Role of Angiotensin-Converting Enzyme in Cognitive Aging: Evidence from Preclinical and Clinical Studies

Abstract

Angiotensin-Converting Enzyme (ACE, EC 3.4.15.1), also termed as kininase II or dipeptidyl carboxypeptidase I, is a crucial component of the Renin angiotensin system (RAS). ACE is extensively recognized for its role in the regulation of the cardiovascular system. Emerging evidence supports a neurobiological role of ACE, promoting investigations into its central functions responsible for the modulation of memory and cognitive function, particularly through the use of clinically approved ACE inhibitors (ACE-Is). This review comprehensively analyzes preclinical and clinical findings to date to evaluate the contribution of ACE to cognitive processes and discusses its potential as a therapeutic target for cognitive improvement. Mechanistically, ACE influences cognition through regulation of angiotensin II (Ang II) signaling, as well as modulating other neuropeptides such as substance P. These pathways intersect with processes implicated in cognitive decline, including oxidative stress, neuroinflammation, and cholinergic neurotransmission. Pre-clinical studies consistently demonstrate that ACE-Is confer neuroprotective effects by attenuating Ang II-mediated signaling, restoring redox and inflammatory balance, and improving synaptic plasticity. Clinical evidence provides partial support to these findings, although results remain heterogeneous. Variability in clinical outcomes appears to depend on factors such as patient age, baseline comorbidities, and central availability of the ACE-I. Collectively, this study highlights a non-canonical role of central ACE inhibition in modulating cognitive function, suggesting its promise as a therapeutic strategy for addressing age and disease-associated cognitive dysfunction. Future research should thus prioritize delineation of tissue-specific actions of ACE along with comprehensive examination of ACE genotype-drug interactions, and head- to-head comparison of centrally active ACE-Is with other RAS modulators for their nootropic potential.

1. Introduction

The canonical role of Angiotensin-converting enzyme (ACE) in the renin–angiotensin system (RAS) has traditionally been studied for its regulation of cardiovascular function. ACE, also called as ACE1 converts the inactive decapeptide angiotensin I (Ang I) to angiotensin II (Ang II), which is a powerful vasoconstrictor octapeptide (Fleming, 2006). Additionally, non-traditional RAS pathway, consists of ACE1 homolog, ACE2 which converts Ang I to Ang 1–9 and Ang II to Ang 1–7, which is not generally inhibited by ACE1 inhibitors (Bhilare et al., 2024). ACE1 inhibitors (Henceforth referred as ACE inhibitors, ACE-Is) lower blood pressure by prohibiting this conversion to Ang II, subsequently helping in the treatment of hypertension (Dimou et al., 2019; Cutrell et al., 2023). Angiotensin II Receptor Blockers (ARBs), beta-blockers (BB), and Calcium Channel Blockers (CCBs) along with ACE-Is are first-line treatments for hypertension (Wright et al., 2018). However, increasing evidence suggests that ACE exerts significant and multifaceted effects in the central nervous system (CNS) that extend beyond its classical homeostatic function. In particular, we and others have documented the role of ACE in modulation of pain perception (Nemoto et al., 2023; Bhilare et al., 2024; Dobariya et al., 2025). ACE also has emerged as a key modulator of cognitive processes through its enzymatic activity on a diverse set of neuroactive substrates and its influence on oxidative balance, inflammatory signaling, and synaptic function (Domeney, 1994). A nuanced appreciation of ACE’s functions in the brain requires an open-minded divergence from the RAS-centric perspective.

ACE is widely expressed in multiple brain regions implicated in memory and learning, including the hippocampus, cortex, and basal ganglia (Trieu et al., 2022). Similar to the periphery, ACE participates in the cleavage of several biologically active peptides, notably Ang I, Ang II, bradykinin, and substance P (SP) within these regions (Figure 1). While historically viewed as the principal effector peptide of ACE activity, the role of Ang II in the brain is complex and extends into modulation of neuroinflammatory pathways, neuronal excitability and cerebrovascular tone. Importantly, Ang II can influence cognitive function both directly, through AT-1/2 receptor-mediated signaling in neurons and glia, and indirectly, by promoting oxidative stress and inflammatory cascades that impair neuronal integrity (Nickenig and Harrison, 2002; Saavedra, 2012). ACE activity, particularly through the generation of Ang II, has been closely associated with increased production of reactive oxygen species (ROS) and damage to cellular biomolecules, lipids, proteins, and DNA, and ultimately impairing neuronal survival.

Figure 1.

Angiotensin converting enzyme (ACE) and its physiological substrates. The canonical dicarboxyl peptidase role of ACE is the cleavage of the decapeptide angiotensin I (Ang I) to angiotensin II (Ang II), the latter being a vasoconstrictor through action on AT1R (angiotensin I receptor). Additional peptides such as Ang 1–7 via their action on Mas receptor (MasR) and action of Ang II on AT2R (angiotensin II receptor) cause vasodilation. ACE also regulates activities of bradykinin and substance P, both known for their neuroinflammatory and vascular permeabilization action post-injury. Additionally, these substrates play a role in synaptic function and oxido-inflammatory stress. Intricate balance between the substrate activities modulated by ACE in the brain contributes toward its equally intricate role in cognition. BK1: Bradykinin receptor 1, NK1R: Neurokinin 1 receptor.

Beyond Ang II, ACE-mediated degradation of bradykinin and SP (Figure 1) introduces additional layers of regulatory control over neural function (Emanueli et al., 1998). Bradykinin, a vasoactive and neuroactive peptide, is released from kininogen by kallikreins. It is associated with inflammation and pain sensitization during tissue injury via enhanced cerebral blood flow and increased vascular permeability by activating endothelial bradykinin (BK1/BK2) receptors (Medeiros et al., 2004; Qadri and Bader, 2018). Similarly, after injury or chronic stress, SP acts as a pro-inflammatory mediator and modulator of neuronal toxicity by interacting with the neurokinin-1 receptor (NK1R), causing vasodilation and releasing inflammatory signals by immune system modulation (Martinez and Philipp, 2016; Johnson et al., 2017). By degrading bradykinin and SP, ACE limits the deleterious CNS effects of these peptides, thereby influencing cognitive performance. Despite their damaging role, bradykinin and SP display complex double-edged, context-dependent role in neuroprotection. These peptides modulate mood, stress responses and synaptic communication by altering neurotransmitter release and neuronal network activity (Noda et al., 2007; Futran-Sheinberg et al., 2025). By modulating peptide substrates that interact with neurotransmitter systems and exhibit context-dependent oxido-inflammatory effects, ACE may shift the balance either toward cognitive resilience or toward neurodegenerative state, thus requiring an intricate examination of its CNS role under physiological and disease state.

This account describes our current understanding of the role of ACE in cognition, with a particular focus on the underlying mechanistic pathways. By examining how the interactions of ACE substrates contribute to oxidative and inflammatory stress, as well as to neurotransmission and synaptic plasticity, we seek to provide a comprehensive framework for understanding ACE as a critical mediator of cognitive function. Importantly, this perspective emphasizes the effects of small molecule ACE inhibitors on cognition in preclinical animal models and clinical studies. With diverse substrates and downstream pathways collectively influencing neuronal health and cognitive performance, ACE should be viewed as a multifunctional regulator within the brain. The insights provided in this review may aid the development of more targeted therapeutic strategies leveraging ACE to preserve or enhance cognitive health.

2. Impact of ACE inhibitors on cognitive function: evidence from pre-clinical and clinical research

2.1. Literature search strategy, inclusion criteria and data extraction

2.1.1. Literature search

A literature search was conducted to identify articles published between January 1988 to April, 2026. Databases including Medline via PubMed, Google Scholar, and Embase via Ovid SP were searched using the keywords such as “angiotensin-converting enzyme in cognition,” OR “ACE inhibition in cognition,” OR “ACE as nootropic agents” OR “Effect of captopril on cognition,” OR “ACE inhibitor and dementia” using the MeSH framework. A separate literature search was performed to find studies relating ACE polymorphism and cognitive ability using key words including “ACE polymorphism,” OR “variant,” “allele,” “genotype,” “rs1799752,” or “rs4340.” This search followed similar practices to the clinical study search with the exception that studies involving patients with prior cognitive impairment were included if a normo-cognitive control group was also present. Relevant references cited within the retrieved publications were also screened to identify additional literature on this topic.

2.1.2. Inclusion criteria

The primary focus for the literature selection was the effect of ACE or ACE-Is on neurobehavioral cognitive function, memory and learning outcomes. Both preclinical animal studies and human clinical studies were included in the review. Only publications written in English were considered. For inclusion in this review, studies needed to either measure cognitive function or the incidence of dementia in subjects taking ACE inhibitors. Studies primarily focused on examining the role of ACE and ACE-Is in classical Alzheimer’s disease pathology, including amyloid-β or tau aggregation, were excluded. Studies were also excluded if the treatment group was composed of fewer than 10 individuals.

2.1.3. Data extraction

Relevant information was extracted from approximately 25 preclinical studies, 16 clinical studies and 9 studies focused on ACE polymorphism. Primarily, study design, experimental model or patient population, treatment duration and dosage, type of ACE inhibitor, cognition function assessments, and major mechanistic findings related to ACE signaling were outlined. Findings from both preclinical and clinical studies were synthesized to evaluate the potential role of ACE inhibition in cognitive modulation.

2.2. Pre-clinical studies examining the effect of ACE inhibitors on cognitive function

Because of the emerging CNS role of ACE, the inhibitors of ACE (ACE-Is) have been increasingly recognized for their beneficial effects in mood disorders and cognitive function. Extensive preclinical studies demonstrate the important cognitive function modulatory effects of ACE-Is with pronounced multifaceted neuroprotective effects through engagement of the central renin angiotensin system (RAS) and its associated downstream pathways, independent of their beneficial effects on neurodegenerative protein aggregation processes associated with dementia disorders (Domeney, 1994; Ciobica et al., 2009).

Early experiments in 1988, conducted by Usinger et al.(Usinger et al., 1988), demonstrated that subchronic administration of an ACE-I, Hoe 288 (1–10 mg/kg P.O. or I.P.), ameliorated scopolamine (muscarinic receptor antagonist) mediated amnesic effect in animals as observed in the step-through avoidance and eight-arm-radial maze tasks. These behavioral findings were further accompanied by dose-dependent alterations in acetylcholine (ACh) release in the brain regions such as striatum and hypothalamus. At an acute dose (0.3 mg/kg. i.p.), Hoe 288 reduced ACh levels, while increased ACh levels were observed after its subchronic dose (3 mg/kg, i.p.) in these brain regions. Such dose-dependent rise in ACh levels was suggested to involve increased calcium uptake by the release of ACE substrate SP. Thus, authors hypothesized that an effective dose of ACE-Is such as Hoe 288 shifts the balance towards SP release, which further enhances neuropeptide signaling and thus improving cognitive function (Usinger et al., 1988). Importantly, this dose-dependent effect of ACE-Is on SP levels essentially does not contradict the pro-inflammatory role of excessive SP described under pathological conditions, but reflects its context-specific action. The results suggest that modest increases in SP levels by ACE inhibition in some experimental context may enhance cholinergic neurotransmission and synaptic activity, without triggering the neuroinflammatory cascade. However, this hypothesis was not supported by experimental evidence. Reduced levels of Ang II as a result of ACE inhibition could also facilitate its inhibitory effect on the cholinergic neurons, further enhancing neurotransmission (Barnes et al., 1989; Barnes et al., 1990).

Additional evidence was provided by subsequent studies using ACE-Is such as captopril and SQ29,852, which confirmed their ability to counteract scopolamine-induced cognitive damage in young 11–15 weeks old rat and 6–8 weeks old mice and aged 13–17 months old rats and 8–10 months old mice. Neurotoxic effects of scopolamine were exacerbated in aged compared to young mice based on the mouse habituation test, which were in turn mitigated by treatment with both ACE-Is. Furthermore, cognitive behavioral studies using the T maze and Morris water maze tests showed improved memory and retention in both young and aged rats receiving SQ29,852 (0.005–0.5 mg/kg, i.p, b.i.d.). These effects of reduced latency in behavioral tasks were notably associated with resistance to scopolamine induced amnesia (Costall et al., 1989). Captopril further demonstrated significant nootropic effect by improving memory function and retention across multiple behavioral paradigms, including electroshock-induced amnesia and both step-down and step-through passive avoidance tests, even after a two-month retention interval following the initial learning trial (Mondadori and Etienne, 1990; DeNoble et al., 1991). A comparative study between an ACE-I and AT1 antagonist (5 & 10 mg/kg, i.p) revealed that while both improved cognition retention tasks, captopril demonstrated a superior effect on the acquisition latency in active avoidance tasks against losartan. Administration of amnesic drugs, including scopolamine (a muscarinic anticholinergic antagonist), dizocilpine (a non-competitive NMDA receptor antagonist), and L-NAME (a nitric oxide (NO) synthase inhibitor), blocked memory retrieval, reversing cognitive benefits of RAS modulators. These interactions suggest the involvement of a linked cholinergic-glutaminergic signaling pathway in ACE-I mediated cognitive effects. Scopolamine mediated reversal of captopril’s neuroprotective effects demonstrated the balance between increased ACh level and reduced Ang II levels resulting from ACE inhibition being responsible for memory retention (Raghavendra et al., 2001). Previously, Ang II was shown to prevent the release of ACh from the entorhinal cortex of animals (Barnes et al., 1989). By inhibiting Ang II synthesis, ACE-Is disrupt the negative modulation of the muscarinic cholinergic system, enhancing cognitive function. This action facilitates NMDA-mediated NO synthesis, which diffuses into the presynaptic neurons to stimulate cGMP formation via activation of guanylyl cyclase and strengthen synaptic plasticity through glutamate release. This NO-mediated retrograde signaling effect is an essential component of long-term learning and memory processes (Raghavendra et al., 2001). While this study suggests a possible mechanistic link between ACE inhibition and cognitive function, strong experimental evidence demonstrating the relationship remains to be fully established. Another study evaluated the effects of orally administered ACE-Is, such as captopril (25 mg/kg) and ramipril (4 mg/kg), and an AT1 receptor blocker, losartan (20 mg/kg), on the cognition using a similar scopolamine mouse model, and showed cognitive improvement in the Y maze test, with no significant difference in the beneficial effects of ACE-Is and the AT1 receptor antagonist (Ababei et al., 2019).

Inquiry into the effect of ACE-Is on age-related cognitive decline within hypertension settings further support the neuroprotective effect of these compounds. Compared to Wistar Kyoto rats (WKY), learning and memory in young spontaneously hypertensive rats (SHR) declined precipitously at the age of 12 months, while at 24 months, both SHR and WKY rats exhibited severe memory impairment in the water maze task. Lifetime treatment of captopril (400 mg/L) substantially reduced and delayed age-associated memory impairment in the SHR and WKY rats compared to delayed captopril treatment initiated after 6 months of age (Wyss et al., 2003).

Given the beneficial effects of ACE-Is against diabetic neuropathy, it was also of interest to study their impact on diabetes related memory impairment. In this context, a study was conducted in a streptozotocin (STZ, 33 mg/kg, intravenous)-induced diabetes model. Enalapril at 24 mg/kg/day given orally, improved hippocampus-dependent memory function and restored long-term potentiation, primarily through improved cerebral blood flow and cholinergic function (Manschot et al., 2003). Similar results were observed when the centrally acting ACE-I perindopril was administered in a similar STZ-induced cognition rat model. Elevated oxidative and nitrosative stress along with reduced cerebral blood flow and ATP levels were observed in the intracerebroventricular (i.c.v.) STZ injected rats. A dose dependent cognitive-enhancing effect of perindopril was apparent, which correlated with increased cerebral blood flow, enhanced ATP metabolism, and reduced oxidative and nitrosative stress. Perindopril treatment increased mRNA expression of ACE, yet simultaneously decreasing central ACE activity, suggesting that despite higher mRNA levels, the functional enzyme activity was suppressed. This further shows that the central RAS system, specifically ACE, plays a critical role in cognition (Tota et al., 2012b). Perindopril given orally for a week at the dose of 0.05 and 0.1 mg/kg, also showed a similar effect on scopolamine-induced memory impairment in a mouse model by increasing ACh release through reduction of acetylcholine esterase (AChE) activity and improved cerebral blood flow (Tota et al., 2012a). Chronic administration of perindopril enhanced cognitive performance of the rats in the water maze test, which was evident from a longer duration in the training zone compared to the control animals and without any sign of anxiety as measured by the elevated plus maze (Jenkins and Chai, 2007). Another comparative study in scopolamine injected rat model between piracetam, a standard nootropic drug, and ACE-Is (perindopril, enalapril and ramipril), showed comparable cognitive improvements by both classes of therapeutics as measured by the Morris water maze test. The results displayed improvement in the cholinergic function by reduction in the AChE activity and oxidative stress. In this study, perindopril showed superior memory retention compared to other ACE-Is tested including enalapril, ramipril and the nootropic agent, piracetam (Jawaid et al., 2015).

Neuroinflammatory and oxidative stress pathways represent additional mechanisms underlying ACE-I mediated cognitive protection. The effect of chronic administration of ramipril (15 mg/L) for 26 weeks in drinking water was assessed in the irradiation-induced cognitive impairment rat model using the novel object recognition test. Continuous administration of 15 mg/L ramipril before, during, and after irradiation ameliorated the fractionated whole-brain irradiation (fWBI)-induced changes in perirhinal cortex-dependent cognitive function, along with microglial activation in the dentate gyrus. Increased activated microglial cells were observed in the hippocampus after fWBI, which were reduced in the group receiving ramipril. It was postulated that the effect of ramipril may be due to reduction in Ang II levels due to latter’s known pro-inflammatory action. Additionally, increased levels of Ang (1–7) were also observed, which itself is reported for enhancing effect on the memory and learning process and for counteracting the action of Ang II in the irradiated brain, this contributing to neuroprotective activity of Ramipril (Hellner et al., 2005; Lee et al., 2012). In a similar study, direct effects of Ang II on cognitive function and its association to oxidative stress in the rat hippocampus were assessed (Bild et al., 2013). Corroborating the previous results, Ang II administration resulted in memory deficits in these animals as evident from the results of Y-maze and passive avoidance tests. These effects were ameliorated by central administration of Ang II receptor blockers, such as losartan, PD-123177, and captopril administered for 7 days. No significant differences were noted among these groups treated with RAS modulators. The oxidative stress status was further examined by measuring the levels of various oxidative stress markers in the hippocampus. Treatment of Ang II caused reduction in the levels of antioxidant enzymes, superoxide dismutase (SOD) and glutathione peroxidase (GPx), along with increased malonaldehyde (MDA) levels. Captopril, but not losartan treatment resulted in increased levels of hippocampal SOD and GPX activity, along with decrement in MDA levels, which suggest the neuroprotective role of captopril, especially, due to its antioxidant nature and ability to reduce the formation of ROS (Bild et al., 2013). In a lipopolysaccharide (LPS)-induced inflammatory rat model, administration of captopril 30 min prior to LPS (1 mg/kg, i.p), mitigated its harmful effects on learning and memory as observed in the cognition function tests, including the Morris water maze, and passive avoidance tests. LPS is known for inducing memory impairment by enhancing the levels of pro-inflammatory cytokines like, TNFα, IL-1β and IL-6 and is associated with downstream inflammatory response. It also induces hippocampal oxidative stress by reducing SOD and catalase activity and enhancing the levels of MDA and NO. Apart from antioxidant effects reported in previous studies, potential anti-inflammatory effects of captopril effectively reduced the LPS-induced memory impairment in rats (Abareshi et al., 2016).

Several pathological conditions as well as treatment interventions also act as a driving factor for cognitive dysfunction. One such example is chemotherapy-induced cognition impairment. About 75% of the cancer patients on chemotherapy suffer from memory related problems during or after treatment (Janelsins et al., 2014). The effect of ACE-Is was studied on the cognitive impairment mediated by the chemotherapeutic drug cisplatin (5 mg/kg, i.p, on 7^th and 14^th day). Cisplatin induced memory impairment by exacerbating the oxidative stress, as evident from increased MDA levels and reduced antioxidant catalase activity. Furthermore, it upregulated key neuroinflammatory markers, like TNF-α, IL-6, glial fibrillary acidic protein (GFAP), and NF-κB. Captopril given for 21 days effectively mitigated these deleterious effects at both neurobehavioral and histopathological levels. Mechanistically, captopril reduced oxidative stress by significantly decreasing MDA production and preserving catalase activity. In addition, it exerted pronounced anti-inflammatory effects by inhibiting NF-κB activation and its downstream pro-inflammatory cytokines, while also suppressing astrocytic activation through downregulation of GFAP expression (Mostafa et al., 2025). Similarly, in a rat epilepsy model induced by kainic acid administration, captopril treatment reduced seizure severity and improved cognitive outcomes by attenuating neuroinflammation and complement-mediated synaptic damage (Dong et al., 2022). Cognitive comorbidities were also observed with epilepsy if left untreated for a longer period of time. The neuroprotective potential of ACE inhibitors in such epilepsy-associated cognitive impairment was demonstrated in animals. This study by Dong et al. showed that captopril (50 mg/kg/day, i.p, started from 3^rd to 7^th week of 14 mg/kg kainic acid administration) significantly ameliorated cognitive deficits in a kainic acid-induced epilepsy model. Short term memory assessments by the Y-maze and novel object recognition tests demonstrated significant improvements in spontaneous alternation behavior and discrimination index, respectively, in captopril-treated rats. Consistent findings were observed while assessing the long-term memory effect, where captopril treatment effectively attenuated kainic acid-induced spatial learning and memory deficits in the Morris water maze test. These effects were attributed to the anti-inflammatory effects of ACE inhibition and its ability to suppress complement-mediated synaptic remodeling. Captopril treatment reduced glial cell activation and reduced the synaptic damage in the hippocampus by inhibiting C3-C3a receptor (C3aR) signaling, a key pathway involved in complement-mediated synaptic phagocytosis and neuroinflammation (Wyatt et al., 2017; Litvinchuk et al., 2018). Suppression of this pathway attenuated the release of pro-inflammatory cytokines and chemokines, thereby mitigating neuronal damage and preserving synaptic integrity (Dong et al., 2022). Supporting these findings, enalapril, when administered in combination with the anticonvulsant sodium valproate in a pentylenetetrazol induced epileptic rat model, prevented cognitive impairment associated with antiepileptic therapy. While sodium valproate alone induced measurable cognitive deficits, co-administration with enalapril significantly improved the cognitive performance in the Morris water maze test (Joshi et al., 2019). Overall, these results suggested that ACE inhibitors not only counteract epilepsy-induced cognitive damage but may also improve the cognitive side effects of anticonvulsant drugs. Collectively, these observations highlight the therapeutic potential of ACE inhibitors as adjunctive agents in epilepsy management, offering both neuroprotection and cognitive preservation through modulation of inflammatory and complement-mediated pathways.

These preclinical findings establish ACE inhibitors as multifunctional neuroprotective agents that improve cognition through integrated mechanisms involving enhancement of cholinergic transmission, modulation of glutamatergic and NO signaling, reduction of oxidative stress and inflammation, and restoration of cerebral hemodynamics (Figure 2). Importantly, these effects are mediated through central RAS modulation and extend beyond their classical cardiovascular actions, positioning ACE inhibitors as promising therapeutic candidates for cognitive impairment associated with diverse neurological and systemic conditions.

Figure 2. Summary of preclinical studies illustrating the pathological mechanisms underlying cognitive impairment and neuroprotective effects of ACE inhibitors (ACE-Is).

The left panel highlights major pathological drivers including aging, diabetes, epilepsy, amnesic agents (e.g., scopolamine, streptozotocin, kainic acid, lipopolysachharide (LPS)), collectively contributing to cognitive impairment in various animal models. Central ACE activation increases production of Ang II, which further exacerbates the effects of these insults and promoting oxidative stress, neuroinflammation, and cholinergic dysfunction, ultimately leading to neuronal damage and memory impairment. Concurrently, elevated acetylcholinesterase (AChE) activity also reduces ACh levels, contributing to cognitive deficits. The right panel summarizes the proposed neuroprotective mechanisms of ACE-Is. Inhibition of ACE reduces Ang II levels, leading to restoration of endogenous antioxidant defences (SOD, CAT, GPX, and GSH), reduction of lipid peroxidation (MDA) and inflammatory cytokines, suppression of C3a/C3aR-mediated synaptic loss, and AChE activity. Collectively, these integrated mechanisms improve cognitive function and restore the brain plasticity. Abbreviations: ROS, reactive oxygen species; C3a, Complement 3a; C3aR, Complement 3a receptor; SOD, superoxide dismutase; CAT, catalase; GPX, glutathione peroxidase; GSH, reduced glutathione; MDA, malonaldehyde; AChE, acetylcholinesterase; Ach, acetylcholine; TNF-α, Tumor necrosis factor-α; IL-6, interleukin-6; IL-1β, interleukin-1β; NF-kβ, nuclear factor kβ; NO: nitric oxide; cGMP, cyclic GMP.

2.3. Clinical studies examining the effect of ACE inhibition on cognition

2.3.1. Retrospective Clinical Studies

The availability of an arsenal of FDA-approved ACE-Is allowed clinical evaluations to assess their cognitive outcomes, which were often mixed. Retrospective studies were conducted with consideration of different populations and cohort size treated with ACE-Is and mostly offered mixed associations between ACE-I usage and cognitive function. Yasar et al. utilized the Ginkgo Evaluation Memory Study and performed a secondary longitudinal analysis over a 6.1 year period in older adults (≥ 75 years), including cognitively normal and MCI participants, to assess the association between various anti-hypertensives (i.e., diuretic, CCB, BB) and the incidence of dementia (Yasar et al., 2013). A 50% reduced risk of dementia was observed in cognitively normal participants taking ACE-Is {HR 5 0.50, 95% CI 0.29–0.83; p=0.008}, with suggestive but less certain benefits in participants with mild cognitive impairment (MCI) {HR (95% CI): 0.53 (0.26–1.08); p= 0.08}. Another longitudinal study (7–10.4 years) conducted using the Prevention of Dementia by Intensive Vascular Care (pre-DIVA) dataset of normo-cognitive individuals taking various anti-hypertensives (Schroevers et al., 2023) reported no association between those taking ACE-Is and the incidence of dementia {HR: 1.07 (95% CI: 0.81–1.43)}. While both of these studies had relatively large sample sizes of patients taking ACE-Is (n = 324 – 620), with mean age range: 74.5–78.8, and were conducted over a relatively long period of time (6.1 – 10.4 years of median follow-up), these data should be interpreted with a degree of uncertainty due to the non-significant results and wide confidence intervals. Neither of these studies separated ACE-Is by their ability to cross the blood-brain barrier (BBB), which could explain the wide variation and contribute to null results.

Retrospective studies considering the central activity of ACE-Is and their relationship with the risk of dementia were reported. One such study analyzed the data from the Cardiovascular Health Study to determine the effects of centrally acting ACE-Is (cACE-Is, including captopril, perindopril, lisinopril, fosinopril, ramipril) on the cognition of normo-cognitive individuals using a battery of cognitive measures (Sink et al., 2009). The MMSE scores indicated that individuals taking cACE-Is were associated with an average 65% slower decline compared to other antihypertensives (mean diff = −0.16 ± 0.11 compared to −0.45 ± 0.06). They also found that non-centrally acting ACE-Is (ncACE-Is) were associated with an increased risk of incident dementia {adjusted HR: 1.20 (95% CI: 1.00–1.43 per year of exposure)}, and a 16% increase in the likelihood of developing a disability in performing instrumental activities of daily living {adjusted OR: 1.16 (95% CI: 1.03–1.30 per year of exposure)}. A prospective study, Italian Longitudinal Study on Aging, was conducted to understand the influence of ACE-Is on the risk of MCI occurrence in cognitively intact hypertensive individuals over a 3.5-year follow-up period. ACE-Is as a class did not appear to be associated with reduced MCI risk (HR: 0.45, 95% CI, 0.16–1.28). However, sub-class analysis suggested that enalapril alone (HR: 0.17, 95% CI, 0.04 –0.84), or in combination with lisinopril (HR, 0.27, 95% CI, 0.08–0.96), was significantly correlated with reduction in MCI occurrence in a fully adjusted model (Solfrizzi et al., 2013). Blocking central ACE activity with ACE-Is to reduce Ang II levels and its associated inhibitory effect on ACh release, were suggested for these acute beneficial effects, similar to those reported in various pre-clinical studies. Hebert et al. conducted a similar study at a significantly larger scale (n=107,079), using Medicare beneficiary data to find an association between cACE-Is and the incidence of dementia (Hebert et al., 2013). The study found that neither new nor current cACE-I users were significantly less likely to be diagnosed with dementia when compared to ncACE-I users {HR (new, current): 0.956, 0.996}. However, the results were based on the observational data collected at three years follow-up, and thus failed to show the protective cognitive effects of the ACE-I after long-term therapeutic application. Additionally, the measure for cognitive decline was not based on an extensive cognitive battery, instead relying on Medicare beneficiaries’ claims based data to measure dementia incidence. Therefore, evidence is limited on whether central activity has an association with the rate of cognitive decline and more research is required on the topic.

2.3.2. Prospective Clinical Studies: Randomized clinical trials and observational studies

Randomized Clinical Trials:

Since the risk of cognitive impairment and dementia is associated with high blood pressure and stroke, a randomized double blinded, placebo clinical trial called the Perindopril Protection Against Recurrent Stroke Study was conducted to determine the influence of the ACE-I perindopril on cognition and dementia associated with cerebrovascular disease (Tzourio et al., 2003). The primary outcomes were Mini-Mental State Examination (MMSE) to assess cognitive function and Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) criteria for mental health. The results of the 3.9-year follow-up indicated that people on ACE-I treatment exhibited an overall risk reduction of 12% (95% CI −8 to 28, p = 0.2) for dementia and 19% (95% CI 4 to 32, p = 0.01) for cognitive decline, which was reduced further to 34% (95% CI 3 to 55, p = 0.03) and 45% (95% CI 21% to 61%, p < 0.001) for individuals with recurrent stroke. Findings of this study supported further consideration of ACE-Is for lowering the blood pressure during cerebrovascular disease to mitigate associated cognitive complications (Tzourio et al., 2003). A follow-up study on a younger cohort (25–55 years old) evaluated the effects of a six week enalapril treatment on cognition along with categorically different non-ACE-I antihypertensive drugs such as, β-blockers, (atenolol, metoprolol), alpha-2 adrenergic agonist (methyldopa), diuretics (hydrochlorothiazide), and CCB (verapamil). Enalapril and other anti-hypertensive medications showed comparable improvement in working memory tests and immediate recall memory, while being associated with reduced motor speed with worsening delayed recall by paired word learning tests (Muldoon et al., 2002). Subsequent evaluations focused on differentiating central availability of these ACE-Is. The effects of concentrations of cACE-Is, lisinopril, to that of ncACE-Is, such as enalapril, on cognition was studied in asymptomatic, hypertensive subjects (Nagy et al., 2022). Lisinopril, despite being centrally available, did not show improvement in cognition. In fact, compared to enalapril, it showed a negative correlation with perceptual motor function (Pearson’s coefficient, r: −0.5779), complex attention (r: −0.5104), and learning (r: −0.5202). While both abovementioned studies demonstrated limited associations between ACE-Is and cognition, they were both studying patients who were relatively young (mean age: 43.3 – 49.53), meaning subjects were less likely to experience cognitive decline. Both of the studies were also conducted over relatively short treatment regimens at 6 weeks and 3 months, respectively. Another limitation of these studies was that they were limited to only 1 or 2 different types of ACE-I, so more trials would be needed to evaluate newer generations of ACE-Is.

Observational Studies:

ACE-Is are most commonly compared with ARBs due to evidence supporting that both are related to improved cognition. A recent prospective observational, 45 and Up Study evaluated the difference in dementia incidence between individuals taking either ACE-Is (n = 27,896) or ARBs (n = 36,507) between 2004 and June 30, 2022. Hypertensive patients taking ARBs showed a lower risk of dementia {HR: 0.72 (95% CI: 0.65–0.80)}. Among patients taking ACE-Is, perindopril was associated with a reduced risk {HR: 0.52 (95% CI: 0.31–0.97}, and captopril was associated with a significantly higher risk of dementia {HR: 4.9 (95% CI: 1.04–23.4)} (Belachew et al., 2026). However, the adverse association between captopril and dementia risk should be considered with great caution due to a comparatively wide CI range and being generated from a low sample size. Exceptionally wide CI reflects substantial uncertainty in the effect estimate, potentially due to limited number of events, and lack of mechanistic validation. Additionally, being an observational study, other limitations related to study design, such as lack of data on medication regimen and blood pressure changes, necessitate cautious interpretation of these findings. Several other observational studies were conducted using the data from the Systolic Blood Pressure Intervention Trial (SPRINT) to compare incidences of amnestic MCI or dementia in ACE-I and ARB users (Cohen et al., 2022; Derington et al., 2025). These studies failed to demonstrate the class-specific differential effect on the incidence of dementia in normo-cognitive new users of these medications. Another prospective observational longitudinal study using data from the Tasmanian Study of Cognition and Gait as well as the Cognition and Diabetes of Older Tasmanians datasets was conducted (n = 575) to determine differential effects of ACE-Is and ARBs on brain atrophy and resulting cognitive decline measured at a 2 and 4-year follow-up. The results suggested that ARBs, but not ACE-Is, were associated with a slower rate of brain atrophy (interaction β = 2.06, p = 0.031) (Moran et al., 2019). However, no relationship was established between baseline cognitive function or cognition decline in the subjects taking either ACE-Is or ARBs. These comparative studies involving ACE-Is and ARBs were conducted on populations of similar ages (mean age: 66.8 – 69.9), with a wide range of sample sizes between groups (n = 125 – 36,507).

The discrepancy between the findings reported in these studies could be due to population heterogeneity, specifically inclusion comorbidities such as diabetes and heart failure that are negatively associated with cognitive resilience. Prospective and randomized trials generally show modest or context-dependent cognitive benefits, particularly in cerebrovascular populations, but limited effects in short-term or younger cohorts. Comparative observational studies that are subject to methodological limitations (residual confounding, short follow-up), often suggest mixed and inconsistent cognitive benefits of ACE-Is. Overall, the clinical evidence remains heterogeneous and inconclusive, highlighting the need for well-controlled studies that limit the possible influence of comorbidities on the association between ACE-Is use and cognition.

2.3.3. Correlative studies examining the association of ACE gene polymorphism with cognitive function

The central RAS system, particularly angiotensin peptides, play a crucial role in maintaining the integrity of the BBB, which is disrupted in many types of dementia. Endogenous ACE activity modulates neuronal activity in crucial brain regions involved in cognition, including the hippocampus and striatum. Thus, the impact of ACE gene polymorphism on cognitive function was studied. A widely known genetic polymorphism of the ACE gene is characterized by an insertion (I) or deletion (D) of a 287 base pair sequence at intron 16, resulting in three genotypes (I/I and D/D homozygotes and DI heterozygotes) (Sommers et al., 2024). The D allele is associated with increased levels of ACE, with the D/D genotype having the highest concentration (Rigat et al., 1990). Given the differential neurological role of ACE polymorphism, several studies were conducted to characterize the effect of the ACE I/D genotype on cognitive phenotypes and brain function. A cross-sectional study conducted by Amouyel et al. demonstrated ACE polymorphism as a contributing factor to cognitive impairment in 228 elderly individuals with MMSE scores < 10 in comparison to 255 normo-cognitive individuals (Amouyel et al., 1996). According to their findings, the D/D genotype of ACE was associated with an increased risk of cognitive impairment compared to healthy controls {OR: 1.60 (95% CI: 1.04 – 2.36, p < 0.03)}. Similar results were obtained from patients with amnesic MCI (aMCI), in which individuals carrying the D allele showed reduced neurological battery scores as indicated by poor performance in delayed recall of the auditory verbal learning test, Rey-Osterrieth Complex Figure Test (CFT), and the Trail Making Test. These patients also showed higher serum ACE levels compared to the I allele carriers, along with poor cerebral activity as demonstrated using magnetic resonance imaging (MRI). Elevated D/D-ACE, compared to I/I ACE, showed increased levels of neuro-inflammatory Ang II peptide in the endothelial cells, inducing endothelial apoptosis via the AT1 and AT2 receptors (Zhang et al., 2010). Additional well-designed studies are needed to bridge the gap between the incidence of cognitive impairment and decline reported in ACE polymorphism studies using neuropsychological batteries of cognitive tests.

Richard et al. studied the effects of ACE polymorphism on cognition progression in normo-cognitive aged individuals over the span of 4 years. Consistent with the previous results, D/D genotype was associated with cognitive impairment as evaluated by the MMSE test, compared to I/I and I/D genotypes {OR: 1.53 (95% CI: 1.04 – 2.24)}, with more susceptibility of developing cognitive impairment after the 4 year follow-up (Richard et al., 2000). These findings were further expanded by Stewart et al. by focusing on ACE polymorphism and cognitive decline in African-Caribbean individuals with age range 55–75 years and 3 years of follow-up (Stewart et al., 2004). The authors found that ACE polymorphism did not contribute to reduced cognitive test scores, but when analyzed in conjunction with aging, the D/D genotype was associated with a 3.6-fold greater chance of experiencing cognitive decline, evident by reduction in verbal memory {D/D OR for every 5 year increase in age: 3.6 (95% CI: 1.9 – 6.7)}. Similar observations were reported and reviewed by others incorporating different populations, wherein higher prevalence of the D/D allele was observed in cognitively impaired individuals (Bartrés-Faz et al., 2000; Kehoe, 2003; Ariza et al., 2006). In contrast to these findings, a retrospective analysis conducted on the Longitudinal Study of Aging Danish Twins and prospective study of aged populations from England and Wales (Frederiksen et al., 2003), showed no association between ACE genotypes and MMSE scores collected over a span of 4 years. These studies were conducted on a wide range of sample sizes (n = 148 – 684) and age range of 64–79 years. The difference in the analyzed age groups could serve as a possible explanation for the differing results, considering Stewart et al. found that cognitive decline had a significantly stronger association with aging in the presence of the D/D genotype. Additionally, larger sample size could be considered to eliminate very small effect sizes present at the ACE genetic locus in these populations (Yip et al., 2002).

The effect of ACE-Is in the context of ACE polymorphism on cognition has also been examined in several reports. Beneficial effects of ACE-Is on memory were associated with the prevalence of specific ACE polymorphism. Schuch et al. investigated the relationship between use of ACE-Is and ACE genotypes on cognition in a cross-sectional study (Schuch et al., 2014). Their findings suggest that individuals with the I/I genotype were associated with higher learning ability scores in the Rey Auditory Verbal Learning Test (RAVLT) only in the presence of ACE-Is (p = 0.015), with a notable interaction between ACE-Is and genotype (p = 0.058). Additionally, the authors reported a trend where I/I and I⁺ genotypes had improved immediate (p = 0.057) and delayed (p = 0.063) memory. Another report analyzed data from the Health, Aging and Body Composition to determine if ACE genotypes affect cognition and their interaction with ACE-Is in older adults (mean age: 73.6 years) over 8 years of follow-up (Hajjar et al., 2010). The results of this study failed to demonstrate an association between ACE-Is with ACE I/D polymorphism and/or cognitive scores. Differences in the sample size and mean age of the cohort used in these studies could have influenced the significance of observations. These data should be replicated in longitudinal studies across age ranges with robust cognitive measures to better understand the relationship between ACE-Is and ACE I/D polymorphism influencing cognition measures. A well-designed pharmacogenomic trial is needed to confirm the drug-gene relationship, which may further facilitate the development of personalized therapeutic strategies for better protection against cognition impairment. A summary of the clinical investigations described in this section is included in Table 1.

Table 1:

Clinical studies evaluating the effect of ACE-Is and ACE polymorphism on cognition.

Sr. No.	Study Design & tools to measure cognition	Demographics	Effect on Cognition	Correlation with Cognitive Measures	Reference
1	Randomized, double blinded trial used MMSE and DSM-IV criteria for cognition and dementia determination, respectively	6,105 participants (3,051 active treatment & 3,054 placebo control) from 172 collaborative institutes across 10 countries (May 1995-Nov 1997), Mean Age: 64 ± 10 years	Combinatorial treatment with ACE-I was able to reduce risk of cognition and dementia occurrence in participants with cerebrovascular disease	Relative risk reduction (treatment vs placebo): Overall participants, dementia 12% (95% CI: −8 – 28%, p = 0.2); cognition impairment 19% (95% CI: 4 – 32 %, p = 0.2), Participant with recurrent stroke: dementia 34% (95% CI: 3–55%, p = 0.03); cognition impairment 34 % (95% CI: 21–61 %, p < 0.001)	(Tzourio et al., 2003)
2	Randomized, double-blinded clinical trial using a cognitive test battery to assess cognition	United States, 88 Caucasian hypertensive men, enalapril and other hypertensive drugs (mean age: 41.0 ± 7.5 years), 32 normotensive men, control (mean age: 41.0 years)	Increase working memory was observed across all antihypertensives including ACE-I	Z-score: Digit-Symbol, backward (number of trials correct): +0.92, p = 0.001. Digit-Symbol Substitution (number of test items correct): +0.9, p = 0.02. Newspaper story immediate recall, number of facts remembered: +0.5, p = 0.009.	(Muldoon et al., 2002)
3	Randomized clinical trial using a cognitive test battery to assess cognition	Hungary, 34 hypertensive patients without dementia taking either lisinopril (16) or enalapril (18); mean age: 49.53 ± 11.14 years	Enalapril and lisinopril are not associated with improvement of cognitive performance	Learning: Enalapril: 70.28 ±10.72, p = 0.006, lisinopril: 65.13 ± 13.04, p = 0.75, Cognitive Effect: Pearson’s coefficient (p-value), perceptual motor function: −0.5779 (0.039), complex attention: −0.5104 (0.043), learning: −0.5202 (0.047)	(Nagy et al., 2022)
4	Retrospective study using incidence of dementia as a measure of cognitive decline	United States, 2,248 adults without dementia taking either ARBs (n = 140, mean age: 78.6 ± 3.3), diuretics (n = 351, mean age: 78.7 ± 3.5), ACE-Is (n = 324, mean age: 78.8 ± 3.2), CCBs (n = 333, mean age: 79.3 ± 3.8), BBs (n = 457, mean age: 78.4 ± 2.9), or controls (n = 643, mean age: 78.3 ± 3.3 years).	ACE-Is are associated with a reduced risk of dementia	Cox proportional hazards regression: ACE-I compared to placebo HR: 0.50 (95% CI 0.29–0.83)	(Yasar et al., 2013)
5	Retrospective study based on dementia prevention trial (preDIVA) along with its observational extension	Netherlands, 1,907 hypertensive adults without dementia ACE-Is; n= 620; mean age: 74.5 ± 2.5, ARBs n = 390; mean age: 74.3 ± 2.5, BBs n = 958; mean age: 74.4 ± 2.5, CCBs n = 512; mean age: 74.5 ± 2.5, diuretics, n = 974; mean 74.5 ± 2.5, CCB, n = 399; mean age: 74.4 ± 2.5,ATII stimulating AHM, n = 1180; mean age: 74.4 ± 2.5 years	No statistical difference between ACE-Is and other anti-hypertensives in dementia diagnoses over a follow up of 10.4 years	Cox proportional hazards regression: ACE-I HR compared to other anti-hypertensives: 1.07 (95% CI 0.81–1.43)	(Schroevers et al., 2023)
6	Retrospective clinical trial using 3MSE scores to assess cognitive decline	United States, 1,054 hypertensive adults without dementia taking either ACE-Is (n = 414, mean age: 74.5 ± 4.7) or other antihypertensive treatment (n = 640, mean age: 75.0 ± 5.0 years)	Patients taking cACE-Is associated with a smaller decline in 3MSE scores, and patients taking ncACE-Is associated with increased risk of incident dementia	3MSE scores per year of cACE-I compared to other hypertensives (mean diff = −0.16 ± 0.11 to −0.45 ± 0.06, p = 0.01), cACE- adjusted HR, 0.88; 95% CI, 0.70–1.09, p = 0.24per year of exposure, cACE-Is adjusted OR, 1.07; 95% CI, 0.97–1.18, p = 0.16 per year of exposure.	(Sink et al., 2009)
7	Retrospective study using incidence of dementia as a measure of cognitive decline	United States, 107,179 adults with hypertension, previously prescribed ACE-Is, and without dementia taking either ncACE-Is (35,147); mean age: 76.3 ± 6.97 or cACE-Is (72,032); mean age: 76.2 ± 7.03. 9,840 adults with hypertension taking newly prescribed ACE-Is (no prescription in the first 485 days of the study), and without dementia taking either ncACE-Is (2,611); mean age: 75.6 ± 7.02 or cACE-Is (7,229); mean age: 75.5 ± 6.98 years	No association between cACE-Is and cognitive decline	Instrumental variable analysis, new cACE-I user risk of dementia HR: 0.956, 95% CI (0.81–1.13), current cACE-I user risk of dementia HR: 0.996, 05% CI (0.96–1.04)	(Hebert et al., 2013)
8	Prospective study using incidence of dementia as a measure of cognitive decline	Australia, 36,507 adults with hypertension and without dementia taking ARBs; mean age: 65.6 ± 8.9 and 27,896 adults with hypertension and without dementia taking ACE-Is; mean age: 66.8 ± 9.2 years	ACE-I perindopril is associated with lower risk of dementia	Cox proportional hazard regression. perindopril HR compared to lisinopril: 0.52 (0.31–0.97, p = 0.014)	(Belachew et al., 2026)
9	Prospective study using incidence of dementia as a measure of cognitive decline	United States. 2,040 hypertensive adults without dementia taking either ARBs (n = 727, mean age: 67 ± 10) or ACE-Is (n = 1313, mean age: 67 ± 9 years)	No association in the rate of MCI or PD in patients taking ACE-Is or ARBss	ACE-I inverse probability weighted HR compared to ARBs: 0.93; 95% CI, 0.76–1.13,	(Cohen et al., 2022)
10	Prospective study using incidence of dementia as a measure of cognitive decline	United States, 1,999 hypertensive adults without dementia taking either ACE-Is (n = 1,289, mean age: 67.1 ± 9.4 years) or ARBs (n = 710, mean age: 67.2 ± 9.7 years)	No correlation between adherence to ACE-I or ARB on MCI or probable dementia diagnoses	ARB IP weighted RR of developing amnestic MCI or probable dementia compared to ACE-Is: 0.94 (95% CI: 0.66–1.29), Absolute risk-ratio (95% CI) at 4 year: ACE-I protocol: 0.15 (0.12–0.19), ARB protocol 0.14 (0.11–0.18)	(Derington et al., 2025)
11	Prospective study, using MRIs to measure brain atrophy, and a cognitive test battery to measure baseline cognition	Australia. 357 adults with hypertension and without dementia taking either ACE-Is (n = 163, mean age: 69.9 ± 7.5), ARBs (n = 125, mean age: 69.6 ± 7.5), or other antihypertensives (n = 69, mean age: 72.2 ± 6.6). 198 adults without dementia as a control (mean age: 68.9 ± 7.3 years).	ARB users associated with a slower rate of brain atrophy ACE-I is not associated with modulation in cognition function or decline	Mixed effect model: global (p = 0.02), executive (p = 0.04), and visospatial (ACE-I p = 0.02, ARB p = 0.004). Global cognitive Z-score (ARB vs ACE-I): 0.13 (%95 CI −0.05 to 0.31) p= 0.17,	(Moran et al., 2019)
12	Prospective study (The Italian Longitudinal Study on Aging), using MMSE scores to measure risk of cognition	Italy, 873 hypertensive individuals without dementia, Age= 72.04±4.93, 204 individual Exposed to ACE inhibitors, Age= 72.17±4.96 years	Some ACE-I are associated with the reduced risk of cognition	Fully adjusted HR (95% CI), ACE alone: 0.45 (0.16–1.28), enalapril alone: 0.17 (0.04–0.84), enalapril + lisinopril: 0.27 (0.08–0.96)	(Solfrizzi et al., 2013)
Clinical study showing the effect of ACE polymorphism on the cognition
13	Prospective study using MMSE scores as a measure to cognitive decline in relation to ACE polymorphism	France. 228 adults with MMSE scores <10 or diagnosis of dementia (mean age: 84 ± 9). 255 adults normo-cognitive adults as controls (mean age: 79 ± 8 years)	ACE DD genotype associated with cognitive impairment	Multivariate logistic regression: ACE DD genotype OR: 1.60 (95%CI: 1.04–2.36, p <0.03)	(Amouyel et al., 1996)
14	Prospective study, change in cognitive effect was assessed by neuropsychological battery scores	China. 84 individuals (mean age: 72.04 +/− 4.42)	ACE DD genotype associated with cognitive impairment in aMCI	Neuropsychological battery score like, AVLT-delayed recall in aMCI individual: DD/ID allele vs II allele: 3 (2–4) vs 4(2.5–6), respectively, p = 0.035; In control: DD/ID allele vs II allele: : 8 (7–10) vs 8 (7–8), respectively, p = 0.65	(Zhang et al., 2010)
15	Prospective study using MMSE scores as a measure to cognitive decline in relation to ACE polymorphism	France. 373 adults with D/D (mean age: 65.0 +/− 3.0), 580 adults with I/D (mean age: 65.2 +/− 3.0), and 215 adults with I/I (mean age: 64.7 +/− 3.0 years)	ACE DD genotype associated with cognitive impairment	Multivariate logistic regression: reduced MMSE score OR DD allele: 1.53 (95% CI: 1.04 – 2.24), ID allele: 1, II allele: 1.18 (0.74–1.88); % Cognitive decline DD allele: 18.9 %, ID allele: 13.2%, II allele: 16.4%	(Richard et al., 2000)
16	Prospective study using a battery of cognitive tests to measure cognitive decline in relation to ACE polymorphism	United Kingdom: 148 African-Carribean individuals (I/I mean age: 65 +/− 5.8, I/D mean age: 64 +/− 5.3, I/I mean age: 64 +/− 5.3 years)	No association between ACE genotype and cognition, but there was a greater association between cognitive decline and age in the presence of the DD genotype	Multivariate logistic regression: OR for cognitive decline for every 5 year increase in age, DD allele: 3.6 (95% CI: 1.9–6.7); ID/II genotype (odds ratio 0.7, 95% CI 0.4–1.2)	(Stewart et al., 2004)
17	Retrospective study using MMSE scores as a measure of cognitive decline in relation to ACE polymorphism	Denmark. 684 individuals. 101 females with I/I (mean age: 78.5 +/− 4.6), 231 females with D/I (mean age: 78.5 +/− 4.6), 118 females with D/D (mean age: 77.0 +/− 4.6), 68 males with I/I (mean age: 76.8 +/− 3.3), 113 males with D/I (mean age: 78.4 +/− 4.3), 53 males with D/D (mean age: 77.9 +/− 3.9 years)	No association between ACE genotype and MMSE scores was observed	Logistic regression. No difference between median MMSE scores: Female ACE genotype II, = 26 (95% CI 23–28); DI = 27 (95% CI 24 – 28);, DD = 27 (95% CI 25 – 29);; Male ACE genotype II = 27 (95% CI 23 – 29);; ID = 27 (95% CI 24 – 29);; DD = 27 (95% CI 25 – 28)	(Frederiksen et al., 2003)
18	Prospective study using the Wechsler Memory Scale-Revised as a measure of cognitive decline in relation to ACE polymorphism	Brazil. 205 normocognitive individuals (mean age: 64.0 +/− 8.08 years)	Trend between ACE genotype and ACE-I usage on immediate and delayed verbal memory. Beneficial influence of I/I genotype was associated with higher learning ability scores only in the presence of ACE-Is	ANCOVA. Interaction between ACE-Is and II genotype on learning ability scores (p = 0.015), post-hoc immediate verbal memory p = 0.057, delayed verbal memory p = 0.063	(Schuch et al., 2014)
19	Retrospective study using a battery of cognitive tests to measure cognitive decline in relation to ACE polymorphism	United States. 3,075 individuals (mean age: 73.6 +/− 0.1), of which 465 were taking ACE-Is	No association between ACE I/D and cognition test scores, and no significant interaction between ACE-I usage, cognition test scores, and ACE I/D	Mixed models: interaction p-value: 0.519	(Hajjar et al., 2010)

HR = hazard ratio, OR = odd ratio, RR = risk ratio, ACE-I = angiotensin converting enzyme inhibitor, cACE-I = centrally acting ACE inhibitor, ncACE-I = non-centrally acting ACE inhibitor, IADL = instrumental activity of daily living, ARB = angiotensin II receptor blockers, AD = Alzheimer’s Disease, BBs = beta-blockers, CCBs = calcium channel blockers, 3MSE = Modified Mini Mental State Exam, MMSE = Mini Mental State Exam, AHM = antihypertensive medication, MRI = magnetic resonance imaging, II = ACE insertion homozygote, DD = ACE deletion homozygote, AVLT = auditory verbal learning test, MCI = mild cognitive impairment

3. Conclusions and Future Direction

Preclinical studies consistently demonstrate that ACE inhibitors exert substantial neuroprotective and cognition-enhancing effects through their pleotropic mechanisms that modulate the central ACE system. By reducing Ang II formation responsible for subsequent AT1 receptor activation, ACE inhibitors counteract the deleterious effects of this peptide on neurotransmitter release in key brain regions such as the hippocampus and entorhinal cortex, which are associated with cognition. An effect of this modulation is observed in the improvement of learning and memory performance measured by using multiple behavioral paradigms, specifically in aged, hypertensive, and cognitively impaired animal models. Moreover, benefits of ACE inhibition on cognitive behavior are supported by well-defined biochemical correlates, including attenuation of neuroinflammation and oxidative stress as well as restoration of redox homeostasis through enhanced endogenous antioxidant defenses. Additionally, ACE inhibition has also shown to improve cholinergic neurotransmission via AChE inhibition and increased ACh levels, NO mediated signaling, and cerebral blood flow, thereby supporting synaptic plasticity and neurovascular remodeling. The ability of certain centrally acting ACE-Is to cross the BBB further potentiates these effects, which highlight the significance of target engagement within the brain. Collectively, these preclinical findings provide compelling evidence that ACE inhibitors hold promise as therapeutic agents for cognitive disorders.

That being said, these findings did not perfectly translate into clinically sound observations. Mixed results from clinical trials call into question the potential efficacy of ACE inhibitors on cognitive decline in humans. ACE inhibitors were more likely to be associated with improving cognitive decline in older cohorts and were more likely to have weaker associations than ARBs. In some of these studies, ACE-I users were significantly more likely to discontinue treatment than ARB initiators. Studies with larger sample sizes and longer follow-up times are needed to more precisely estimate the effects of initiating and continuously adhering to ARB- versus ACE-I based antihypertensive medication regimens (Derington et al., 2025). Another potential explanation for this discrepancy could be the additional role of ACE in converting the neurotoxic amyloid β_1–42 to the less neurotoxic amyloid β_1–40 (Zou et al., 2007). This mechanism implies that the inhibition of ACE could contribute to cognitive decline and the development of neurodegenerative diseases such as Alzheimer’s Disease through the accumulation of amyloid plaques as described in reviews elsewhere (Rygiel, 2016; Quitterer and AbdAlla, 2020; Salvo et al., 2026).

Contrasting this, there is more clarity on the association between ACE inhibitors and cognitive decline in patients diagnosed with Alzheimer’s Disease or other forms of dementia. There is a trend among clinical trials that centrally active ACE inhibitors have a stronger association with improving cognition in AD patients (Ohrui et al., 2004; Gao et al., 2013; O’Caoimh et al., 2014; Fazal et al., 2017). Although a select number of studies have seen an association in the class regardless of central activity (Soto et al., 2013). Multiple studies have found that the beneficial effect has the strongest association within the first 6–8 months of either AD diagnosis or centrally active ACE inhibitor treatment (Gao et al., 2013; Fazal et al., 2017). The mechanism for this effect is largely unknown. Leading theories indicate that the stimulation of ACh levels could be responsible for the time-limited therapeutic effect (Fazal et al., 2017).

Additional research needs to be conducted to better understand the relationship between ACE inhibitors, cognitive decline, and ACE polymorphism in individuals without dementia. There is a specific need for well-powered randomized controlled trials targeting older cohorts stratified by ACE genotype that could provide information necessary to understanding the discrepancies between the association of ACE-Is in normo-cognitive compared to cognitively impaired individuals. Head-to-head studies comparing centrally active ACE-Is with alternative RAS-modulators, such as Mas receptor (MasR) agonists or AT2R activators, could help delineate whether observed cognitive benefits are driven primarily by suppression of Ang II/AT1R signaling or by activation of another protective counter-regulatory RAS pathway. There is also a need to further research the effects of ACE polymorphism on cognition, specifically research into how ACE-Is could function as a mediator between them. Prospective pharmacogenomic trials stratified by ACE (I/D) genotype could clarify the current heterogenous landscape of ACE-I clinical studies. In addition, biomarker-enriched cohort studies, specifically in vascular cognitive impairment and dementia (VCID) population, may help identify individuals most likely to benefit from central RAS modulation and would provide insights into whether ACE-targeting interventions truly alter cognitive performance rather than merely providing symptomatic benefits.