Rationale and Design of the Mechanistic Potential of Antihypertensives in Preclinical Alzheimer’s (HEART) Trial

Abstract

Research indicates that certain antihypertensive medications alter Alzheimer's disease (AD) biomarkers in Caucasians. The renin angiotensin system (RAS) regulates blood pressure (BP) in the body and the brain and may directly influence AD biomarkers, including amyloid-β (Aβ) neuropathology, cerebral blood flow (CBF), and inflammatory markers. This hypothesis is supported by studies, including ours, showing that antihypertensives targeting the RAS reduce the risk and slow the progression of AD in Caucasians. While mounting evidence supports a protective role of RAS medications in Caucasians, this mechanism has not been explored in African Americans. To assess the mechanism by which RAS medications modify the brain RAS, cerebrospinal fluid (CSF) Aβ, CBF, and inflammatory markers in African Americans, we are conducting an eight month, Phase Ib randomized, placebo controlled trial, enrolling 60 middle-aged (45-70 years), non-demented individuals, at risk for AD by virtue of a parental history. Participants include normotensive and treated hypertensives that have never been exposed to a RAS medication. Participants are randomized (1 : 1:1) by gender and BP medication use (yes/no) to one of three groups: placebo, or 20 mg, or 40 mg telmisartan (Micardis), to determine the dose required to penetrate the CNS. Our overarching hypothesis is that, compared to placebo, both doses of telmisartan will penetrate the CNS and produce salutary, dose dependent effects on the brain RAS as well as CSF Aβ, CBF, and CSF inflammatory markers in African Americans, over eight months. This manuscript describes the trial rationale and design.

The association of multiple anti-hypertensive medication classes with Alzheimer’s disease incidence across sex, race, and ethnicity

“…We analyzed the association between use of RAS-acting AHTs and AD onset across sex and race/ethnicity, and allowed for the possible separate biological roles of ACEIs and ARBs as has been suggested for AD [ 18 , 40 , 41 ]. While there is some evidence of risk reduction from RAS-acting AHTs, most of that association is driven by ARBs rather than ACEI use.…”

“…Multiple components of the RAS are associated with changes to amyloid-beta (Aβ) and tau levels in both pre-clinical models as well as human post-mortem studies [ 18 , 24 , 44 – 46 ]. Furthermore, RAS-acting AHTs have been reported to reduce the incidence of AD and slow the progression from MCI to AD in African Americans and Caucasians, leading to new studies whereby RAS-acting drugs are being tested as interventions for AD [ 12 , 18 , 19 , 40 , 41 , 47 ].…”

The Coming of Age of the Angiotensin Hypothesis in Alzheimer’s Disease: Progress Toward Disease Prevention and Treatment?

“…A similar design and sized (SARTAN-AD) Phase II trial in hypertensive AD patients will compare perindopril with telmisartan (Study NCT02085265 at https://clinicaltrials.gov/ct2/show/NCT02085265 ). The smaller pilot Phase I ( n = 66) HEART study (Study NCT02471833 at https://clinicaltrials.gov/ct2/show/NCT02471833 ) will compared two doses of telmisartan against placebo for effects on CSF levels of RAS components in African Americans at increased risk of AD [ 236 ]. A similarly sized ( n = 72) CEDAR study (Study NCT02646982 at https://clinicaltrials.gov/ct2/show/NCT02646982 ) will compare the effect of candesartan and placebo on a number of cardiovascular outcome measures in people with MCI, while the CALIBREX study (Study NCT01984164 at https://clinicaltrials.gov/ct2/show/NCT01984164 ) will compare lisinopril with candesartan for effects on the primary outcome of executive function in people with hypertension and MCI.…”

Antihypertensive agents in Alzheimer’s disease: beyond vascular protection

“…We did not find published clinical studies on ARBs in AD, underlining the gap between a wealth of encouraging preclinical data and the paucity of clinical trials in AD. Few clinical trials are ongoing [67,68], using mostly telmisartan and losartan, with an estimated study completion in 2021.…”