Therapeutic Implications of Renin–Angiotensin System Modulators in Alzheimer’s Dementia

Abstract

The Renin–Angiotensin System (RAS) has attracted considerable interest beyond its traditional cardiovascular role due to emerging data indicating its potential involvement in neurodegenerative diseases, including Alzheimer’s dementia (AD). This review investigates the therapeutic implications of RAS modulators, specifically focusing on angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), and renin inhibitors in AD. ACEIs, commonly used for hypertension, show promise in AD by reducing angiotensin (Ang) II levels. This reduction is significant as Ang II contributes to neuroinflammation, oxidative stress, and β-amyloid (Aβ) accumulation, all implicated in AD pathogenesis. ARBs, known for vasodilation, exhibit neuroprotection by blocking Ang II receptors, improving cerebral blood flow and cognitive decline in AD models. Renin inhibitors offer a novel approach by targeting the initial RAS step, displaying anti-inflammatory and antioxidant effects that mitigate AD degeneration. Preclinical studies demonstrate RAS regulation’s favorable impact on neuroinflammation, neuronal damage, cognitive function, and Aβ metabolism. Clinical trials on RAS modulators in AD are limited, but with promising results, ARBs being more effective that ACEIs in reducing cognitive decline. The varied roles of ACEIs, ARBs, and renin inhibitors in RAS modulation present a promising avenue for AD therapeutic intervention, requiring further research to potentially transform AD treatment strategies.

Exposure to angiotensin-converting enzyme inhibitors that cross the blood-brain barrier and the risk of dementia among patients with human immunodeficiency virus

“…The advantages of our study are that it was performed in a defined patient population with an easily identifiable diagnosis in EHRs (PLWH) and for whom the elevated risk of HAND and dementia is known. In the biomedical literature, there are growing connections between the RAAS system and neurocognitive disorders, chiefly in models of Alzheimers [33][34][35][36] , but to our knowledge this is the first report of a connection to dementia in PWLH. Future studies are planned to explore the mechanistic underpinnings of these observations in vitro and in vivo, as well as further analysis of EHRs to better understand the depth of the effect regarding timing and duration of BBB ACE exposure.…”

Classical and nonclassical effects of angiotensin-converting enzyme: How increased ACE enhances myeloid immune function

“…While there is universal agreement that brain β-amyloid (Aβ) accumulation is associated with and promotes AD, the precise sequence of events leading to disease is still not understood. What is acknowledged is that hypertension contributes to both vascular dementia and AD ( 38 , 39 ). In particular, a number of studies have focused on the potential utility of ACEi and ARBs in slowing the onset of dementia.…”

“…The net effect is increased nerve cell projections and postulated facilitation of axonal regeneration. There is also reduced oxidative stress, increased nitric oxide, and reduced amyloid deposits ( 38 , 39 ).…”

“…The effects of ACEi are more complex in that these agents have the positive effects of reducing neuro-vasoconstriction and blood pressure, but they also block the catalytic effects of ACE which can degrade neurotoxic Aβ 1–42 into the less toxic Aβ 1–40 ( 41 , 42 ). Further, ACEi reduce the formation of Ang 1 to 7 and the hexapeptide Ang IV which promote neurologic health ( 38 , 39 ). The dichotomy between the predominantly advantageous effects of ARBs and the mixed effects of ACEi is reflected in several clinical studies comparing the neuroprotective effects of ACEi versus ARBs; most such studies have found a distinct advantage of ARBs over ACEi ( 38 , 39 ).…”

Integrated approach to reducing polypharmacy in older people: exploring the role of oxidative stress and antioxidant potential therapy

“…In this regard, the most common comorbidities in people with dementia include DM2, CVD and hypertension. For example, hypertension as a risk factor for the development of AD is directly linked to the role of angiotensin II, which through its G protein-coupled receptor AT1 pathway, induces a variety of deleterious effects at the brain level, including the induction of proinflammatory pathways, ROS synthesis and apoptosis [ 120 , 121 ]. Against this background, treatment with different RAAS modulators has been shown in in vitro and in vivo models to have a beneficial role in the prevention and treatment of cognitive impairment, with ARBs and ACE inhibitors having the strongest evidence.…”