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.

KEYWORDS:

• Alzheimer’s disease
• pathology
• vascular risk factors
• hypertension
• antihypertensive agents
• prevention
• neuroprotection
• treatment

Article highlights

• Observational studies showed that the use of antihypertensive therapy is associated with a lesser incidence or prevalence of cognitive impairment and dementia, whereas randomized trials and data on established AD are issuable.

• Action on the concurrent vascular pathology is probably the main cause of cognitive decline reduction by antihypertensive drugs.

• Action on the vascular component of Alzheimer’s pathophysiology is the most appealing of the possible modes of action of antihypertensive drugs; several ARBs and CCBs demonstrated positive effects on vascular amyloid clearance and alterations of vascular function in AD models.

• Action on nonvascular targets could explain anti-AD properties of selective antihypertensive drugs, such as CCBs with high brain penetration or some ARBs with PPARγ agonist properties. Off-targets may be detrimental as well, as was shown with ACE and neprilysin inhibitors – even though their theoretical pro-amyloidogenic properties do not seem to be clinically meaningful.

• From this review of literature, ARBs (telmisartan in particular) and CCBs (nilvadipine in particular) may offer the most benefit by interfering in amyloid formation, breakdown and clearance, and also improving endothelial function.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer Disclosures

Peer reviewers on this manuscript have no relevant financial relationships or otherwise to disclose.

Additional information

Funding

This paper was not funded.