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.

Methods

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.

Results

Animal and Human Mechanism Studies

Searches retrieved 138 PubMed records and 522 records from Medline, PsycINFO® and Embase. Of these, seven were review articles [6–12], 19 articles presented results from animal studies exploring mechanisms [13–31], and there were five human studies of which one was an autopsy study [32], two human cerebrospinal fluid (CSF) studies [33, 34], one small RCT [35], and one in vivo human cell study [36].

The methodology of the 19 animal studies varied widely in the selection of animals and drugs used, length of treatment times, and outcomes. Animal models ranged from mouse models using wild-type mice [13, 23], aged Swiss mice [31], wild-type mice treated with icv amyloid beta 25–35 to be used as an AD mouse model [27], and transgenic (Tg) AD mice alone [17, 19, 21, 29, 30], to rat models such as Wistar [18, 20], Sprague-Dawley [16, 22], or spontaneously hypertensive rats (SHR) [14, 15, 24, 26, 28]. Regarding AHM used, 17 of the 19 studies used CCB, ACE-I, or ARB alone or in combination. Commercially available ACE-Is used were captopril [17, 18, 29], enalapril [27], imidapril [27], lisinopril [14], perindopril [26, 27], and trandolapril [19]. ARBs used included losartan [18, 19, 25], olmesartan [24], telmisartan [15, 22, 28], and valsartan [14]. The renin inhibitor aliskiren was used in one study [13]. CCBs used included azelnidipine [24], isradipine [20, 30], lercanidipine [14], nicardipine [14, 16, 19, 20, 30], nifedipine [30], nimodipine [16, 20, 22, 30], and a nonselective CCB flunarizine [31]. Other antihypertensives included BBs such as carvedilol and propranolol [19], diuretics such as amiloride and furosemide [19], and hydralazine [14, 19]. Experimental drugs such as angiotensin II [18], PD-123177 (angiotensin 2 receptor blocker) [20], and ICI 11,551 (a selective beta 2 receptor antagonist) [21] were also used. One study did not use antihypertensive medication [23]. One of the five identified human studies reported use of telmisartan and amlodipine [35], while four studies compared ARB users with other AHMs [32–34, 36]. Comparators used differed, as did the length of treatment times, which varied between 4 days and 15 months.

Outcome measures ranged from cognitive tests to biomarkers. Cognitive measures included water maze [15, 16, 19–21, 25, 26, 31], Y maze [13, 18], object recognition [21, 27], passive avoidance [18], open field [15, 22], and spontaneous alternation [27] tests. Locomotor function was assessed in five studies [22, 24, 26, 27, 31]. Numerous studies used serum, cerebrospinal fluid, or histopathological measures of amyloid beta and/or tau levels as their outcome [17, 19, 21, 23, 25, 29, 30]. Additional histopathological measures included pyramidal neurons in hippocampus [14], hippocampus morphology [16], and vascular pathology [24, 25]. Alteration in markers of oxidative stress [13, 18, 22, 24–26, 31], inflammation [13, 16, 22, 24, 26], apoptosis [20, 26], brain-derived neurotrophic factor (BDNF), and alpha tubulin levels [15] were also frequently used alone or in conjunction with cognitive measures. Some studies included measurement of various proteins of the renin angiotensin system (RAS) in the brain as their outcomes [13, 23, 25–27, 30]. Outcomes included infarct size [24, 31] and cerebral blood flow [13, 16, 24, 25] in studies evaluating the effect of antihypertensive medication in cerebral ischemia models. Surprisingly, only seven studies included blood pressure measurements as their outcome [13–15, 19, 24, 26, 28]. Human study outcomes also varied and included AD and vascular pathology in one autopsy study [32], amyloid and tau levels in cerebrospinal fluid (CSF) [33, 34], cognitive measures [36], and, in the small RCT, blood pressure measurements and cognitive outcomes [35].

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).

Table 1 Extraction table for mechanism studies: calcium channel blockers (CCB)
Full size table

Eight animal studies reported results of treatment with CCB alone [14, 16, 19, 20, 30, 31] or in combination with ARB [22, 23]. Azelnidipine decreased blood pressure, infarct size, and also reduced markers of oxidative stress and inflammation [24]. The nonselective CCB flunarizine reversed impairment in learning, memory, and motor function after cerebral ischemia and reversed cerebral ischemia-associated decrease in anti-oxidative stress markers [31]. Isradipine increased angiogenesis [30] and improved memory acquisition [20]. Lercanidipine decreased blood pressure and protected against neuronal death [14]. Nicardipine reduced Aβ1–42 and Aβ1–40 in the brain [19] and increased angiogenesis [30], but did not improve cognition [19]. Nifedipine increased angiogenesis [30]. Nimodipine improved regional cerebral blood flow and protected hippocampal morphology [16], reduced inflammatory markers [16], increased angiogenesis [30], improved memory acquisition [20], and prevented learning impairment in animals with cerebral ischemia [16] (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).

Table 2 Extraction table for mechanism studies: angiotensin receptor blocker (ARB), angiotensin converting enzyme inhibitor (ACE-I), and diuretic
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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].

Table 3 Extraction table for mechanism studies: beta blockers
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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 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 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.