Antihypertensive agents in Alzheimer’s disease: beyond vascular protection

Abstract

Introduction: Midlife hypertension has been consistently linked with increased risk of cognitive decline and Alzheimer's disease (AD). Observational studies and randomized trials show that the use of antihypertensive therapy is associated with a lesser incidence or prevalence of cognitive impairment and dementia. However, whether antihypertensive agents specifically target the pathological process of AD remains elusive. Areas covered: This review of literature provides an update on the clinical and preclinical arguments supporting anti-AD properties of antihypertensive drugs. The authors focused on validated all classes of antihypertensive treatments such as angiotensin-converting enzyme inhibitors (ACEi), angiotensin receptor blockers (ARB), calcium channel blockers (CCB), β-blockers, diuretics, neprilysin inhibitors, and other agents. Three main mechanisms can be advocated: action on the concurrent vascular pathology, action on the vascular component of Alzheimer's pathophysiology, and action on nonvascular targets. Expert opinion: In 2019, while there is no doubt that hypertension should be treated in primary prevention of vascular disease and in secondary prevention of stroke and mixed dementia, the place of antihypertensive agents in the secondary prevention of 'pure' AD remains an outstanding question. ARTICLE HISTORY

Brain Renin–Angiotensin System at the Intersect of Physical and Cognitive Frailty

“…Finally, an observational study showed that ACEIs increase the risk of mortality in AD patients (Kehoe et al, 2013). However, this finding was not replicated in other cohorts (Lebouvier et al, 2020).…”

“…DRIs directly inhibit generation of Ang I from angiotensinogen, acting upstream of both ARBs and ACEIs (Riccioni, 2013). RAS inhibitors can reduce Aβ deposition and its consequences, and also suppress inflammation, oxidative stress, vascular damage/ischemia, and increase acetylcholine release and glutamate uptake (Gebre et al, 2018;Lebouvier et al, 2020). Especially, ARBs can prevent impairment of the BBB and reduce infiltration of inflammatory mediators observed in many neurodegenerative disease such as AD (Gebre et al, 2018).…”

“…Some ARBs especially telmisartan were found to be partial agonists of peroxisome proliferator-activated receptor-γ (PPAR-γ) which is a target in AD with its anti-inflammatory, anti-amyloidogenic and insulin-sensitizing effects. In this regard, it was hypothesized that beneficial effects of telmisartan are attributed not only to its AT 1 R antagonist properties but also to the activation of PPAR-γ ( Heneka et al, 2007 ; Torika et al, 2016 ; Lebouvier et al, 2020 ). In line with this, it was shown that diabetes-induced increases in BBB permeability was attenuated by telmisartan through PPAR-γ activation to improve diabetes-induced cognitive decline ( Min et al, 2012 ).…”

Neprilysin expression and functions in development, ageing and disease

“…Currently a novel angiotensin receptor/neprilysin inhibitor (ARNI) sacubitril/valsartan has been approved for treatment of hypertension and prevention of heart failure in elderly hypertensive patients (for review see Kario, 2018 ). While there is no doubt that hypertension should be treated for prevention of cardiovascular diseases as well as of stroke and vascular dementia, the role of NEP inhibitors as antihypertensive agents in AD pathogenesis remains unclear and needs further investigation ( Lebouvier et al, 2020 ).…”

Genetically Determined Blood Pressure, Antihypertensive Medications, and Risk of Alzheimer’s Disease: A Mendelian Randomization Study

“…One RCT found bene cial cerebrovascular effects of calcium antagonists on AD [31].However, one recent MR analysis have showed that lowering SBP via AHMs is unlikely to affect the risk of developing AD, and if speci c AHM classes do reduce the risk of AD, the mechanism may not be via SBP pathway [10]. Actually, studies have pointed out that some drugs, such as those acting through angiotensin receptor and calcium channel blocking mechanisms, have protective effects on AD, independently of BP lowering [32]. For example, the intracellular buildup of calcium in neurons can be neurotoxic and thus CCB might result in neuroprotection [33].…”