Relationship Between Antihypertensive Medications and Cognitive Impairment: Part II. Review of Physiology and Animal Studies

Purpose of Review There is an established association between hypertension and increased risk of poor cognitive performance and dementia including Alzheimer’s disease; however, associations between antihypertensive medications (AHM) and dementia risk are less clear. An increased interest in AHM has resulted in expanding publications; however, none of the recent reviews provide comprehensive review. Our extensive review includes 24 mechanistic animal and human studies published over the last 5 years assessing relationship between AHM and cognitive function. Recent Findings All classes of AHM showed similar result patterns in animal studies. The mechanism by which AHM exert their effect was extensively studied by evaluating well-established pathways of AD disease process, including amyloid beta (Aβ), vascular, oxidative stress and inflammation pathways, but only few studies evaluated the blood pressure lowering effect on the AD disease process. Summary Methodological limitations of the studies prevent comprehensive conclusions prior to further work evaluating AHM in animals and larger human observational studies, and selecting those with promising results for future RCTs.


Introduction
Alzheimer's disease (AD), the most common cause of dementia [1], is characterized by extracellular amyloid beta (Aβ) deposition in the form of neuritic plaques, intracellular deposition of hyperphosphorylated microtubule-associated tau protein which culminates in synaptic loss, neuronal cell death, Aβ angiopathy, oxidative stress, and inflammatory processes resulting in cognitive impairment [2]. However, the exact mechanisms are still unclear.
There is a long established association between hypertension and increased risk of cognitive decline and AD in humans [3], but the potential association between antihypertensive treatment and reduced risk of AD has been harder to determine. Attempts to understand possible mechanisms have shifted attention toward the potential pleiotropic effects of the different classes of antihypertensive medication (AHM) and their potential impact on cognitive function [4,5]. As a result, there are an increasing number of animal studies evaluating AHM, such as AHM acting through renin angiotensin system or altering calcium homeostasis.
This review aims to provide such an update in two parts. Part 1 provides an overview of the recent human observational and clinical trial literature, and part 2 reviews the recent physiological and animal work. This article is part of the Topical Collection on Antihypertensive Agents: Mechanisms of Drug Action

Search Strategy
The databases Embase, PsycINFO®, Medline, Medline in process, and other nonindexed citations and PubMed were searched from 2010 to February 2016 using the search terms: dementia or cognit* or mild cognitive impairment, and antihypertensives, or antihypertensive agents, or diuretic or diuretics or thiazide-like or calcium channel blocker or calcium channel blockers or calcium antagonist or angiotensin converting enzyme inhibitor or angiotensin-converting enzyme inhibitors or ACE inhibitors or angiotensin receptor blocker or angiotensin receptor blockers or angiotensin receptor blockers (ARB) or beta blocker or adrenergic beta-antagonists. Where review articles were identified, reference lists were searched for original research articles published within the last 5 years.

Inclusion and Exclusion Criteria
Included animal or mechanistic studies required exposure to one of the antihypertensive classes of interest, calcium channel blockers (CCB), ARB, angiotensin converting enzyme inhibitors (ACE-I), beta blocker (BB), and diuretics, and to have a control or comparator group; however, a specific outcome measure was not required.

Article Selection
Abstracts were double read by SY and MS. Discrepancies were resolved by discussion. Full text articles were double read by the same team and data extracted into standard tables, collated by antihypertensive class.

CCB
One human study reporting on the effect of CCB use found that of the 167 AHM users, only nifedipine users had significantly lower Aβ levels when compared to 107 matched AHM never users [36] (Table 1).

ACE-I
The most extensively studied ACE-I was captopril, which was associated with genetic upregulation of proteins associated with neuronal function and membranes [17], reduced Aβ burden in the brain [17], decreased conversion of Aβ1-43 to Aβ1-42 [28], increased anti-oxidative stress markers [18], decreased oxidative stress markers [17], and better performance on learning and memory tasks [18]. Captopril treatment also inhibited ACE activity and decreased angiotensin II levels [17,29]. Lisinopril did not protect against neuronal death even with significant blood pressure reduction [14]. Perindopril and enalapril inhibited plasma ACE activity by 90 % but only perindopril inhibited brain ACE activity by 50 % [27]. Perindopril decreased blood angiotensin II levels [26] and also levels of oxidative stress markers [26]. Perindopril improved memory function [26]. Trandalopril treatment reduced Aβ burden in the brain [19] (Table 2).

ARB
Losartan decreased angiotensin 1 and 4 receptor levels in the brain [25] and improved cerebral blood flow [25]. In one study, it decreased Aβ1-42 [19], while in another, it did not alter Aβ1-42 in the brain [25]. Treatment with losartan also resulted in better performance on learning and memory tasks [18,25]. Telmisartan improved cerebral blood flow in humans [35], reduced neurologic deficits and improved locomotor function after cerebral ischemia [22,35], reduced inflammatory and oxidative stress markers [22], reduced low-density receptors and apolipoprotein E expression in the brain [28], and increased BDNF levels in the hippocampus [15]. Treatment with telmisartan resulted in better performance on learning and memory tasks in animals [15]; however, there was no improvement in memory in people [35]. Olmisartan did not reduce blood pressure but reduced infarct size in cerebral ischemia and inflammatory markers [24]. Valsartan reduced blood pressure but did not protect against neuronal death [14] (Table 2).
ARBs were studied as a class in human studies. One brain autopsy study showed that ARB use was associated with significantly lower AD pathology, while no alteration of vascular pathology was observed when compared to other or no antihypertensive medication users [32]. Additionally, it was found that ARB use in people with normal cognition or mild cognitive impairment (MCI) was associated with lower levels of tau and phosphorylated tau [32,34] and higher levels of Aβ1-42 in cerebrospinal fluid [34], and with decreased risk of dementia [34] when compared to other antihypertensive medication users ( Table 2).

Diuretics
Only one animal study evaluated a diuretic, furosemide, and found that it reduced brain Aβ1-42 without affecting blood pressure [19].

BBs
Two animal studies reported on the effect of BB use (Table 3). Treatment with nonselective beta adrenergic receptor blockers, carvedilol and propranolol, resulted in decreased brain Aβ1-40 and Aβ1-42 levels; however, this did not translate into improved cognition [19]. Carvedilol reduced Aβ1-42 in the brain without affecting blood pressure [19]. In contrast, treatment with a selective beta 2 adrenergic receptor (β2AR) antagonist resulted in significantly worse working memory and increased amyloid plaque burden, Aβ1-42 levels, tau phosphorylation, and accumulation in the hippocampus, suggesting involvement of β2ARs in the amyloid pathway and in cognitive function [21].

Discussion
The importance of dementia as a clinical and public health issue is rapidly increasing as the population ages [37]. Thus, identifying new and effective approaches to prevention or treatment is critical. Due to the lengthy process of developing new medications, there has been a recent surge in interest ANOVA -Blood pressure and heart rate was not changed in any of the treatment groups -Animals treated with telmisartan alone or with GW9662 or with ANA-12 had  ANOVA -BP and pulse decreased while body weight and rCBF remained stable in all treatment groups compared to control group -Infarct volume decreased in olmisartan and azelnidipine-treated group, and it was more effective than low-dose monotherapy; however, high-dose azelnidipine (better BP reduction) was more effective than high-dose olmesartan -All treatments reduced oxidative markers, inflammatory markers, and preserved neurovascular unit in a dosereponse matter Ongali et al.  toward re-purposing currently available medications for the treatment of AD, including AHM. In this paper, we provide an extensive review of 24 mechanistic animal and human studies published over the last 5 years assessing the relationship between AHM and cognitive function. Previous studies have shown a possible protective effect of certain AHM against AD risk [1], and it has been suggested that this protective effect is independent of, or in addition to, the blood pressure lowering effect [4,5]. It is therefore not surprising that the mechanistic studies have focused on evaluating effects of AHM on well-established pathways in the AD disease process, including Aβ, vascular, oxidative stress, and inflammation pathways [2].
Of the six CCBs, nimodipine has been the most widely studied, and it was associated with angiogenesis and neuroprotection in the hippocampus, reduced inflammation, and improved cognitive function, but not with improved cerebral blood flow. Flunarizine and isradipine also improved cognition and had some effect on some of the above mentioned pathways.
Of the five ACE-Is studied, most studies evaluated effects of captopril and perindopril. Captopril was associated with neuroprotection [17], reduced Aβ burden in the brain [17,29], decreased oxidative stress [17,18], and better cognitive performance [18]. This effect was mediated by alteration of ACE activity and angiotensin II levels in the brain [17,29]. Perindopril was associated with decreased oxidative stress [26] and improved cognitive function [26] and was shown to inhibit ACE activity in both blood and the brain ACE [27]. These findings suggest the beneficial effect of ACEs when crossing the blood-brain barrier; however, a previous observational study by Sink et al. did not support this hypothesis [38].
Of the four ARBs studied, losartan and telmisartan were examined in detail. Losartan use was associated with improved cerebral blood flow [25]. Yet, its effect on Aβ1-42 was equivocal with one study showing decreased levels [19], while another unchanged levels of Aβ1-42 [25]. Treatment with losartan also resulted in better performance on learning and memory tasks [18,25]. These findings suggest beneficial effect via vascular rather than amyloid pathways, which is supported by its angiotensin 1 and 4 receptor lowering effect in the brain [25]. The other medication evaluated in detail was telmisartan, which, similar to losartan, was associated with improved cerebral blood flow in humans [35], reduced inflammation, oxidative stress [22], and markers of brain lipid metabolism [28]. Telmisartan also improved cognitive performance in animals [15], however, not in humans [35]. This negative finding in humans was replicated in a large multinational double-blind randomized placebo controlled trial, TRANSCEND, comparing ARB (telmisartan) use to placebo [3].
Previous animal studies and also RCTs with AHM have shown that blood pressure reduction, particularly in close proximity to development of cognitive impairment, does not alter dementia risk. Additionally, it is possible that treatment comes too late to mitigate the injury related to chronic exposure, suggesting an earlier window of benefit after which neural damage is hard to remediate. Thus, other mechanisms involved in AD development should to be explored. Medications explored in mechanistic studies have been different agents to those used in RCTs.

Conclusions
Similar to human observational studies and RCTs, different classes of AHM show similar result patterns in animal studies.
Inconsistencies in the sources of evidence from the use of different animal types, ages, treatment times, and outcome ANOVA -Significantly better performance on Morris water maze in non-Tg-AD mice treated with NaCl, while worse in non-Tg mice treated with ICI, and non-Tg mice treated with NaCl, and worse when treated with ICI -Aβ42 and tau levels in hippocampus of ICI-treated 3xTg-AD mice was significantly higher than when treated with NaCl suggesting increased Aβ production measures limit the possibility of drawing firmer conclusions. Similar to observational studies, the relative lack of information on blood pressure levels is a major limitation. These limitations restrict our ability to draw wider ranging conclusions about use of specific antihypertensive classes, subclasses, or individual drugs. However, AHM that have had promising results in animals and larger human observational studies should be selected for future RCTs.