Health Evaluation in African Americans Using RAS Therapy (HEART)

The purpose of this study is to determine if telmisartan, an FDA approved blood pressure medication, may also have beneficial effects on Alzheimer's disease prevention in African Americans, who are at high risk for Alzheimer's disease.

This study will assess if telmisartan, an FDA approved blood pressure medication, may also have beneficial effects on Alzheimer's disease (AD) prevention in African Americans, who are at high risk for Alzheimer's disease. Blood pressure medications known as angiotensin-receptor blockers have been associated with reduced risk of Alzheimer's in Caucasians because they act on the renin-angiotensin system (RAS), a key regulator of blood pressure in the body and the brain. The drugs appear to slow the progression of the disease by affecting flow of blood and the amount of plaque in the brain, but these benefits have not been tested in African Americans. The investigator will evaluate if telmisartan is able to influence the renin-angiotensin system in the brain and produce favorable effects on brain blood flow and enzymes that cause the brain plaques in Alzheimer's disease.The investigator will assess the mechanism by which telmisartan modifies the brain renin angiotensin system, cerebrospinal fluid amyloid-β, cerebral blood flow (CBF) and inflammatory markers in hypertensive African Americans.

African American participants with and without hypertension and at high risk for Alzheimer's disease randomly assigned to receive telmisartan 20mg once a day orally.

African American participants with and without hypertension and at high risk for Alzheimer's disease randomly assigned to receive telmisartan 40mg once a day orally.

African American participants with and without hypertension and at high risk for Alzheimer's disease randomly assigned to receive a placebo to match telmisartan once a day orally.

Participants will be given 20 mg of telmisartan to be taken orally once a day before bedtime, for a duration of 8 months.

Participants will be given 40 mg of telmisartan to be taken orally once a day before bedtime, for a duration of 8 months.

Participants will be given placebo to be taken orally once a day before bedtime, for a duration of 8 months.

The cerebrospinal fluid renin-angiotensin system (RAS) will be assessed by measuring levels of angiotensin metabolites sample 1ml of cerebrospinal fluid (CSF). ACE 1 helps to regulate blood pressure by converting angiotensin I to angiotensin II. Normal values for ACE are below 40 micrograms/L.

The cerebrospinal fluid renin-angiotensin system (RAS) will be assessed by measuring levels of angiotensin metabolites sample 1ml of cerebrospinal fluid (CSF). ACE 2 regulates levels of circulating angiotensin II. ACE 2 increases during illness and with Alzheimer's disease.

Levels of amyloid β40 (Aβ40) in the cerebrospinal fluid will be measured using LUMIPULSE® technology. The relationship between Aβ40 is non-linear with moderate levels showing the highest risk of future cognitive decline in some studies.

Levels of amyloid β42 (Aβ42) in the cerebrospinal fluid will be measured using LUMIPULSE® technology. Decrease in concentrations of amyloid β42 are indicative of a decrease in cognitive function.

Levels of T-tau in the cerebrospinal fluid will be measured using LUMIPULSE® technology. Increase in concentrations of T-tau are indicative of a decrease in cognitive function.

Levels of P-tau in the cerebrospinal fluid will be measured using LUMIPULSE® technology. Increase in concentrations of P-tau are indicative of a decrease in cognitive function.

Echoplanar T1 mapping scans will be used for image registration and a scout image of the head will be obtained in order to choose the appropriate location for spin labeling and flow imaging. Arterial Spin Labeling images will be acquired using a custom 3D stack of interleaved spirals fast spin echo sequences and will be averaged in order to improve the signal-to-noise ratio. Images will be interpolated and smoothed in a panel by using a 0.5-pixel, full-width, half-maximum Gaussian kernel. Regional perfusion will be quantified in each hemisphere and maps of cerebral vasoreactivity will be obtained by co-registration of perfusion and anatomical images.

High-resolution anatomical images will be acquired using a 3D-Fast Spoiled Gradient Recalled Echo (FSPGR) Sequence. White Matter Hyperintensities (WMH) will be identified by a 3D T2 Fluid Attenuated Inversion Recovery (FLAIR) Fast Spin Echo sequence. The images will be co-registered using a within-subject inter-modal alignment between structural and perfusion images. T1-weighted Spoiled Gradient Recalled (SPGR) images will be used to identify cerebrospinal fluid and white and gray matter. Increased volumes of white matter hyperintensities indicate impaired cognitive function.

Soluble Platelet-Derived Growth Factor Receptor Beta (sPDGFRβ) is a marker of breakdown in the blood brain barrier. Increased levels of sPDGFRβ indicate cognitive dysfunction.

Inclusion Criteria: Mean resting systolic blood pressure ≥ 110 mmHg and ≤ 170 mmHg Family history of Alzheimer's disease African American Exclusion Criteria: Currently in another investigational drug study Potassium >5.0 meq/dL at baseline Creatinine >1.99 mg/dL at baseline History of stroke or transient ischemic attack (TIA) Dementia Current use of a RAS acting medication Contraindication for lumbar puncture or magnetic resonance imaging Heart failure Diabetes Types I and II Pregnant or nursing women

Wharton W, Goldstein FC, Tansey MG, Brown AL, Tharwani SD, Verble DD, Cintron A, Kehoe PG. Rationale and Design of the Mechanistic Potential of Antihypertensives in Preclinical Alzheimer's (HEART) Trial. J Alzheimers Dis. 2018;61(2):815-824. doi: 10.3233/JAD-161198.