established yet. It is thought to be difficult to remove amyloid β at an advanced stage after deposit, thus, early detection of cognitive impairment, early stage of dementia, by screening and management of hypertension from middle-age are crucial issues1).
Hypertension is the most pivotal risk factors for cognitive impairment and dementia, and the renin-angiotensin-aldosterone system (RAAS) play pivotal roles for hypertension in a blood pressure (BP)-dependent or independent manner. Thus, the RAAS is a pivotal target for prevention of dementia (Figure). In this review, we focus on effects of the RAAS on cognitive impairment resulting in dementia.
Renin-angiotensin-aldosterone system (RAAS), especially aldosterone of the most downstream of the cascade, plays a pivotal role on progression of dementia. Mineralocorticoid receptor (MR) blockers might have beneficial effects on preventing dementia.
Major phenotype of dementia includes Alzheimer’s disease (AD) and vascular dementia (VD), and it has been thought that the major cause of these two types of dementia is amyloid β deposition through a damage of cholinergic neurons and vascular injury, respectively. The two phenotype of dementia shares the risk factors of life-style related disease, especially hypertension. AD is a neurodegenerative disease evoked by damage of cholinergic neurons, leading to deposition of amyloid β peptide, especially in the cerebral limbic system which includes the hippocampus. VD is evoked by neural damage from a single stroke blocking brain circulation for memory and cognition or from multiple strokes. VD also results from damage of subcortical small vessels of the medullary arteries through exposure to highly pulsatile pressure and flow, leading to white matter damage, lacunae and loss of cortical connection1). These two types of dementia are sometimes overlapped; thus, it is sometime difficult to distinguish the phenotype of dementia only from symptoms, biomarkers, and imaging studies. The prevalence of this mixed-type dementia has been increasing. Dysfunction of the drainage pathway of amyloid β in the perivascular space due to hypertension and/ or other atherosclerotic risk factors leading to disruption of the blood-brain barrier (BBB) is thought to be one of the causes of amyloid β deposition. Enhanced interstitial fluid drainage in the hippocampus leading to sieving of high molecular weight solutes and increased concentration of waste products are thought to be other causes of amyloid β deposition4).
Hypertension is related to increased risk for dementia. Longitudinal cohort studies have shown that there is a positive association between hypertension and dementia5). These results suggest that lowering of BP reduce the incidence of dementia. Especially elevated systolic BP in mid-life was associated with cognitive function. Thus, lowering BP from an old age does not prevent dementia and BP lowering beginning in the mid-life period is thought to be important strategy for preserving dementia.
However, interventional studies failed to establish the relationship between BP lowering and dementia. The Syst-Eur study reported that antihypertensive treatment with nitrendipine, a calcium channel blocker, in elderly patients reduced the incidence of dementia, especially AD rather than VD6). The HYVET-COG trial reported that antihypertensive treatment with indapamide, a diuretic, in elderly patients did not reduce the incidence of dementia7); however, meta-analysis showed that there were significant favorable effects of antihypertensive treatment when these data were combined with data from other placebo-controlled trials of antihypertensive treatment, and the combined risk ratio favored treatment7). BP lowering, thus, seems to have a potential role in prevention of dementia.
Several animal studies showed that RAAS activation is associated with dementia. In systemic RAAS, Angiotensin II also stimulates the release of aldosterone from the adrenal cortex to the circulation. Circulating aldosterone activation enhances oxidative stress, resulting in neurovascular damage.
Not only systemic RAAS activation but also local RAAS activation is thought to play a crucial role in neurovascular damage. In the local RAAS, The RAAS components have been identified in various organs such as the heart, kidney, and brain. The brain expresses genes that encode all components of the RAAS8). The local RAAS could be activated independently of the systemic RAAS, indicating that neurovascular damage can occur even though the systemic RAAS is suppressed by RAAS inhibitors. In addition to the production of local RAAS components, local infiltration of RAAS components, especially angiotensin II, plays an important role in the progression of dementia. Angiotensin II receptors are abundantly expressed in the brain, especially in the circumventricular organs, where BBB does not exist between the vasculature and neurons and various bioactive chemicals are transmitted from the vasculature to the neurons.
Enhanced permeability of the BBB due to hypertension promotes the infiltration of angiotensin II into the perivascular space, leading to activation of perivascular macrophages, which results in enhanced oxidative stress through NOX2 activation. Thus, inflammation of the perivascular space damages the neurovascular unit, leading to dementia9).
Local RAAS blockade is, thus, crucial to prevent dementia in addition to systemic RAAS blockade; however, controversy has remained regarding which drugs are useful for blocking the brain RAAS.
Recent studies have indicated that the ability of prevention of dementia depends on BBB penetration and is independent of BP-lowering effects1). Thus, RAAS inhibitors with ability of BBB penetration might have beneficial effects compared without those without ability of BBB penetration.
There has been a concern that angiotensin-converting enzyme (ACE) activation is associated with amyloid β deposition since ACE is involved in amyloid β metabolism. In a memory clinic cohort, ACE activity in the cerebrospinal fluid (CSF) was reportedly associated with brain atrophy and cerebral small vessel disease, suggesting that ACE inhibitors, which may lower CSF ACE levels, are not preferred for antihypertensive treatment10). However, whether ACE activity is associated with the prevalence of dementia is still controversial. Recently, sacubitril-valsartan has been widely used in patients with heart failure and hypertension. Neprilysin is involved in the degradation of amyloid β; thus, there has been another concern that sacubitril-valsartan may evoke dementia. Several studies have been shown that administration of sacubitril-valsartan is not associated with the onset of dementia during a short-term observational period. Therefore, long-term studies assessing cognitive outcomes are needed to establish the effects of sacubitril-valsartan on cognitive function11).
Aldosterone is a key player in the reabsorption of sodium and fluid, and in potassium excretion in epithelial cells of the renal collecting ducts via cytosolic mineralocorticoid receptor (MR) activation12). It has been believed that the main role of aldosterone was to maintain extracellular volume after sodium absorption in renal distal tubules, leading to elevating BP, as a result of activation of RAAS cascade13). Human-being has developed RAAS through evolutionary process because of transition of living place from water to land, however, over-intake of salt in the age of gluttony leads to RASS activation, resulting in cardio-cerebro vascular events and dementia.
Higher aldosterone levels were associated with increased BP and incidence of hypertension with aging14). Several studies have revealed that aldosterone also has additional physiological and/or pathophysiological effects, including suppression of nitric oxide (NO) bioavailability and enhancing oxidative stress, leading to vascular inflammation15). In addition, MR can be activated in a ligand independent manner under the RAAS activation through Rac1, small G protein16). Aldosterone therefore causes vascular damage and remodeling in a BP-independent manner as well as in a BP-dependent manner15).
It is well known that an increased plasma aldosterone level is a risk factor for the development of cardiovascular diseases1). Previous studies have reported that blockade of the MR prevents cerebrovascular events and that MR blockers improve cognitive function and prognosis in a BP-independent manner17).
A cohort study showed that potassium-sparing diuretics including spironolactone are related to reduced incidence of AD compared with other antihypertensive drugs, which suggests that potassium-sparing diuretics have beneficial effects on prevention of dementia19). We previously reported that high plasma level of aldosterone is a risk factor for cognitive impairment and that MR blockers prevents decline of cognitive impairment in patients with hypertension20,21).
The MR has been identified the brain, especially in the hippocampus as well as in blood vessels. Moreover, aldosterone is synthesized in the brain and enters the brain from circulation13). Therefore, blockade of aldosterone in the brain with BBB-penetrating MR blockers is a potential target for preventing cognitive impairment in addition to systemic RAAS inhibition. Activation of the RAAS has been indicated to be involved in dementia through possible contributors to dementia pathogenesis including enhancement of oxidative stress, inflammation, platelet aggregation and vasoconstriction leading to neurovascular damage 15).
MR blockage, thus, might have beneficial effects in terms of preventing dementia compared with other hypertensive drugs.
Activation of the RAAS is associated with dementia in a hypertension dependent/independent manner. The RAAS in the brain might be a potential target for the prevention of cognitive impairment and MR blockade might be beneficial for preventing dementia.
Disclosures: M.S. has received speaking honoraria from Bayer Yakuhin, Ltd., Mitsubishi Tanabe Pharma Corporation, Takeda Pharmaceutical Company, Ltd., Daiichi Sankyo Company, Ltd., and Nippon Boehringer Ingelheim Company, Ltd., clinical research funding from Bayer Yakuhin, Ltd., and scholarship grants from Mitsubishi Tanabe Pharma Corporation, Takeda Pharmaceutical Company, Ltd., and Daiichi Sankyo Company, Ltd. M.S. is involved with the Department of Cardio-Diabetes Medicine funded partly by Boehringer Ingelheim Company, Ltd. The other authors declare no conflicts of interest. S.Y. declares no conflicts of interest.
