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 , two human cerebrospinal fluid (CSF) studies [33, 34], one small RCT , and one in vivo human cell study .
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 , wild-type mice treated with icv amyloid beta 25–35 to be used as an AD mouse model , 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 , imidapril , lisinopril , perindopril [26, 27], and trandolapril . ARBs used included losartan [18, 19, 25], olmesartan , telmisartan [15, 22, 28], and valsartan . The renin inhibitor aliskiren was used in one study . CCBs used included azelnidipine , isradipine [20, 30], lercanidipine , nicardipine [14, 16, 19, 20, 30], nifedipine , nimodipine [16, 20, 22, 30], and a nonselective CCB flunarizine . Other antihypertensives included BBs such as carvedilol and propranolol , diuretics such as amiloride and furosemide , and hydralazine [14, 19]. Experimental drugs such as angiotensin II , PD-123177 (angiotensin 2 receptor blocker) , and ICI 11,551 (a selective beta 2 receptor antagonist)  were also used. One study did not use antihypertensive medication . One of the five identified human studies reported use of telmisartan and amlodipine , 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 , open field [15, 22], and spontaneous alternation  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 , hippocampus morphology , 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  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 , amyloid and tau levels in cerebrospinal fluid (CSF) [33, 34], cognitive measures , and, in the small RCT, blood pressure measurements and cognitive outcomes .
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  (Table 1).
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 . 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 . Isradipine increased angiogenesis  and improved memory acquisition . Lercanidipine decreased blood pressure and protected against neuronal death . Nicardipine reduced Aβ1–42 and Aβ1–40 in the brain  and increased angiogenesis , but did not improve cognition . Nifedipine increased angiogenesis . Nimodipine improved regional cerebral blood flow and protected hippocampal morphology , reduced inflammatory markers , increased angiogenesis , improved memory acquisition , and prevented learning impairment in animals with cerebral ischemia  (Table 1).
The most extensively studied ACE-I was captopril, which was associated with genetic upregulation of proteins associated with neuronal function and membranes , reduced Aβ burden in the brain , decreased conversion of Aβ1–43 to Aβ1–42 , increased anti-oxidative stress markers , decreased oxidative stress markers , and better performance on learning and memory tasks . 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 . Perindopril and enalapril inhibited plasma ACE activity by 90 % but only perindopril inhibited brain ACE activity by 50 % . Perindopril decreased blood angiotensin II levels  and also levels of oxidative stress markers . Perindopril improved memory function . Trandalopril treatment reduced Aβ burden in the brain  (Table 2).
Losartan decreased angiotensin 1 and 4 receptor levels in the brain  and improved cerebral blood flow . In one study, it decreased Aβ1–42 , while in another, it did not alter Aβ1–42 in the brain . Treatment with losartan also resulted in better performance on learning and memory tasks [18, 25]. Telmisartan improved cerebral blood flow in humans , reduced neurologic deficits and improved locomotor function after cerebral ischemia [22, 35], reduced inflammatory and oxidative stress markers , reduced low-density receptors and apolipoprotein E expression in the brain , and increased BDNF levels in the hippocampus . Treatment with telmisartan resulted in better performance on learning and memory tasks in animals ; however, there was no improvement in memory in people . Olmisartan did not reduce blood pressure but reduced infarct size in cerebral ischemia and inflammatory markers . Valsartan reduced blood pressure but did not protect against neuronal death  (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 . 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 , and with decreased risk of dementia  when compared to other antihypertensive medication users (Table 2).
Only one animal study evaluated a diuretic, furosemide, and found that it reduced brain Aβ1–42 without affecting blood pressure .
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 . Carvedilol reduced Aβ1–42 in the brain without affecting blood pressure . 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 .