Clinical trial NCT02471833
Conditions: Alzheimer's Disease
Keywords: hypertension prevention family history inflammation blood brain barrier amyloid
Sponsor: Emory University
Start date: 2015-04-01; Completion date: 2022-04-15
Enrollment: 61 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
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.

Detailed description:
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.

Arms: arm 1: African American participants with untreated or treated hypertension and at high risk for Alzheimer's disease who are randomly assigned to receive telmisartan 20mg once a day orally. arm 2: African American participants with untreated or treated hypertension and at high risk for Alzheimer's disease who are randomly assigned to receive telmisartan 40mg once a day orally. arm 3: African American participants with untreated or treated hypertension and at high risk for Alzheimer's disease who are randomly assigned to receive a placebo to match telmisartan once a day orally.
Interventions: intervention 1: Telmisartan 20mg intervention 2: Telmisartan 40mg intervention 3: Placebo
Intervention descriptions: intervention 1: Participants will be given 20 mg of telmisartan to be taken orally once a day before bedtime, for a duration of 8 months. intervention 2: Participants will be given 40 mg of telmisartan to be taken orally once a day before bedtime, for a duration of 8 months. intervention 3: Participants will be given placebo to be taken orally once a day before bedtime, for a duration of 8 months.

Protocol documents:
Prot_SAP_001.pdf: 
Study Protocol 
 
Title: Health EvaluaƟon in African Americans using RAS Therapy: The 
HEART Project 
 
NCT Number: NCT02471833 
 
Protocol date: January 10, 2022 


1
Title: Health Evaluation in African Americans using RAS 
Therapy:
The HEART Project
Principal Investigator:
Whitney Wharton, PhD, Emory University 
Collaborators:
Felicia Goldstein, PhD
Allan Levey, MD, PhD
Arshed Quyyumi, MD, FRCP, FACC
John Hanfelt, PhD
William Hu, MD, PhD
Funding Sponsor
Alzheimer’s Association
Version 12, January 10, 2022
Contact information:
Whitney Wharton, PhD
Associate Professor
Emory University
School of Nursing, Academic Advancement; 
School of Medicine, Department of Neurology
Atlanta, GA


2
Study Objectives:
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 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 progression of AD in Caucasians. We have 
shown that 1) blood brain barrier (BBB) crossing RAS medications exert protective cognitive and 
cerebrovascular effects in hypertensive individuals with executive dysfunction and 2) BBB crossing RAS 
medications are able to significantly alter brain RAS levels in Caucasians ‘at risk’ for AD due to a parental 
history. 
While mounting evidence supports a protective role of RAS medications in Caucasians, this mechanism 
has not been explored in African Americans. The rate of AD in African Americans is twice that of Caucasians. 
Moreover, African Americans are at higher risk hypertension, which likely independently contributes to AD, 
possibly via RAS regulation. African Americans have low circulating renin and increased aldosterone and 
sodium levels and are typically not prescribed RAS antihypertensives, which are those medications believed to 
exert AD-related benefits in Caucasians. If RAS medications are prescribed, high doses are required to 
achieve BP control, though the dose needed to alter RAS levels in the brain is unknown. Because we know 
that the brain RAS is implicated in AD neuropathology in Caucasians, research should investigate whether 
RAS medications same also confer AD-related benefits in African Americans. As a first step, we analyzed data 
from the NIH National Alzheimer’s Coordinating Center database in 784 participants with Mild Cognitive 
Impairment at baseline. We found that African Americans taking RAS acting medications are less likely to 
convert to AD and exhibit slower cognitive decline than African Americans taking non RAS acting 
antihypertensives over 3 years. Because these data were retrospective, we were unable to determine whether 
the brain RAS was the mechanism responsible for these AD related benefits, and thus is the focus of our 
proposed trial. Importantly, because both Aβ accumulation and RAS dysfunction begin during midlife, it is 
imperative to investigate these issues in middle-aged, presymptomatic adults, while there is time to stage an 
intervention, before the irreversible AD cascade begins. Further, exploring the potential benefit of existing 
drugs that are generally recognized as safe (i.e. “repurposing”) such as RAS medications, shortens the time to 
provide urgently needed treatment options for this devastating illness.  
To assess the mechanism by which RAS medications modify the brain RAS, CSF Aβ, cerebral blood 
flow (CBF) and inflammatory markers in hypertensive African Americans, we propose a Phase Ib double blind, 
randomized, placebo controlled trial, enrolling 66 middle-aged (30yrs and over), non-demented individuals, at 
risk for AD by virtue of a family history. Participants will include untreated and treated hypertensives that have 
never been exposed to a RAS medication. Participants will be randomized by gender and antihypertensive use 
(y/n) to one of three groups: placebo, or 20mg, or 40mg telmisartan, 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. 
Aim 1: Establish the dose of telmisartan necessary to penetrate the CNS and to significantly alter components 
of the brain RAS in 66 African Americans with a family history of AD. 
HYPOTHESIS: We hypothesize that, compared to placebo, both doses of telmisartan will penetrate the CNS 
and that we will observe a dose effect of telmisartan’s ability to significantly alter brain RAS function.
Aim 2: Determine whether telmisartan significantly alters CSF Aβ, CBF and CSF inflammatory markers. 


3
HYPOTHESIS: We hypothesize that, compared to placebo, both doses of telmisartan will produce slower 
decline in CSF Aβ levels, CBF and lower inflammation, and that we will observe a dose dependent effect of 
20mg vs 40mg telmisartan, over eight months.
2. BACKGROUND AND SIGNIFICANCE
2. 1. Physiological Changes in Preclinical AD and the Importance of Prevention: Use of certain 
antihypertensive medications during midlife is associated with cognitive decline and Alzheimer’s disease (AD). 
Specifically, blood Pressure (BP) medications acting via the renin angiotensin system (RAS) have been 
implicated in Aβ neuropathology, cerebrovascular regulation, and inflammation – all of which have been 
identified as early change mechanisms in AD. Therapies that preserve or improve brain RAS function may 
reduce early AD related neuropathology may interrupt this cascade to delay the development of AD pathology.
2. 2. Brain RAS dysfunction increases the risk of Alzheimer’s disease: Angiotensin converting enzyme 
(ACE) is a central component of the RAS system and has been directly implicated an Aβ neuropathology in 
Caucasians. The role of ACE is to convert angiotensin I (Ang I) to angiotensin II (Ang II), which is a potent 
vasoconstrictor. Caucasians with MCI and early AD exhibit elevated ACE activity in cerebrospinal fluid (CSF) 
and hypoperfusion in the parietal cortex, a region expressing Ang I and Ang II receptors and therefore a 
potential site for increased vasoconstriction in early AD. Studies involving postmortem tissue suggest that the 
RAS itself seems to be significantly altered in AD, such that the tissue exhibits elevated ACE activity, which 
correlates with AD severity and parenchymal Aβ load (See Preliminary Data )[1]. Moreover, increased ACE 
activity reportedly mediates decreases in acetylcholine release via increased Ang II production, which may also 
contribute to AD-related cognitive decline. Thus, medications designed to target ACE activity in the brain, and 
subsequent reduction of Ang II, could potentially serve as an alternative AD treatment via direct actions on Aβ 
pathology CBF and inflammation. This hypothesis is supported by studies, including ours (Preliminary Data), 
reporting that treatment with centrally acting RAS medications (ACE inhibitors (ACE-I) and angiotensin II 
receptor blockers (ARBs)) have the ability to reduce ACE activity in CSF and may reduce the likelihood or slow 
the progression of AD in Caucasians. 
2. 3. Racial Discrepancies in RAS function: Research documenting blood pressure (BP) and systemic RAS 
differences between African Americans and Caucasians has existed for decades. African Americans have low 
circulating renin levels and increased aldosterone and sodium levels, which has led some to believe that, in 
African Americans, the RAS is not the primary system involved in systemic vascular regulation. While the 
importance of systemic RAS function in African Americans is still under investigation, no studies have been 
conducted to investigate the potential importance of the brain RAS in African Americans. Because we know 
that the brain RAS plays an important role in AD pathology and cognition in Caucasians, this mechanism 
needs to be explored in African Americans, who stand to benefit the most from AD therapies targeting the brain 
RAS. 
2. 4. Blood Pressure Medication Prescription Practices: Discrepancies exist in the types of BP medications 
prescribed to Caucasians vs. African Americans based in part on past studies on past studies of clinical 
efficacy and the overall belief that the RAS may be of little importance in African Americans. If certain BP 
medications are found to beneficially influence AD biomarkers and hence AD risk – it is important to 
understand this mechanistic relationship in the presence of potential racial differences in RAS function and 
differences in BP medication assignment between African Americans and Caucasians. Research shows that, 
compared to Caucasians, African Americans are more likely to be prescribed antihypertensive therapy in 
general, and more likely to be prescribed aggressive therapies and combination regimens. Also, African 
Americans are more often prescribed calcium channel blockers and diuretics, while Caucasians are often 
prescribed RAS acting antihypertensives – those medications implicated in having salutary effects on cognition 
and AD incidence, independent of their effect on BP reduction. While many researchers now argue that the 
racial prescription practices are unwarranted, these trends persist in clinical practice and were recently upheld 
in the Guidelines for the treatment of hypertension in February, 2014, and thus is a central component the 
proposed project.


4
2. 5 Significance: While evidence linking the RAS and AD continues to mount, there are no therapeutic 
strategies targeting the RAS to prevent or delay AD. This Phase Ib RCT is the first step in understanding the 
potential of RAS acting medications in regard to CNS penetration and AD biomarkers with the future goal of 
repurposing an existing, inexpensive, safe drug. African Americans are not generally prescribed RAS 
medications, but when they are, doses higher than those prescribed to Caucasians are required to achieve BP 
control. It is unknown how these high doses alter systemic RAS levels or what dose is adequate to penetrate 
the CNS and alter brain RAS levels in African Americans. The dose is likely to be LOWER than the dose 
needed to alter BP, which is the case in Caucasians. Targeting individuals at high risk will help prevent and 
slow AD progression in as many people as possible, as fast as possible. Toward this goal, we must first 
understand the mechanistic potential of these medications in regard to the dose required to achieve CNS 
permeability, while safely controlling BP levels.
3. INNOVATION 
3. 1. This study will provide POC and data for power calculations for Phase IV clinical trials toward the 
goal of repurposing safe, inexpensive, RAS targeting medications for use in AD prevention trials in 
high risk populations. This trial will investigate the potential of an existing, affordable FDA approved 
medication as a potential therapy for AD prevention. Because research shows that higher doses of RAS acting 
medications are needed to achieve adequate BP control, we are testing whether telmisartan can penetrate the 
CNS and alter brain RAS indices irrespective of changes in BP. In doing this –telmisartan could be tested in 
larger phase IV clinical trials to determine whether similar pharmacological therapies may be helpful in 
preventing AD in African Americans, and whether these therapies could be used in addition to existing BP 
regimens.  
3. 2. This study will explore the role of brain RAS function in African Americans: While African 
Americans represent only 13% of the U.S. population; they comprise 1/3 of the cost incurred from AD, half of 
which is concentrated in the South. African Americans comprise 61.4% of the population of Atlanta and 28.7% 
of the Georgia population. Thus, this trial has a unique opportunity to examine the influence of RAS 
medications in this high risk group. Emory is located in the “Stroke Belt” which has a high incidence of 
morbidity and mortality from cerebrovascular disease. In addition to having a two-fold risk for AD, African 
Americans are at increased risk for a host of vascular disorders. By characterizing the brain RAS, and its 
response to RAS medications in African Americans, we stand to glean invaluable information that could be 
used for prevention and treatment of vascular disease as well as AD and vascular dementia.
3. 3. We will implement a state-of-the-art methodology to ascertain all components of the brain RAS.  
The RAS-fingerprint™ is a multiplex parameter designed and developed for the comprehensive analysis of the 
renin angiotensin system. Ten different angiotensin metabolites are measured simultaneously in a single 
sample of less than 1ml CSF. This methodology will provide optimal characterization of the RAS before and 
after drug, which, when coupled with the RAS measures we are collecting in plasma – will provide the most 
comprehensive characterization of systemic and brain RAS function in African Americans to date.
4. APPROACH
4. 1. Preliminary Data: Research [2-6] conducted by the PI and Key Personnel has led to the development of 
the project. Studies demonstrate productivity, feasibility and provide preliminary results suggesting that 
regulation of the brain RAS is a risk factor for cognitive impairment and longitudinal decline and may have AD-
modifying potential in African Americans. This Phase 1b trial will clarify these research questions in African 
Americans with a family history of AD.
4. 2. Studies supporting a link between RAS function and AD pathobiology: Dr. Whitney Wharton (PI) has 
reported that centrally acting ACE-Is have the ability to alter CSF ACE activity and these changes are 
detectable in middle aged Caucasians at risk for AD [6]. Dr. Patrick Kehoe (Key Person) has reported that 


5
therapies targeting the RAS likely improve diminished CBF, which is common in AD and can contribute to Aβ 
pathology. Importantly, while some studies support a beneficial effect of ACE-I on Aβ, others report that ACE 
may have the potential to degrade Aβ, though the cleavage site is still under investigation and this has not 
been confirmed in humans. This issue is exceedingly important and this project is designed to address this 
question in at-risk individuals.
4. 3. Studies supporting less amyloid deposition in Caucasians treated with RAS acting 
antihypertensives: Dr. Ihab Hajjar (Key Person) analyzed data from the NACC cohort (N = 890) and has 
reported that individuals with AD treated with RAS acting therapy showed less amyloid deposition markers 
upon autopsy compared to participants treated with other antihypertensive medications [7]. 
4. 4. Studies supporting less disease conversion and slower cognitive decline in MCI participants 
treated with RAS medications. We recently analyzed data from the National Alzheimer’s Coordinating 
Committee (NACC) database in 8187 participants who had at least 3 annual cognitive testing sessions 
(publication in revision). Participants taking RAS acting medications (N = 488) were less likely to convert to AD 
(p = 0.04) and had slower decline on the CDR Sum of Boxes (SOB) (p < 0.01) and digit span forward (p = 
0.02) than participants taking non-RAS acting antihypertensives. Moreover, BBB crossing RAS 
antihypertensives users (N=312) exhibited slower cognitive decline on multiple tests of cognitive and functional 
ability compared to non BBB crossing RAS users. RAS acting medications were associated with beneficial 
cognitive effects in both African Americans and Caucasians. African Americans had more pronounced benefits 
relative to Caucasians on the MMSE (p = .05) category fluency (p = 0.04) and Digit Span Backwards (p = 0.03) 
tests. These important findings suggests that the brain RAS plays a role in disease conversion and AD related 
cognitive function in African Americans, and highlights the need to address the neurobiological underpinnings 
of this relationship. 
4. 5. Summary of Preliminary Data: Our data indicate that African Americans and Caucasians at-risk for AD 
demonstrate pathological and cognitive changes suggestive of preclinical disease, and that these changes are 
likely influenced, at least in part, RAS function in the brain during midlife, which is both detectable and 
modifiable. While our results shed some light on individual components to be addressed in the proposed trial, 
the interplay among the factors (brain RAS activity, race, and AD biomarkers) has yet to be explored. 
5. RESEARCH DESIGN AND METHODS
5.1. 
Participants: 
Sixty-six 
non-Hispanic 
African 
American 
participants from the Emory ADRC will be enrolled in this trial. 
Inclusion and exclusion criteria are outlined in Table 1. We will enroll 
African Americans age 30 and over, all of whom will have a family 
history of AD. Participants must not be taking a RAS acting 
antihypertensive and their BP must be ≥110 and ≤ 170 mmHg 
systolic at both the screening and Baseline visits. Participants were 
selected because they are at high risk for AD and would most likely 
benefit from an intervention. The ADRC cohort contains a unique 
registry of individuals that have a parent with either autopsy-
confirmed or probable AD as defined by NINDS-ADRDA criteria. 
Familial AD diagnosis will be verified using the validated Dementia 
Questionnaire and medical records when available. Exceptions to 
these guidelines will be rare but may be considered on a case-by-
case basis at the discretion of the PI in consultation a Study 
Physician (Dr. William Hu or Dr. Lynn Marie Trotti ). Additionally, at 
PI discretion, participants with a contraindication for LP or MRI may 
be enrolled with contraindicated or refused procedure omitted in 
order to expand enrollment pool.  


6
Recruitment
Participants will be recruited directly from the ADRC cohort and via the following: 
Community-based recruitment: This will include announcement and recruitment information in 
periodicals and local newspapers. Blood pressure education sessions in local communities e.g. churches or 
barbershops will also be conducted. 
 Physician recruitment: Local physicians (primary care or specialty physicians) will be informed of the 
study and its requirements and provided information about referral to the study personnel. In addition, flyers for 
the study will be posted at outpatient areas in the following facilities: Emory University Hospital, Emory Clinic, 
Grady Memorial Hospital, and the VA medical Center if possible and all will be approached for the project. Of 
note, the PI has recruited this population in her ongoing past observational and clinical trials and reached her 
recruitment goal within the award period, supporting the feasibility of our recruitment goal. This enrollment rate 
allows us ample time to finish recruitment two years into the 5-year grant period and complete preliminary 
analyses by end of year 2 to support submission of a NIA R01 application in 2018. Also, we will write 
manuscripts using this data soon after analyses are completed.
5. STUDY INTERVENTIONS
5.1 Interventions, Administration, and Duration
 Participants will be randomized by gender and antihypertensive use (y/n) into either telmisartan (20mg 
or 40mg) or placebo groups. Treatment will be provided in a capsule format to be taken once a day orally. All 
three medication arms will be formulated into identical capsules. Investigators, study personnel and 
participants will be blinded for drug assignment. Participants will be on medication for 8 months. A study 
physician Dr. William H, MD, PhD or Dr. Lynn Marie Trotti will ensure participants blood pressure does not fall 
to unsafe levels and if a participant’s blood pressure is too low (systolic <90 mmHg), we will contact the 
participant and the participant’s PCP.
5.2 Handling of Study Interventions
 The drugs will be stored in the medication room in the Investigational Drug Service (IDS) Pharmacy. 
Standardized randomization by gender and active antihypertensive use (y/n) was calculated by John Hanfelt, 
the HEART Project biostatistician. The location of the IDS pharmacy is The Emory Clinic Bldg. A, Suite 1200, 
1365 Clifton Road, NE, Atlanta, Georgia 30322. Access to the med room is limited to the IDS Pharmacists via 
a badge swipe. Accountability records are maintained for all investigational product (IP). A courier will deliver 
prescriptions to study location to give to subjects or study staff will be able to pick up prescriptions. Subjects 
will receive four months of pills for their baseline visit and four months’ worth during at their 4 Month follow-up. 
Study coordinators will hand study medication to participants, but will not answer any questions about study 
medication. All questions about study medication will be answered by study physician or nurse practitioner 
during the visit or by using the contact information on the study medication label. 
5.3 Concomitant Interventions
    The goal of this Phase I trial is to safely assess the BBB permeability of low and clinical starting doses of an 
FDA approved ARB. Participants who are currently taking a RAS acting medication, (ACE-I or AR2RB) will not 
be enrolled. The clinical starting dose of Telmisartan for BP control in Caucasians is 40mg. This study will test 
the BBB permeability at 20mg vs 40mg vs placebo. Participants taking antihypertensives will be instructed to 
continue their current BP medication regimen. All participants’ PCP will be sent a letter describing the HEART 
Project and will be contacted by a study physician, Dr. William Hu or Dr. Lynn Marie Trotti, if their medication 
needs to be altered.
5.4 Allowed Interventions


7
Participants will continue to receive their usual care from their regular primary physicians. Hypertension 
management will be addressed by the study physician only insofar as communication with the participant’s 
PCP. The purpose of this Phase I RTC is not to control BP, therefore, we will not assume control of the 
participants BP maintenance as long as they are within safe limits. 
5.5 Required Interventions
In addition to the study medication (telmisartan or placebo), other non-RAS acting medications (e.g. 
HCTZ, amlodipine, and metoprolol) are allowed to achieve blood pressure control to below 140/90 mm Hg. All 
participants will remain on their medications as prescribed by their PCP in addition to taking the study 
medication or placebo pill. 
5.6 Prohibited Interventions
 Once participants are enrolled, addition of RAS acting antihypertensive medications by non-study 
providers is not allowed. However, non-RAS acting medications and non-hypertensive medications are allowed 
as part of usual care.
5.7 Adherence Assessment
Participants will be asked to bring their study medication bottles to the study center at each visit. 
Medication compliance will be assessed using pill count at the safety visits, Month 4 and Month 8. We will 
define a compliance rate for a time period, t, as the ratio of:  (the used number of pill prescribed for the number 
of days t- number of pills remaining or unused for the time t/ number of pills prescribed for time t) multiplied by 
100. 
Data to be collected in the proposed study:  
Blood Test: 
Blood chemistries including a Basic Metabolic Panel (glucose; calcium; electrolytes:  sodium, potassium, 
carbon dioxide, bicarbonate, chloride; kidney tests: BUN, creatinine) and a CBC (Complete Blood Count)   will 
be measured at Screening and optionally at Baseline and Safety Visit(s) per study doctor’s discretion as part of 
the safety monitoring for hyperkalemia and renal insufficiency. We estimate that only a subset of 33 subjects 
will have the basic metabolic panel and CBC performed on more than one Safety Visit. Blood will be drawn 
after application of a tourniquet, by use of a small gauge needle, from an ante-cubital vein, and by an 
appropriately trained professional from subjects. 
Additionally, research blood will be drawn at Baseline, Month 4, and Month 8 visits, including for APOE 
genotyping. Standard PCR and DNA sequencing techniques are used in a CLIA certified lab using the FinchTV 
program and not divulged to participants. We will utilize existing resources to assess levels of systemic RAS 
function in blood, including aldosterone, angiotensinogen, renin and ACE, to determine the relationship 
between circulating and brain RAS function among African Americans.
Arterial Function Measure via Ultrasound – PWV: Pulse wave velocity (PWV) is non-invasive and 
will be administered at Baseline and Month 8. PWV is a measure of artery wall stiffness, is highly 
reproducible and has a strong correlation with cardiovascular events and all-cause mortality. Dr. 
Wharton collects these measures in her ongoing NIH funded study and is familiar with the procedures. 
Neuropsychological testing: Testing will ensure a dementia-free diagnosis and will be used to determine the 
extent to which brain RAS function affects cognition in African Americans using a comprehensive battery in 
several cognitive domains (memory, executive function and language), with a focus on executive function. 


8
These tests are currently being used in the PIs ongoing NIH funded study and were selected for our cognitively 
normal, middle aged sample and because data show they are particularly sensitive to fluctuation in blood 
pressure. 
Executive function will be assessed using the NINDS-initiated EXecutive Abilities: Measures and Instruments 
for Neurobehavioral Evaluation and Research or “EXAMINER” tool box. This test battery reliably and validly 
assesses executive function in clinical trials [http://examiner.ucsf.edu/].115-117 The battery includes 11 tasks that 
generate 15 primary variables. Within this set, the EXAMINER investigators identified tasks measuring four 
domains that fit well in a single factor model of executive function: working memory, inhibition, set shifting, and 
fluency. The EXAMINER battery has excellent psychometric properties with test-retest reliability of over 0.9 
and correlates by over 0.60 with an informant-based measure of day-to-day executive functioning, the Frontal 
Systems Behavior Scale. The parts of EXAMINER that we selected include: 
1) Flanker task (inhibition) which involves responding to a central stimulus while ignoring flanking stimuli 
that are either compatible or incompatible with the central stimulus.118 
2) Set-shifting, a measure of mental flexibility assessing the subject's ability to attend to the specific 
attributes of compound stimuli, and to shift that attention when required.119 
3) Spatial N-Back test assesses spatial working memory
Data will be scored using an open source web-based data management and scoring system available through 
the EXAMINER project Using item response theory, a single composite executive function score will be 
calculated from the available data points.117 
To assess additional cognitive domains/mood, we will use these tests included in the National Alzheimer’s 
Coordinating Center Uniform Data Set.122,123 
Tests include (but are not limited to): MOCA, MMSE, WAIS-Working Memory subtests, WMS-III Faces, Brief 
Visuospatial Memory Test-Revised, WMS-R Logical Memory, and the Rey Auditory Verbal Learning Test. By 
utilizing the results of the AT RISK assessment of repeat testing, the project is more cost efficient and ensures 
that participants are not overburdened and practice effects are avoided. If an effect of uncontrolled BP levels is 
observed, we predict that they will manifest on executive function tasks. Of all the cognitive domains, executive 
function is more vulnerable to hypertension and is selectively impaired in early AD associated cognitive decline
Ambulatory Blood Pressure Monitoring: Ambulatory measures provide a superior predictive value for 
cardiovascular events compared to clinic BP measures and have been used in prior AD research including the 
PI’s projects. These data will add insight into the relationship between BP and brain RAS in African Americans. 
This procedure is optional due to the difficultly of returning the ABPM equipment for some participants. 
Procedure will be omitted only for participants who cannot return monitor.
CSF Biomarkers:  CSF samples (Aβ and RAS Fingerprinting) will be collected at Baseline and Month 8 by a 
HEART study team member using a 24 gauge Sprotte needle and a gentle extraction technique widely used in 
CSF biomarker research in AD. About 22ml of CSF will be collected, aliquoted and stored at -80°C until time of 
analyses. Aβ42 will be measured using xMAP technology by the ADRC team who are experts in AD 
biomarkers. Visits will occur in a designated clinical room at the ADRC memory clinic at 12 Executive Park or 
the ACTSI in the EUH. All CSF samples will be collected after an 8-hour overnight fast. A member of the 
ADRC biomarker team will perform all LPs. 
All CSF collection is completed according to guidelines put forth in the “Biospecimens Best Practice Guidelines 
for the ADCs” published by the National Alzheimer's Coordinating Center (NACC) and available on their 
website. CSF collection occurs at approximately the same time at each visit to control for diurnal variability. 
Participants are placed in the sitting position and asked to maximally flex their knees, hips, back, and neck. 
The skin over L4-L5 is prepped and draped in a sterile manner. 1% lidocaine is used as a local anesthetic, 
followed by insertion of a spinal needle with introducer into the L4-L5 interspace using sterile technique. 


9
Approximately 25ml of CSF will be collected using sterile polypropylene collection tubes. The samples will be 
immediately divided into aliquots and transferred for storage in a freezer for future assays. Risks of LP are 
discussed under Protection of Human Subjects.
RAS analysis in CSF:  CSF samples will be collected in all participants. 
State of the art technology will measure 10 individual components of the 
brain RAS system including Analyses will be performed by Dr. Marko 
Poglitsch in Austria, developer of the RAS-Fingerprint™ technology 
http://www.attoquant.com/sites/info_renin.html (Figure 2). 
Tau and Abeta: CSF T-tau, and P-tau181, Aβ40 and Aβ42 and other 
proteins related to Alzheimer’s disease risk will be measured by Dr. 
Henrik Zetterberg in Sweden using XMap technology. Dr. Zetterberg is a 
nationally recognized biofluid and Alzheimer’s disease expert and Dr. 
Wharton has collaborated with him and utilized her services and 
expertise in all of her current and past studies. All samples will be coded 
with a unique identifier to keep the laboratory blinded to factors such as 
subject identity or treatment group.   
Neuroimaging: The sequence is fasting takes one hour. The primary scan of interest is ASL, and T1, T2, T2 
FLAIR, and DTI are also measured. Data is acquired while the participant is awake with no cognitive task or 
contrast. All scans are FDA approved. Flow images are manually processed with in-house developed Matlab & 
C programs. The sequence is described as follows:
(i) ASL-MRI: ASL methods were previously described.137,138 Briefly, 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. ASL images will be acquired using a custom 3D stack of interleaved 
spirals fast spin echo sequence and will be averaged in order to improve the signal-to-noise ratio. An algorithm 
to remove subtle motion artifacts will be used for individual images prior to signal averaging.137-140 Images will 
be interpolated and smoothed in a panel by using a 0.5-pixel, full-width, half-maximum Gaussian kernel. 
Perfusion values will be calculated as describe elsewhere138 and converted to ml/100g/min. Regional perfusion 
will be quantified in each hemisphere.141 Maps of cerebral vasoreactivity will be obtained by co-registration of 
perfusion and anatomical images allowing us to have perfusion and vasoreactivity maps before and after 
treatment. 137-140 ASL reliability is high  with ICC ≥0.75.142
(ii) Structural MRI and WMH: High-resolution anatomical images will be acquired using a 3D-Fast Spoiled 
Gradient Recalled Echo (FSPGR) Sequence. WMH regions will be identified by a 3D T2 Fluid Attenuated 
Inversion Recovery (FLAIR) Fast Spin Echo sequence. Obtained images will be co-registered using a within-
subject inter-modal alignment between structural and perfusion images. T1-weighted SPGR images will be 
used to identify cerebrospinal fluid and white and gray matter (WM, GM), both global and regional.  The 
FreeSurfer analysis suite (http://surfer.nmr.mgh.harvard.edu/) will be used to conduct automated extraction of 
volumes of targeted regions (in mm3) including hippocampal volume.129-131 Hippocampal volume will be used 
as an index of Alzheimer’s disease (AD) pathology.132 WMH volumes (in mm3) will be obtained from FLAIR 
imaging according to a semi-automated analysis protocol developed and validated by DeCarli et.al.133,134 The 
reliability assessed by the intra class correlation (ICC) is 0.79 to 0.85135 for regional volumes and 0.99 for 
WMH.136 All volumes will be adjusted for intracranial volume in our analyses.  
 (iii) Diffusion tensor imaging and tractography: DTI is ideal in our study because it is highly sensitive to detect 
structural changes over a short time, less than 1 year, as compared to traditional MRI.59 DTI is based on the 
imaging of water molecules’ diffusion and direction. (see review143) Microstructural damage in WM will be 
quantified using voxel based morphometry (VBM) of diffusion tensor metrics including mean diffusivity (MD), 
which is a measure of the extent of diffusion, the fractional anisotropy (FA), which measures the difference 
among the tensor eigen values reflecting microstructural integrity, and axial and radial diffusivity, which 


10
measure diffusion or structural integrity along the axial and radial directions respectively. These measures are 
highly reliable with ICC ≥0.88 for FA, and ICC ≥0.84 for MD values,144,145 and increased MD and decreased FA 
are highly correlated with executive function.146 A novel Independent Component Analysis (ICA) based multi-
fiber-per-voxel streamline tractography developed by Dr. Singh147 will be used to quantify microstructural 
changes along specific tracts known to be involved in executive function including the fronto-occipital, cingulum 
and uncinate. Whole-brain multi-fiber-per-voxel tracts in the native space of each subject will be mapped to the 
T1 template space using the DARTEL transformation, and a statistical analysis of diffusion metrics of voxels 
lying along specific pathways (sorted in a common template space for all subjects) will be performed. For each 
participant baseline and post treatment images will be compared qualitatively as well as quantitatively using 
pairwise voxel-based comparisons (Statistical Parametric Mapping (SPM8), Wellcome Trust Center for 
Neuroimaging, UK) for the various within tract metrics described by Correia et al.148 
(iv) Resting functional MRI (r-fMRI): This protocol, developed in the last few years, is designed to assess the 
communication or "functional connectivity" between brain regions.149 Functional connectivity has a key role in 
important complex cognitive processes.149  It focuses on spontaneous, rather than task-induced, low frequency 
(<0.1 Hz) fluctuations in the blood oxygenation level-dependent (BOLD) signals. r-fMRI supplements structural 
connectivity measured by DTI (see above) with functional connectivity of the brain. This method avoids 
performance related variability seen in activation fMRI, is less complicated to acquire and standardize, does 
not require radio-isotopes, and may be more effective at identifying functional pathology associated with risk of 
future cognitive decline compared to non-resting fMRI techniques.150 Participants are instructed to lay still with 
eyes closed and remain motionless as much as possible while a series of images is acquired for 6 minutes. 
The first 10 image acquisitions of the resting state will be excluded from analysis to allow for adaptation of the 
subjects to the circumstances. The remaining images will be motion-corrected co-registered as mentioned 
previously. The functional images will be re-sampled to 3-mm isotropic voxels followed by spatial smoothing 
with a 4-mm full width at half maximum (FWHM) Gaussian kernel. Finally, temporal filtering (0.01 Hz < f < 0.08 
Hz) will be performed on the time series of each voxel to reduce the effect of low-frequency drifts and high-
frequency noise.151 Other image processing includes time shifts and motion correction; removal of cardiac, 
respiratory, white matter, and cerebrospinal fluid signal effect and applying a low-frequency filtering. A seed 
based functional connectivity analysis (model-dependent) will be performed by calculating the correlation 
between the BOLD time series activity in one or several a priori voxel  region(s)-of-interest (ROI),or “seed 
region”, and activity in all other time series activity voxels in the brain.151,152  Voxels with high degree of 
correlation form a connectivity map or a "resting functional connectivity map". 153 Prior studies suggest that the 
brain is comprised of few global networks or hubs that are intimately connected.154 Using this seed-region 
method we will assess brain connectivity in the dorsal medial prefrontal cortex subsystem which is involved in 
executive cognitive function155-158  which is likely to be affected DM and hypertension.159,160 More recent 
methods have been used that are independent of an a-priori ROI which overcomes the drawback of missing a 
potential target region or tract. Using graph theory, metrics can be derived about brain functional connectivity 
based on the distance between vertices (voxels) and the degree of connectivity (number of edges connecting 
to the voxel).161,162 Using this method, we can derive a matrix that reflects overall connectivity and efficiency of 
brain function: N=number of nodes; k=mean degree; d=connection density; C=clustering coefficient; L=path 
length; =path length scaled to random graph; =clustering coefficient scaled to random graph; =scalar small-
worldness measure.161,162
F. 7. Tissue Banking
We will collect blood and CSF for future research. Tissue banking will be accomplished with the assistance of 
HEART Project, ADRC and staff and facilities. Vials containing blood samples will be labeled with subject ID 
numbers, name of the study, date collected, barcoded and temporarily stored at the EP6, Rollins, or Whitehead 
buildings. The label will include the study name, study visit number, contents of each collection vial, and the 
date of collection. Tubes will be labeled with a barcode by an ADRC Technician. All samples from this protocol 
will be kept in a research freezer in a secure research freezer space located in the EP6, Rollins or Whitehead 
building. Access to the freezer is protected, and equipped with backup power and a telephone alarm system. 
The research freezer space can only be accessed by authorized study personnel.


11
All samples are collected for research purposes only. If blood is used for future assays, blood remaining after 
completion of laboratory tests will be discarded. Any genotype information obtained from blood will be stored in 
a coded and secure database, located in the ADRC and HEART Project lab space. Only authorized and 
certified study personnel will have access to the code which will be held in a password protected database on 
the Emory network server, access to which will be restricted to small number of approved study personnel. 
Tissue specimen banking (blood and CSF) is not an optional part of the study. The samples will be kept until all 
analysis for this project is complete or until the samples are exhausted. Future study results obtained from 
these samples may not be reported to subjects. Subjects (or their designated representative) wishing to 
withdraw their consent to bank specimens will need to contact the PI with a written request to have stored 
samples destroyed (autoclaved). If the PI leaves Emory University, the samples will stay with Emory (not leave 
with the PI).
Having these additional banked samples will allow for future analysis of Alzheimer’s disease or other disease 
biomarkers if/when new analytical technique for analysis for these samples becomes available. Furthermore, it 
allows for comparison between various techniques for analysis of these samples, thus furthering the research 
in this area. 
F.9 Questionnaires and handouts
F. 9. 1. Personal Health Questionnaire Depression Scale (PHQ-8)): This standardized tool measures 
depression.  If participant scores 10 or greater its considered major depression, 20 or more is severe 
depression., The PI will be notified at once, who will then notify an ADRC clinical neuropsychologist who will 
contact the participant.
F. 9. 2. Exercise: This short questionnaire asks about the participant’s exercise routine, specifically 
cardiovascular activities and weight-lifting. The exercise history questionnaires assess normal activity levels, 
which is important when assessing blood pressure patterns.
F. 9. 3. Medical: This questionnaire asks about alcohol and smoking history, education and other 
demographics, surgeries, medications, allergies, and current symptoms. 
F. 9. 4. Sleep: This questionnaire asks about normal sleep patterns on work and non-work days, about 
snoring, sleep apnea, and other sleep problems. These problems can affect blood pressure and cognition.
F. 9. 5. Blood Pressure Information Handout: This handout explains basic information about blood pressure, 
why it is important, and how it can be lowered
F. 9. 6. Diary form: this form allows the participant to keep a diary of their activities while wearing the blood 
pressure cuff. 
F. 9. 7. Nutrition Survey: This survey is an online diet questionnaire and is optional. The decline to complete 
this survey will not affect the participant study participation.
F. 9. 8. Stress Questionnaires:  These questionnaires include but are not limited to mood, stress, the quality 
of life of your family member with Alzheimer’s disease, nutrition, and exercise.
F. 9. 9. Perceived Discrimination Survey Battery: This battery of questionnaires consists of: Chronic Work 
Discrimination and Harrassment Scale; Coping with Discrimination Scale; Heightened Vigilance Scale: Major 
Experiences of Discrimination Scale; The Expanded Everyday Discrimination Scale. These surveys will be 
administered online, are optional, and will not affect study participation if declined.
5. 2 Procedures:  
5. 2. 1. Intervention and randomization: We will recruit 66 participants to account for a potential 10% drop 
out rate over the 8 month trial. Standardized randomization by the study biostatistician will be used to assign 
participants by gender and antihypertensive use (y/n)by the Emory Pharmaceutical Research Center to receive 
20mg telmisartan (N = 22), 40mg telmisartan (N = 22) or placebo (N = 22) to be taken once daily before bed. 
Study drug and placebo will be formulated into identical capsules. The PI, study personnel and participants will 
be blinded for drug assignment. A study physician will ensure BP control and will be the only unblinded study 


12
personnel. Participants are not required to stop their current medications to test this POC, mechanistic 
research question (i.e. pre vs. post RAS medication exposure and CNS permeability). Participants requiring 
additional BP medication in addition to study drug, or participants whose BP values drop too low will be 
referred to their PCP in addition to HEART Project personnel contacting the participant’s PCP to request 
medication alteration for the duration of the trial. If a participant requires an additional medication, 
supplemental antihypertensives will not act via the RAS. Participants will return every 2 weeks until control is 
established. 
5. 2. 2. Study Visit Description Summary: Participants will complete approximately 8 visits over the course of 
the 8 month trial depending on the number of Safety visits required. (Figure 1). We will utilize the Emory 
ADRC participant registry and contact the adult children who are study partners of individuals who have an AD 
diagnosis. First, a verbal consent and a phone interview will be conducted which will determine eligibility and 
introduce the study protocol using standardized questions. AD diagnosis is verified using the diagnosed family 
member’s medical records or the validated Dementia Questionnaire (DQ). Based on the make-up of the 
identical Wisconsin ADRC AT RISK cohort, we predict that approximately 45% of participants with a family 
history of AD are APOE4 positive.
Those who are eligible will be invited for a screening visit, which includes: obtaining informed consent, 
cognitive 
screening, 
medical 
history, 
current 
medications, 
2 
seated 
BP 
measurements 
and 
baseline metabolic blood panel and 
CBC. 
Participants 
who 
are 
untreated hypertensives or currently 
taking BP medication are eligible as 
long as existing therapies do not act 
via the RAS. After this screening, 
eligible participants are asked to 
return for a baseline evaluation and 
randomization. Baseline and month 
8 visits are fasting for 8 hours prior 
to the visit, take approximately 4 
hours 
and 
consists 
of 
BP 
measurements, 
physical 
exam, 
blood draw, lumbar puncture, brain 
MRI, 
vascular 
ultrasound, 
ambulatory BP monitoring (optional) 
and 
cognitive 
testing. 
Randomization and treatment will 
start after baseline data collection. 
Participants will then be seen in approximately two weeks following baseline for their safety visit, to ensure BP 
values have not dropped to unsafe levels (90 mm Hg systolic). Subsequent safety visits (up to 3) will be 
scheduled in two week intervals at the study physician’s discretion. Blood pressure, heart rate, weight, adverse 
events (AE) and serious adverse events (SAE) screening, pill count (to assess compliance), metabolic blood 
panel and/or CBC, use of other medications data will be collected. Participants will return at Month 4 for a 
blood draw (metabolic blood panel and/or CBC), pill count and medication dispensing Participants will return 
again at month 8 for a second lumbar puncture, MRI, blood draw vascular ultrasound, ambulatory BP 
monitoring (optional) and cognitive testing. All aspects of the trial will be overseen by a data safety and 
monitoring board (DSMB) comprised of 2 physicians and a biostatistician not involved in the trial. Specifics of 
the procedures are detailed below.
7.2.1 Screening: Initial eligibility will be determined via phone interview by a member of the HEART team. 
When an individual responds to our recruitment activity by phone, a screening consent, I/E eligibility 
questionnaire and a Dementia Questionnaire regarding their family member will be obtained. This screening 


13
process will determine the specific inclusion and exclusion criteria that can be evaluated by self-report, 
including age, hypertension or blood pressure diagnosis, and prior medical issues detailed in the 
inclusion/exclusion criteria. Those who are eligible via phone interview will be invited for a clinic screening visit 
along with their next-of-kin, if possible. The screening visit will include: explaining study details and obtaining 
informed consent, medical history, current medications, 2 seated blood pressure measurements, and baseline 
metabolic panel and/or CBC. Eligible participants will be asked to return for baseline evaluation and 
randomization. 
7.2.2 Consenting Procedure: A signed consent form will be obtained from each participant. A single informed 
consent form will describe both the screening and study procedures. The consent form will describe the 
purpose of the study, the procedures to be followed, and the risks and benefits of participation. A copy will be 
given to each participant and will be documented in the participant’s study record.
7.2.3 Enrollment, Baseline, and Randomization: During this phase, blood pressure measurements, detailed 
neuropsychological assessments, physical exam, brain MRI, and lumbar puncture will be completed. Blood 
samples will also be collected for APOE, inflammatory and endothelial markers and RAS functioning. 
Randomization and study intervention will occur after baseline data collection.  Participants will then be started 
on the study medications, which they will be instructed to begin that evening. All study medication questions 
will be answered by study physician or nurse. 
Follow-up Visits: Following the Baseline (randomization) visit, participants will be seen at two weeks. Blood 
pressure, heart rate, weight, adverse events (AE) and serious adverse events (SAE), pill count (to assess 
compliance), and use of non-study medications data maybe collected at some or all of these safety visits. New 
medication will also be dispensed during these visits. If blood pressure levels indicate hypotension (90 mm Hg 
systolic) we will contact the participant’s PCP during that study visit and request treatment modification for the 
duration of the trial. As we are administering the lowest doses possible for this drug and because only 37% of 
individuals on an antihypertensive actually achieve proper BP control – we do not foresee hypotension being a 
common occurrence. The initial starting clinical does for telmisartan is 40mg once daily, which is considered 
our ‘high’ dose. Another 1/3 of the participants will be given the ‘low dose,’ 20 mg once daily and the third 
group is placebo. While 20mg is lower than the clinically recommended starting dose, this mechanistic study 
aims to assess the brain permeability of the active medication and thus higher doses are not necessary. If all 
measures are within normal limits, the participant will return at Month 4. If any NP or blood levels are NOT 
within normal limits, we will contact the participant’s PCP and the participant will be advised to schedule a visit 
with their PCP for treatment. The participants will then be asked to return in 2 weeks for another safety visit. 
Completion/Final Evaluation: The final visit (8-month visit) will include: blood pressure, heart rate, weight, 
adverse events (AE) and serious adverse events (SAE), pill count (to assess compliance), use of non-study 
medications, neuropsychological testing, neuroimaging, vascular ultrasound, lumbar puncture and blood 
collection. This visit will be identical to the Baseline visit except for randomization and medication dispensing. 
Participants will fast 8 hours prior to this visit. 
8. SAFETY ASSESSMENTS 
All data derived from this study is for research purposes only. Subjects will be monitored at all times for 
adverse events. 
Potential Risks
Risk of Study Drug: The study will utilize a medication (Telmisartan), approved by the Food and Drug 
Administration for the treatment of hypertension and Cardiovascular Risk Reduction. It is well tolerated by 
young and elderly individuals and has been used extensively in clinical practice. Possible side effects include: 
dizziness, weakness, fatigue, lower extremity edema and hypotension. Renal failure and hyperkalemia are also 
potential complications. Adverse events will be queried at each visit. Alternatives to antihypertensive 
medications include no therapy, which is not safe or ethical in patients with hypertension. If there is 


14
contraindication to telmisartan and another of the participant’s medications then he/she will not be able to 
enroll in the study. Use of lithium is a contraindication telmisartan and hence lithium users are excluded. 
Aliskiren cannot be used in combination with telmisartan, which is why diabetes or use of any diabetes 
medication is exclusion. Use of drugs that act on the renin-angiotensin system during the second and third 
trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death and 
thus women who are pregnant or planning to become pregnant will not be able to participate in this study. 
J.1 Risk of Ambulatory BP Monitoring: Thought the BP monitor is lightweight and noninvasive, it can cause 
discomfort due to the repeated BP readings via tightening of the BP cuff. The most common risk pertaining to 
24 hour BP monitoring is a skin rash. Participants with extremely sensitive skin or who have had prior reactions 
to BP monitors or skin patches are advised that this is a possibility in the current study, and they should 
consider this before opting to enroll. Participants will be advised to simply remove the BP cuff and turn off the 
monitor, should the discomfort become significant. All parts of the BP monitors are latex free and will be 
washed before use with nonabrasive, antibacterial soap. 
J.2 Blood Vessel Function Measures: The vascular ultrasound is painless and is non-invasive and will be 
performed by the PI or a trained member of the HEART Project. We will place a pencil-like sensor gently 
against the inside the elbow and record a blood pressure signal from the subjects pulse. Dr. Wharton has used 
this procedure in her prior trials and is familiar with the data processing.
J.3 Risks of MRI: Subjects will have their MRI performed at the Wesley Woods Health Center 1841 Clifton 
Road Atlanta, GA 30329. Subjects with the following should not participate in MRI studies: metallic implants, 
such as prostheses, shrapnel, or aneurysm clips, or persons with electronic implants, such as cardiac 
pacemakers or claustrophobic individuals. The magnetic field generated by the MRI machine can cause a 
displacement or malfunctioning of these devices. There are no known risks or adverse effects from the radio 
signals used in this study. Also, subjects who have anxiety or claustrophobia will not be recommended to 
participate since the head must be placed fully inside the MRI scanner tube. In addition, fatigue and physical 
discomfort due to the length of the scan session are possible. The MRI scanner makes a great deal of high-
pitched “beeping” noises during the scanning. To minimize this risk, we offer participants earplugs. 
J.4 Risks of Cognitive Testing: In general, participation in cognitive testing is well tolerated by the majority of 
participants. However, if necessary, breaks in testing will be provided to those feeling either undue stress or 
frustrations during administration of tests. 
J.5 Risk of Blood Draw: We will collect a blood sample at all main visits (Baseline, Month 4 and Month 8) as 
well as screening and safety visits. Blood draws can cause mild pain in the arm and may cause bruising, 
infection, and occasional fainting.
J.6 Risks of Lumbar Puncture (LP): An experienced member of the Emory ADRC and HEART Project will 
perform LPs for the study. The most common complication of a lumbar puncture is post-dural puncture 
headache. Studies show that the rate of headache occurrence can be reduced to as low as 1.7% with use of 
small needles (21-gauge or less), most commonly, we use a smaller 25-gauge Sprotte spinal needle. All 
subjects will be counseled on the signs and symptoms of post-dural headache and given information on 
management (ibuprofen, caffeine, and rest) and instructed to promptly contact the on-call study physician. A 
blood patch procedure by an anesthesiologist will be available to participants experiencing serious post-dural 
headaches. Bacterial meningitis is a very rare complication of lumbar puncture, occurring in less than 0.2%. 
Uncal or tonsillar herniation is a very uncommon complication, occurring in <1% of very high-risk subjects with 
known primary or metastatic neoplasms. Therefore, we do not anticipate such significant complications during 
the course of this study. A member of the ADRC research team and the current HEART Project trained in 
these procedures will perform a neurologic and fundoscopic exam on each subject prior to lumbar puncture 
and those participants thought to have papilledema or gross neurologic deficits consistent with a central 
nervous system mass will not have a lumbar puncture performed. Each subject will be called the day following 
his or her lumbar puncture to ask about any side effects. All subjects will be given a telephone number to reach 
a physician 24-hours a day. 


15
J.7 Social: The social risk is a breach of confidentiality regarding risk for development of AD. Subject names 
and research data will be handled with utmost confidentiality and discretion. Subjects will be assigned a unique 
identification number that can be traced only by the research coordinator and Principal Investigator. All subject 
information will be kept in locked drawers, file cabinets, or secure computer files, with access only allowed to 
research personnel.
J.8 Ethical, Psychological, Legal, Other: Although participants will be given information on their circadian BP 
levels at the conclusion of their participation, they will not be given information about their APOE4 status, CSF 
or plasma biomarkers. This will be clearly stated in the informed consent process. Although ApoE4 allele is 
associated with a higher risk of developing AD, not all people with ApoE4 develop AD and not all AD patients 
are ApoE4 allele carriers. Also, there are no clear standards in cognitively healthy adults for identifying higher 
risk individuals using CSF or plasma biomarkers. Furthermore, although these markers may predict who is at 
higher risk of developing AD, they are still in the research stages and do not have proven roles in clinical 
practice. In addition, since there are no established effective preventive therapies for AD, providing individuals 
with individual risk data may only add to their psychological burden and not provide them any benefit. If, during 
the course of the study, a new medication is approved by the FDA for AD prevention in high-risk individuals, 
then current policies will be revised to ensure good clinical care for study participants. Insurability of 
participants may be affected if there is any breach of confidentiality, which we do not anticipate. 
J.9 Protection of Subjects: As stated above, the physical, social, and psychological risks associated with this 
study are small. Confidentiality will be assured by assigning a unique subject number to each participant. All 
subject information will be kept in locked drawers, file cabinets, or secure computer files, with access only 
allowed to the HEART research personnel. 
J.10 Risks and expected benefits for subjects and society: Although individual participants will likely not 
derive any benefit from participation, they may benefit from future research that builds on these data should BP 
control eventually be proven to have a role in AD prevention. The benefits to society may be considerable. 
Society, specifically individuals at risk for AD, will benefit by learning the extent to which AD biomarkers 
markers indicating risk for cognitive decline are related to vascular risk factors and blood pressure fluctuations. 
This is not a treatment study and there are thus no alternatives to participation.
Data Safety and Monitoring
Safety procedures will be implemented in accordance with NIH safety policies for clinical trials. The safety 
monitoring will be conducted by the PI and a Data and Safety Monitoring Board (DSMB) on an annual basis. 
The DSMB is comprised of 3 members including at least 1 physician familiar with RCTs and African American 
HTN studies, a researcher whose area of expertise aligns with the primary outcome of the study and an 
experienced biostatistician. Once an SAE has been identified, it will be reported to the Emory-IRB. The 
Alzheimer’s Association (the funding organization) will also be notified. The DSMB will be asked to review the 
event. Once a year, the DSMB will review progress of the trial (recruitment and follow-up, protocol violations), 
assess the safety of the protocol, and address any issue that limits the study success. Instructions and a 
template for documents for the DSMB (i.e., ICF, source documents, notes to file, protocol deviations, AEs) will 
be provided to the DSMB in advance of their annual review.  The report will include all AE and SAEs to be 
reviewed by the DSMB. If concerns arise about safety issues, the DSMB may request additional data and 
propose specific analyses. A report summarizing the review, discussions, and recommendations for 
continuation of the trial will be generated and signed by DSMB members and provided to the IRB.
8.4 Methods and Timing for Assessing, Recording, and Analyzing Safety Parameters 
At each encounter, standardized adverse event (AE) monitoring forms will be completed. At any point during 
the study period an adverse event is identified, it will be recorded in the participant research record along with 
the time/place of the event. The study physician will be immediately notified and the participant evaluated 
either by phone (if participant is not on site) or face-to-face (if participant is on site). If the AE is related to 


16
anticipated AE lumbar puncture headache, the SOP for Lumbar Puncture headache AEs will be followed and 
the information will be reported to the study physician. Depending on the physician assessment, further 
evaluation maybe performed such as further lab work, exam, or referral to the emergency department. Details 
about the safety parameters will be recorded and entered into a database. Comparisons between the 3 groups 
will be conducted to assess overall and between group differential safety.
8.5 Adverse Events and Serious Adverse Events
During the screening process, if the participant is identified to have a problem requiring medical attention such 
as severely elevated blood pressure, they are referred to their primary care physician or the emergency room. 
The primary care physician will be notified of all screening results by mail or fax upon the participant request. 
Adverse events will be reported to the Emory IRB, the DSMB, the funding agency, and the primary care 
provider of the participant. If the participant does not have a primary care provider, they will be referred to one. 
The timing of reporting depends on whether the adverse event is expected, is serious or not, and whether it 
suggests that other participants are at higher risk of harm. Any subject who develops a serious adverse event 
(SAE) requiring emergency medical care during the study visit will be given immediate medical care at the local 
hospital by the medical investigators, intervention will be stopped and the participant will be referred back to 
their primary care physician for ongoing hypertension care. SAEs will be reported to the above-named 
agencies within 24 hours of their discovery. Other adverse events (non-serious) will be reported within 2 weeks 
of their discovery. 
8.6 Incidental findings
Incidental blood chemistry abnormalities, such as elevated blood sugar, will be reported to the subject and 
primary care provider. Incidental findings on brain imaging such as brain masses, prior stroke, and 
hemangiomas, will be evaluated by the PI and the study physician and relayed to the subject and her/his 
provider. In the unlikely event that an incidental finding requires immediate attention such as bleeding on MRI, 
urgent care will be provided in a facility of the participant's preference.
8.7 Reporting Procedures
Expected side effects described within the safety parameters will be reported to the IRB, DSMB and NIA as 
part of ongoing progress. SAEs will be reported to the DSMB, the Alzheimer’s Association and IRB within 24h. 
A detailed report will follow within 7 days, and then a final resolution report will be sent. Other causes or 
existing health issues will be investigated and ruled out as the inciting factor prior to the determination of an 
adverse reaction.  
8.8 Follow-up for Adverse Events
With the permission from the participant, we will contact the participant’s primary care doctor and help him/her 
get medical follow-up. Adverse events that require follow-up such as increased potassium or increased 
creatinine will be monitored until resolved or are further followed by the primary care provider. If emergency 
care or hospitalization was necessary, the study physician will conduct a follow-up phone or face-to-face 
evaluation. If the event requires intervention discontinuation, the participant will be referred back to the primary 
care provider. They will also be invited to perform the final visit evaluation including all study procedures 
planned for that visit.
9. INTERVENTION DISCONTINUATION 
A subject may choose to withdraw from the study for any reason. The investigators may also request that the 
subject withdraw from the study, for safety or other reasons. Withdrawn participants will continue to be 
monitored by the study personnel after the event if possible and invited to complete the final visit evaluation. 
The criteria for discontinuing a subject’s participation include:


17
(1) the subject’s request, 
(2) serious adverse events that requires un-blinding, 
(3) new stroke, transient ischemic attack, or myocardial infarction that limits ability to complete the 
study 
(4) Symptomatic dysrhythmia 
(4) anaphylaxis or allergic reaction to study medications
(5) inability to participate due to relocation or other personal reasons
(6) renal failure (increase in serum Creatinine above 2.5 mg/dl) or hyperkalemia (greater than 5.1 meq)
(7) pregnancy or planning to become pregnant
11. DATA COLLECTION AND QUALITY ASSURANCE
11.1 Data Collection Forms
Data collected during interviews and exams will be documented on trial-specific data forms. Neuroimaging data 
will be saved in digital formats on a HIPAA-compliant server.
11.2 Data Management
Once a subject is enrolled into the study, he/she will be assigned a unique identifier number and be referred to 
by initials and the study number only.  Only research team members will have access to the files. Data will be 
entered on a web-based secure trial data system; the data system will include must enter fields, range checks, 
and simple logic checks.   The trial database will include for all variables an electronic data audit of data edits 
(who, when, and why).  A data query report (including missing, out of range, and logic checks) will be 
generated by the trial statistician weekly; timeliness and completeness of responses to data queries will be 
monitored.  Trial databases will be stored on a secure server. A copy of the master participant list will be kept 
by the PI in a locked office. The investigators will keep subjects’ medical records private as far as the law 
allows. The IRB and officials of the sponsor/funding agency will have access to these records as needed within 
legal guidelines. If study results are published in journals or presented at meetings, we will not use the 
subjects’ name. All investigators and research team members have successfully completed the online CITI 
program for working with Human Subjects in Research.
11.3 Quality Assurance 
11.3.1 Training: Research personnel will be trained by the PI and the ADRC investigators and staff. The 
process of training consists of data forms completion, neuropsychological assessment, data storage and 
human subjects protection, and vital sign evaluation will be documented in a training log for each study 
personnel. 
11.3.2 Quality Control: To assess quality of data collected the PI along with another investigator will randomly 
and on intervals review data obtained. In addition, quarterly assessment of personnel competencies in 
obtaining data (e.g. Blood pressure checks, neuropsychological assessments etc.) will be performed. 
11.3.3 Protocol Deviations: Every attempt will be made to maintain compliance with the approved study 
protocol. In the unanticipated event when a deviation is noted, the Emory IRB will be notified. The PI will 
conduct an investigation about the setting, reasons and potential remedies that need to be instituted to rectify 
the deviation and prevent future similar instances. The DSMB will also be notified.
K. Inclusion Report
Inclusion of Women: All participants will be invited through clinic visits, recruitment registry or individual flyers 
to participate in this study. Since approximately 70% of AD cases are women, we expect that percentage to be 
reflected in our study population and we will emphasize the importance of AD prevention research in the 
context of women’s health to those invited to participate.


18
Inclusion of Minorities: Self-reported African American status is an inclusion criteria for this Phase I RCT, 
thus all participants would be classified as ‘minorities.’ 
L.1 Adequacy of Protection against Risks
Recruitment and Informed Consent    
To ensure that participants have adequate time to review participation in the study and discuss the risks with 
their friends and family, we will email a blank ICF to each participant prior to their Screening visit. While this 
does not in any way take the place of the in-person consenting process, this extra step allows participants to 
grasp the details of the study visits and have time to formulate questions to ask the coordinator during the visit. 
Dr. Wharton has employed this procedure in her ongoing and prior trials and her participants have responded 
very favorably to the additional time to peruse the study specifics.
The actual consent process is conducted as a face-to-face interview with the participant during their screening 
visit. No study procedures are initiated until the consent process is complete. After all questions have been 
answered by a study team member, the participant signs the consent form and they are given a copy for their 
records.
L.2 Potential Benefit to Subjects:
There are no direct benefits from participation in this research study. 
L.3 Importance of the knowledge to be gained:
The information gathered in this study may be of benefit to persons with AD in the future. The scientific data 
gathered in this study may possibly provide a better understanding of the brain regions that are affected in AD, 
which may consequently lead to methods for earlier detection and treatment monitoring. Furthermore, scientific 
data from this study may improve prediction of incident AD. Currently there is no cure or effective treatment for 
AD, though several promising drugs are under investigation. As better treatments become available, it will be 
important to identify candidates for treatment as early as possible, and to develop methods to monitor 
treatment effects on the brain. Methods for examining the brain using MRI combined with CSF biomarkers may 
greatly facilitate detection and observation of preclinical AD.
L.4. Compensation
Participants will be compensated a total of $150 for their participation. $75 will be given at the conclusion of the 
baseline visit and the remaining $75 after the conclusion of the Month 8 visit. Compensation will be given in the 
form of gift cards. 
5. 5. Analyses and Power Calculations: John Hanfelt, PhD (Key Person), ADRC Data Core Co-Leader will 
oversee data analyses for the proposed trial. We will conduct Wilcoxon-Mann-Whitney tests to assess whether 
the change in the level of each CSF biomarker (month 8 vs baseline) differs between the treated group and 
placebo group. Tests will be conducted separately for each dose group (20mg and 40mg) but we will also 
consider testing for a dose-response by conducting Jonckheere-Terpstra trend tests. P-values < 0.05 will be 
regarded as significant. We will consider linear regression analysis (outcome is 8-month change in a 
biomarker) to adjust for demographic or clinical confounders. Power calculations for ACE, CBF, and Aβ 
comparisons are based on data from our previous trials in similar populations. With 20 participants per group, 
will have 99% power to detect change in ACE levels and 80% power to detect differences in CSF Aβ and CBF 
between the treated groups and placebo (based on 2-sided tests and Type I error rate α =0.05). 
5. 6. Relationship to Future Grants: Data from the proposed trial will be used in conjunction with Dr. 
Wharton’s prior studies for POC regarding CNS penetration, dose effects, and data for power calculations for 
an NIA R01 Phase IV application to be submitted in 2018, examining brain RAS function, Aβ and RAS acting 
medications longitudinally, in normotensive and hypertensive African Americans and Caucasians at-risk for 
AD. 


19
Data Safety Monitoring Board Committee (DSMB): 
Our DSMB consists of the following members.
Donald Bliwise, PhD
Professor of Neurology (primary appointment)
Professor of Psychiatry and Behavioral Sciences (secondary appointment)
Emory University School of Medicine
Sleep Center
(404) 712-7241
dbliwis@emory.edu
 
Chadwick Hales, MD, PhD
Assistant Professor of Neurology
Emory University School of Medicine
Alzheimer’s Disease Research Center
cmhales@emory.edu
Michael Kutner, PhD
Professor, Department of Biostatistics and Bioinformatics
Rollins School of Public Health
Emory University
(404) 712-9708
mkutner@emory.edu

ICF_000.pdf: 
Informed Consent Form 
 
Health Evaluation in African Americans using RAS 
Therapy: 
 
The HEART Project 
 
 
 
IRB Approval Date: January 13, 2021 
 
 
 
NCT Number: NCT02471833 
 
 


Page 1 of 11
Version Date 4/22/2020 
You Are Being Asked to Be in a Research Study
What Is a Research Study?
The main purpose of research studies is to gain knowledge. This knowledge may be used to help others. Research studies are not 
intended to benefit you directly, though some might.  
Do I Have to Do This?
No. Being in this study is entirely your choice.  If you decide to join this study, you can change your mind later on and withdraw from 
the research study. 
Taking part in a study is separate from medical care. The decision to join or not join the research study will not affect your status as a 
patient.  
What Is This Document?
This form is an informed consent document. It will describe the study risks, procedures, and any costs to you.
This form is also a HIPAA Authorization document. It will describe how your health information will be used and by whom.
Signing this form indicates you are willing to take part in the study and allow your health information to be used.
What Should I Do Next?
1.
Read this form, or have it read to you.
2.
Make sure the study doctor or study staff explains the study to you.
3.
Ask questions (e.g., time commitment, unfamiliar words, specific procedures, etc.) 
4.
If there will be medical treatment, know which parts are research and which are standard care.
5.
Take time to consider this, and talk about it with your family and friends.
IRB00080192
IRB Approved
1/13/2021


Page 2 of 11
Version Date 4/22/2020 
Emory University
Consent to be a Research Subject / HIPAA Authorization 
Title: Healthy Evaluation of African American using RAS Therapy
Principal Investigator: Dr. Whitney Wharton, PhD., Associate Professor
Emory School of Nursing Department of Academic Advancement; Emory School of Medicine Department of Neurology
Sponsor: Alzheimer’s Association; National Institute of Health
Sites: Wesley Woods Health Center, Executive Park
Introduction
You are being asked to be in a medical research study. This form is designed to tell you everything you need to think about before 
you decide if you want to be a part of the study.  It is entirely your choice.  If you decide to take part, you can change your mind 
later on and withdraw from the research study. The decision to join or not join the research study will not cause you to lose any 
medical benefits.  If you are a member of the Alzheimer’s disease Research Center (ADRC), your participation in that research will 
also not be affected if you decide not to participate in this study. If you decide not to participate, the health care provided to you by 
Emory University and its affiliates will not be affected in any way. 
Before making your decision:
•
Please carefully read this form or have it read to you
•
Please listen to the study doctor or study staff explain the study to you 
•
Please ask questions about anything that is not clear
You can take a copy of this consent form, to keep. Feel free to take your time thinking about whether you would like to participate. 
You may wish to discuss your decision with family or friends. Do not sign this consent form unless you have had a chance to ask 
questions and get answers that make sense to you.  By signing this form you will not give up any legal rights.
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by U.S. law. This Web site will not 
include information that can identify you. At most the Web site will include a summary of the results. You may search this Web site 
at any time.
The purpose of this study: This trial is going to see if an FDA approved blood pressure medication may also have beneficial effects 
on Alzheimer's disease (AD) prevention in African Americans. 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. This trial will evaluate if 
Telmisartan is able to influence the RAS in the brain and produce favorable effects on brain blood flow and enzymes that cause the 
brain plaques in Alzheimer’s disease.
You have been invited to participate because you are 30 years or older and have a family history of Alzheimer’s. We will test your 
blood pressure, blood, and ask questions about your health and thinking abilities at our first meeting to confirm that you are eligible 
to take part in the study. 
About 66 individuals will take part in this research study at Emory University
Study Design: If you decide to take part in this study you will sign this informed consent form and your participation will last 8 
months. Your participation in the study involves coming to the study sites at Emory University Executive Park (Buildings 6 and 12) 
and Wesley Woods CSI for interviews, brain scans, a vascular ultrasound (PWV), a collection of cerebral spinal fluid and blood tests. 
You will receive all blood pressure medications during your involvement in this study. The duration of this study is 8 months. You will 
be asked to visit the study site approximately 5-8 times during the months of your participation. The table below shows the outline 
IRB00080192
IRB Approved
1/13/2021


Page 3 of 11
Version Date 4/22/2020 
of the HEART PROJECT procedures 
by visits (screening, baseline, safety 
visits, month 4 and month 8). The 
procedures and timeline are 
described below. 
Screening visit (approximately 2 
hours): During this visit, we will sign 
the informed consent, explain the 
study details, ask you questions 
about your medical conditions and 
medications, check your blood 
pressure, take a blood sample 
(about 1 teaspoon), and questions 
about your health and thinking 
abilities. Please note that a large 
proportion of potential participants 
will not be eligible based on the 
results of these tests. If your systolic 
blood pressure reading (the upper 
number) must be equal or greater 
than 110 mmHg but less or equal to 
170 mmHg (average of two bpm 
readings), if your systolic (upper number) is not within this range then,  for your safety, you will not be enrolled in the study. We will 
also test your kidney function and potassium levels in your blood and your complete blood count (CBC). If these levels are not in a 
normal range, you will not be enrolled in the study.
If you do not qualify then we will not proceed with your study participation and you will not undergo any of the procedures in the 
reminder of this document. 
We will call you with the results of the blood tests and let you know your eligibility to participate. 
If you are eligible based on the results of your screening visit and agree to participate, we will enroll you in the study. At this time, 
we will give you a letter to inform your primary care doctor that you are interested in participating in a research study and that we 
will be placing you on the study blood pressure medication (or placebo).  We will provide you with a supply of the study drug 
(Telmisartan 20 mg, Telmisartan 40 mg or placebo) and ask you to start the study medication starting at your Baseline visit, after you 
perform the baseline study procedures. This medication will be taken before bedtime. Any questions about the medication can be 
answered by the study physician or nurse.
As a required intervention and to achieve blood pressure control to below 140/90 mm Hg, other non-RAS acting medications (e.g. 
HCTZ, amlodipine, and metoprolol) may be commonly prescribed by your primary care doctor 
Baseline Visit (3 and a half to 5 hours): This visit can happen all in one day or take place over two days, depending on your schedule. 
During this phase, blood pressure measurements, detailed neuropsychological assessments, physical exam, brain MRI, lumbar 
puncture and vascular ultrasound will be completed. Blood samples will also be collected for inflammatory and endothelial markers. 
This blood sample will also be used for APOE genetic testing. This testing can reveal information about your risk for Alzheimer's 
disease. You will not be informed of these results through this study. You will also be asked to wear a blood pressure monitor for 24 
hours, which we will ask you to return the next day or at the second baseline visit, if everything is completed over two days. This 
procedure can be omitted, if you are unable to return the monitor. When you return the cuff or all mandatory procedures are 
completed, you will receive the first half of your gift card for participating ($75).
Once you have completed these tests, we will then randomly assign you (like flipping a coin) to receive Telmisartan 20 mg, 
Telmisartan 40mg or placebo. We will give you a 1 month supply of your assigned drug, a study physician or nurse will answer 
questions on you on how to take it, and ask you to come back in 2 weeks. The study will be double-blinded meaning that neither you 
IRB00080192
IRB Approved
1/13/2021


Page 4 of 11
Version Date 4/22/2020 
nor the principal investigator or study personnel will know which study drug you are taking. However, the study doctor will be aware 
of the study drug you are taking for safety reasons but will not disclose this information to you or the other members of the study 
team. 
Safety visits (approximately an hour): These visits will last about 30-60 minutes. The first safety visit occurs about 2 weeks after the 
date of randomization (first visit where you received your study medication). We will measure your blood pressure in the seated 
position during these visits and address any adverse events or changes to your non-study medications. A blood sample may be 
drawn (half to 1 teaspoon) to check your potassium level and kidney function (if needed). 
If your blood pressure is systolic (upper number) is lower than 90 mmHg then the study physician will advise you to immediately see 
your primary care physician. With your permission, we will also contact your physician. Blood pressure higher than 140/90 or lower 
than 90/60 after randomization will not exclude you from the study. 
If your blood pressure and blood levels are all within normal limits, you will return for the Month 4 visit. If your limits are not in the 
normal range, you may be asked to return for additional safety visits or asked to visit your Primary Care Physician. 
Month 4 (approximately 1 to 2 hours): You will be asked to bring your study medication bottles to this visit and the study team will 
perform a pill count on any remaining study medication for medications compliance purposes. We will then give you new 
medication bottles which will last you for the duration of the study. We will measure your blood pressure in the seated position and 
address any adverse events or changes to your non-study medications. We may also collect height and weight. A blood sample will 
be drawn for research purposes. Dispense of your next supply of study medications will be given or mailed to you.
Month 8 (approximately 3 to 4 hours): This visit is exactly like your baseline visit and is done in one day with the option to divide 
into 2 days. You will be asked to return your study medication pill bottles. During this phase, blood pressure measurements, detailed 
neuropsychological assessments, physical exam, brain MRI, lumbar puncture and ultrasound will be completed. Blood samples will 
also be collected for inflammatory and endothelial markers. You will also be asked to wear a blood pressure monitor for 24 hours, 
which we will ask you to return the next day. This procedure can be omitted, if you are unable to return the monitor. As with the 
Baseline visit, you will receive your remaining gift of $75.00 when you return the blood pressure monitor or all mandatory 
procedures are completed.
Study Procedures:
MRI Scan: The MRI scanner will be used to collect detailed pictures of your brain while you are lying still on the scanner bed.  You 
are asked to fast (not eat) for 8 hours prior to this procedure.  Two monitors will be comfortably secured to you to measure your 
pulse and respiration rates during the scan.  During the scans it is essential for you to remain as still as possible to avoid any blurring 
of the images. Your head will be held in place by foam padding to help you keep still during the scan.  The procedure takes 
approximately 1 hour. We will situate you as comfortably as possible and then run several scans that take 2-10 minutes each. In 
between scans, you will be able to communicate to the scan operator through an intercom. The MRI will be performed at the 
Wesley Woods Health Center.  Before your scan, you will be asked a series of medical history questions to make sure you are safe to 
go into the scanner.  This type of brain scan is not designed to detect problems of the brain. A radiologist will not be reading the 
scan. However, it is still possible that we will see something on your scan that is potentially abnormal, but may be nothing. If this 
happens, we will discuss it with you. This may cause you to seek further medical treatment and incur costs associated with that.
Risks of MRI: Some people should not participate in MRI studies. These include persons with shrapnel or certain metallic implants, 
such as prostheses, or aneurysm clips, or persons with electronic implants, such as cardiac pacemakers or implanted hearing 
devices. The magnetic field generated by the MRI machine can cause a displacement or malfunctioning of these devices. There are 
no other known risks to body tissues associated with the magnetic field strength used in this study. Some participants report some 
anxiety or claustrophobia in the MRI scanner since the head must be placed fully inside the scanner tube. If anxiety or 
claustrophobia occurs, please let us know and we will stop the scan and bring you out of the scanner. In addition, fatigue and 
physical discomfort are possible. The MRI scanner makes a great deal of noise when taking images. To minimize the level of noise, 
you will be fitted with disposable earplugs or headphones to wear during the procedure. These may be a bit uncomfortable to wear, 
and will not eliminate all sound, so that communication with you is still possible.
IRB00080192
IRB Approved
1/13/2021


Page 5 of 11
Version Date 4/22/2020 
Cognitive Testing:  At baseline and 8 month study visits, you will undergo about 60 minutes of cognitive testing. This will include 
computerized and paper and pencil tests that will look at areas of cognitive functioning such as verbal ability, spatial ability and 
memory. 
Questionnaires: You will be asked to complete medical and health related surveys. The surveys ask questions about your sleep 
habits and problems; about your medical history and medications; about your exercise habits; about your mood and mood changes; 
and about your diet and stress levels. The surveys are the same each time and take about an hour total to complete. You may 
complete these questionnaires prior to your visit via email.
During the course of this eight month study, you may be asked to complete additional questionnaires, some of which may be 
completed online. These questionnaires include but are not limited to – mood, stress, the quality of life of your family member with 
Alzheimer’s disease, nutrition, and exercise.
Risks of Cognitive Testing & Questionnaires: During tasks that involve memory, you may become bored, fatigued, or frustrated by 
their difficulty. There are no physical risks to these tests. Some of the questions you will be asked on the questionnaire are personal 
and may make you feel embarrassed. You may skip any questions you do not feel comfortable answering, but it is important for you 
to give your best effort.
Blood Sample: About five to six tablespoons of your blood will be drawn from a vein in your arm.  This should only take about 5 
minutes.
Risk of Blood Draw: We will collect a blood sample at all visits. Blood draws can cause mild pain in the arm and may cause bruising, 
infection, and occasional fainting.
Neurologic Exam:  A physician or nurse practitioner will do a neurological and physical exam prior to the lumbar puncture.    
Lumbar Puncture: A lumbar puncture is a procedure using a needle to remove spinal fluid from the lower back. For this fasting 
lumbar puncture, you will be asked to lie on your side with your knees drawn as close to the chest as possible or to sit with your 
arms and head resting on a table.  Your lower back will then be numbed with a drug called Lidocaine.  Lidocaine will help reduce any 
pain that may be caused by this procedure.  A thin needle (typically 1/48 of an inch wide, and 3.5 to 4 inches long) will be placed into 
the space that contains the spinal fluid, which is below where the spinal cord ends.  One and a half tablespoons of spinal fluid will be 
removed and the needle withdrawn. If you have your lumbar puncture for this study done at the same time as a lumbar puncture for 
another study, then we might draw up to 25 mLs (about 5 teaspoons of fluid) from your back. During either of the two study visit 
lumbar puncture procedures, if no spinal fluid is obtained on the first attempt, a second attempt will be made after numbing the 
area with Lidocaine.  If the sample of spinal fluid is not drawn, you will be offered the opportunity to attempt to repeat the 
procedure or you will not undergo another lumbar puncture and remain in the study. The lumbar puncture procedure will take 
approximately 30 minutes.  After the lumbar puncture is completed, you will lie on your back for about 20 minutes. 
Risks of Lumbar Puncture (LP): Approximately 22-25 milliliters (1 ½ Tbs) of spinal fluid may be taken during each LP and your body 
will make up for the loss. During the procedure, you may have temporary pain and discomfort in your back. The most common 
complication of spinal fluid collection is a headache. When done in most clinical settings, headache occurs in about 10 out of every 
100 people who have the procedure. On the other hand, the number of people who get headaches is less than 2 out of every 100 
people when a special needle is used. This special needle is used for spinal fluid collection in every lumbar puncture in this study. 
Drinking a lot of water before the spinal fluid collection may also help prevent headaches, and drinks with caffeine may help treat 
headaches from spinal fluid collections. If this headache persists it may require additional treatment with over the counter 
medications. This often relieves the headache immediately. Rarely a blood patch (injection of some of your blood into the lumbar 
puncture site to patch the spinal fluid leak) may be required. We will call you the day after your spinal fluid collection to see if you 
have any side effects. 
During the spinal fluid collection, about 13% of people feel brief sensitivity if the needle touches a nerve. Damage to the nerves that 
come off the spinal cord can rarely occur that may result in leg tingling. In 1 out of every 150,000 people, bleeding from a broken 
blood vessel can cause a pocket of blood that may affect the spinal cord or brain. If the procedure is performed at the improper 
IRB00080192
IRB Approved
1/13/2021


Page 6 of 11
Version Date 4/22/2020 
level, the needle may injure the spinal cord. A nurse practitioner or doctor does a physical exam and will speak with you before the 
spinal fluid collection to make sure you have no neurological conditions that would make spinal fluid collection unsafe.
Infection is a rare, but possible side effect. To minimize this risk, sterile gloves and equipment are used for the procedure and 
betadine is used to clean the skin at the lumbar puncture site.
Lidocaine:  Lidocaine is the drug used to numb the lower back before the collection of spinal fluid. There are rare cases of allergic 
reactions to lidocaine, such as redness and swelling of the skin. If you have had a previous reaction to lidocaine, please inform study 
personnel right away.
Pulse Wave Velocity (Vascular Ultrasound): This procedure is non- invasive and will be used to measure arterial stiffness. The 
procedure will require you to lie still on your back while a trained study team member administers the testing. This procedure will 
take approximately 30 minutes to an hour and is performed on baseline and month 8 study visits.   
Risks of Blood Vessel Function Tests: The brachial artery ultrasound is safe and only mildly uncomfortable due to tightness in the 
arm and/or leg when the cuff is inflated. We will use ultrasound to painlessly bounce sound beams off of your carotid artery to 
determine how much blood is flowing out of it. We will place a pencil-like sensor gently against the inside your neck and record a 
blood pressure signal from your pulse. This measure is also painless and is non-invasive.
Ambulatory Blood Pressure Monitoring: The ambulatory blood pressure monitoring device is non-invasive and only mildly 
uncomfortable due to tightness in the arm when the cuff is inflated. The monitor consists of a blood pressure cuff, like you have 
probably seen in the doctor’s office, which is connected to a small lightweight battery pack that can be worn on a belt or placed in 
your pocket. You will wear the cuff for 24 hours. The blood pressure cuff will inflate and take your blood pressure automatically 3 
times per hour while you are awake and 1 time per hour while you are asleep. You blood pressure information will automatically be 
stored in the monitor and this information will be used by the Principal Investigator and The HEART project team.  You can wear the 
blood pressure monitor home with you and do all of your normal activities, except that you should take it off to shower, bathe, or 
swim. The cuff inflates 3 times per hour while you are awake, and once an hour while you are asleep. You will be asked to fill out a 
diary of your activities during these 24 hours. The cuff is expected to be returned back to the study team at the second scheduled 
baseline visit or Safety Visit that will be scheduled within two weeks.
Risks of Blood Pressure Cuff:  The blood pressure monitoring device is non-invasive and the most common complaint is potential 
discomfort due to the blood pressure cuff inflating. If this occurs, you simply can take off the cuff.
Distribution of Medication: The medicine that you will take will be dispensed by the Emory pharmacy and delivered to the principal 
investigator or study team member.  The principal investigator or health care providers on the research team will provide the 
medicine to you.  If you have questions about the medicine, you should ask the principal investigator or study physician.  You may 
also call the pharmacy if you have questions about the medicine. The number for the pharmacy is included on your medicine 
package.
Study information and Samples: If you join this study, you will be donating your samples and study information.  You will not receive 
any compensation if your samples or information are used to make a new product. We will use and disclose your PHI for the conduct 
and oversight of the research study.  We will use and share your PHI to conduct normal business operations.  We may share your PHI 
with other people and places that help us conduct or carry out the study, such as laboratories, data management centers, data 
monitors, contract research organizations, Institutional Review Boards (IRBs) and other study sites. If you leave the study, we may 
use your PHI to determine your health, vital status or contact information.
Genetic Information: The Genetic Information Nondiscrimination Act (GINA) is a federal law that protects against genetic 
discrimination. This law makes it illegal for health insurance companies, group health plans, and most employers to discriminate 
against you based on you genetic information. This law does not protect you from being discriminated in life insurance, long-term 
care insurance, or from employers with less than 100 workers.
Risks and Discomfort: There may be side effects from the study drug or procedures that are not known at this time.  
The medications that will be given during the course of the study are Telmisartan and are approved by the Federal Drug 
Administration (FDA) and are commonly used by doctors to treat high blood pressure.
IRB Approved
1/13/2021


Page 7 of 11
Version Date 4/22/2020 
The possibility of side effects or an allergic reaction related to these medications is no different than if your doctor prescribed them.  
You will be carefully monitored throughout the study for any side effects related to these medications. The potential side effects are 
listed below. Please tell the study doctor or personnel if any of these symptoms are severe or do not go away. 
Telmisartan: headache, dizziness, asthenia, coughing, nausea, fatigue, weakness, edema, face edema, lower limb edema, 
angioneurotic edema, urticaria, hypersensitivity, sweating increased, erythema, chest pain, atrial fibrillation, congestive heart 
failure, myocardial infarction, blood pressure increased, hypertension aggravated, hypotension (including postural hypotension), 
hyperkalemia, syncope, dyspepsia, diarrhea, pain, urinary tract infection, erectile dysfunction, back pain, abdominal pain, muscle 
cramps (including leg cramps), myalgia, bradycardia, eosinophilia, thrombocytopenia, uric acid increased, abnormal hepatic 
function/liver disorder, renal impairment including acute renal failure, anemia, and increased CPK, anaphylactic reaction, tendon 
pain (including tendonitis, tenosynovitis), drug eruption (e.g. toxic skin eruption mostly reported as toxicoderma, rash, and urticaria), 
and angioedema (with fatal outcome).
Because each person reacts differently to medications, you may experience other side effects that are not listed above. Please tell 
the study doctors if you experience any discomfort or unusual symptoms after starting the medications provided by this study.
If you will be taking the study drug home, keep it out of the reach of children or anyone else who may not be able to read or 
understand the label.  Do not let anyone else take the study drug besides you.
Certificate of Confidentiality
There is a Certificate of Confidentiality from the National Institutes of Health for this Study.  The Certificate of 
Confidentiality helps us to keep others from learning that you participated in this study.  Emory will rely on the 
Certificate of Confidentiality to refuse to give out study information that identifies you.  For example, if Emory received a 
subpoena for study records, it would not give out information that identifies you.
The Certificate of Confidentiality does not stop you or someone else, like a member of your family, from giving out 
information about your participation in this study.  For example, if you let your insurance company know that you are in 
this study, and you agree to give the insurance company research information, then the investigator cannot use the 
Certificate to withhold this information. This means you and your family also need to protect your own privacy.
The Certificate does not stop Emory from making the following disclosures about you:
•
Giving state public health officials information about certain infectious diseases,
•
Giving law officials information about abuse of a child, elderly person or disabled person.
•
Giving out information to prevent harm to you or others.
•
Giving the study sponsor or funders information about the study, including information for an audit or 
evaluation.
Benefits: This study is not designed to benefit you directly. You may gain knowledge about your blood pressure, and thinking 
abilities. The study results will be used to help others in the future.
Compensation: Participants will be compensated a total of $150 for their participation, $75 will be given at the conclusion of the 
baseline visit and the remaining $75 after the conclusion of the Month 8 visit. Compensation will be given in the form of gift cards.  
Other options: This is not a treatment study. If you decide not to enter this study, there is care available to you outside of this 
research.  You can continue with your current care for your blood pressure.  If you have high blood pressure and you are not 
receiving blood pressure medications, your primary doctor may use other blood pressure medications to lower your blood pressure.  
The study team will discuss this with you.  
IRB00080192
IRB Approved
1/13/2021


Page 8 of 11
Version Date 4/22/2020 
Protection of private information collected in this study: Emory will keep any research records that it creates private to the extent 
that this is required to do so by law.  Whenever possible, a study number, rather than your name, will be used on study records.  
Your name and other identifying information will not appear when we present or publish the study results.
Any data or samples leaving Emory will be coded. Researchers at Emory might need to know your identity in order to match your 
information and samples with the information we collect from you in other studies that you participate in.
It is possible that the researchers will learn something new during the study about the risks of being in it.  If this happens, they will 
tell you about it. Then you can decide if you want to continue to be in this study or not.  You may be asked to sign a new consent 
form that includes the new information if you decide to stay in the study.
Medical Record: If you have been an Emory Healthcare patient before, then you already have an Emory Healthcare medical record.  
If you have never been an Emory Healthcare patient, you do not have one.   An Emory Healthcare medical record will be made for 
you if an Emory provider or facility gives you any services or procedures for this study.  
Copies of the consent form/HIPAA authorization that you sign will be put in any Emory Healthcare medical record you have now or 
any time during the study.  
Emory Healthcare may create study information about you that can help with your care.  For example, the results of study tests or 
procedures.  These study results will be put in your Emory Healthcare medical record. Anyone who has access to your medical 
records will be able to have access to all the study information placed there.  The confidentiality of the study information in your 
medical record will be protected by laws like the HIPAA privacy rule.  State and federal laws may not protect the research 
information from disclosure. 
The results of some study tests and procedures will be used only for research purposes and will not be placed in your medical 
record.  For this study, those items include: Ambulatory blood pressure readings and study visit blood pressure readings, cognitive 
testing results, ultrasound results, MRI imaging, research blood results, and CSF results.
Tests and procedures done at non-Emory places may not become part of your Emory medical record. Also, if you decide to be in this 
study, it is up to you to let your other health providers know, though we will provide a letter to the physician who is treating your 
high blood pressure so that she/he is aware of the study.
In Case of Injury: If you get ill or injured from being in the study, Emory will help you to get medical treatment. Emory and the 
sponsor have not, however, set aside any money to pay you or to pay for this medical treatment. The only exception is if it is proven 
that your injury or illness is directly caused by the negligence of an Emory or sponsor employee.  “Negligence” is the failure to follow 
a standard duty of care. 
If you become ill or injured from being in this study, your insurer will be billed for your treatment costs.  If you do not have 
insurance, or if your insurer does not pay, then you will have to pay these costs.  
If you believe you have become ill or injured from this research, you should contact the study staff at telephone number at 
. You should also let any health care provider who treats you know that you are in a research study. 
Costs: The study sponsor will pay for certain items or services that you may receive if you take part in this study.
You will have to pay for the items or services for which the study sponsor does not pay. The sponsor will not pay for your regular 
medical care. If you have insurance, Emory will submit claims to your insurance for items and services that the sponsor does not 
cover. Emory will send in only those claims for items and services that it reasonably believes your insurance will pay and that the 
sponsor has not paid.
The actual amount that you have to pay depends on whether or not you have health insurance and whether or not that insurance 
will pay for any research study costs. Generally, insurance companies will not pay for items and services that are required just for a 
research study. Some insurance companies will not pay for regular medical treatment or treatment for complications if you are in a 
IRB00080192
IRB Approved
1/13/2021


Page 9 of 11
Version Date 4/22/2020 
study. How much you will have to pay for any co-payments, deductibles or co-insurance depends on your plan. Emory and the 
sponsor will not pay for these costs.
It is a good idea to contact your insurance provider and tell them you want to be in this research study. Ask them what they will pay 
for and what they will not pay for. You can also ask the study team for help in figuring out what you will have to pay.
Withdrawal from the Study: You have the right to leave a study at any time without penalty. The researchers also have the right to 
stop your participation in this study without your consent for any reason, especially if they believe it is in your best interest or if you were 
to object to any future changes that may be made in the study plan.
Authorization to Use and Disclose Protected Health Information
The privacy of your health information is important to us.  We call your health information that identifies you, your “protected 
health information” or “PHI.”  To protect your PHI, we will follow federal and state privacy laws, including the Health Insurance 
Portability and Accountability Act and regulations (HIPAA).  We refer to all of these laws as the “Privacy Rules.”  Here we let you 
know how we will use and disclose your PHI for the study: 
PHI that Will be Used/Disclosed:  
The PHI that we will use or share for the main research study includes:
•
Medical information about you including your medical history and present/past medications.
•
Results of exams, procedures and tests you have before and during the study.
•
Laboratory test results.
Purposes for Which Your PHI Will be Used/Disclosed: We will use and share your PHI for the conduct and oversight of the research 
study.  We will use and share your PHI to provide you with study related treatment and for payment for such treatment.  We will 
also use and share your PHI to conduct normal business operations.  We may share your PHI with other people and places that help 
us conduct or carry out the study, such as laboratories, data management centers, data monitors, contract research organizations, 
Institutional Review Boards (IRBs) and other study sites. If you leave the study, we may use your PHI to determine your health, vital 
status or contact information. 
Use and Disclosure of Your Information That is Required by Law:  We will use and disclose your PHI when we are required to do so 
by law. This includes laws that require us to report child abuse or abuse of elderly or disabled adults. We will also comply with legal 
requests or orders that require us to disclose your PHI. These include subpoenas or court orders.  
Authorization to use PHI is required to participate: By signing this form, you give us permission to use and share your PHI as 
described in this document. You do not have to sign this form to authorize the use and disclosure of your PHI.  If you do not sign this 
form, then you may not participate in the research study or receive research-related treatment.  You may still receive non-research 
related treatment.  
People who will use/disclose your PHI: The following people and groups will use and disclose your PHI in connection with the 
research study:
•
The Principal Investigator and the research staff will use and disclose your PHI to conduct the study and give you study 
related treatment.
•
Emory may use and disclose your PHI to get payment for study related treatment and to run normal business operations. 
•
The Principal Investigator and research staff will share your PHI with other people and groups to help conduct the study or 
to provide oversight for the study.
•
The Alzheimer’s Association is the Sponsor of the study.  The Sponsor may use and disclose your PHI to make sure the 
research is done correctly and to collect and analyze the results of the research.  The Sponsor may disclose your PHI to 
other people and groups like study monitors to help conduct the study or to provide oversight for the study.  
•
The following people and groups will use your PHI to make sure the research is done correctly and safely:
IRB00080192
IRB Approved
1/13/2021


Page 10 of 11
Version Date 4/22/2020 
o
Emory offices that are part of the Human Research Participant Protection Program and those that are involved in 
study administration and billing.  These include the Emory IRB, the Emory Research and Healthcare Compliance 
Offices, and the Emory Office for Clinical Research. 
o
Public health agencies.
o
Research monitors and reviewer.
o
Accreditation agencies.
o
The Data Safety and Monitoring Board for this study.
o
Government agencies: U.S. Food and Drug Administration (FDA) and Office of Human Research Protections.
As part of this study, we will collect information about your health and your individual genes. 
This information will be sent to a National Institutes of Health (NIH)-designated data repository that includes all kinds of genomic 
data from studies funded by the NIH. 
The aim of collecting this information is to look for genetic connections that:
•
may increase the likelihood of getting a certain disease (such as asthma, cancer, diabetes, heart disease or mental illness) 
or a condition (such as high blood pressure or obesity)
•
may affect the progress of a certain disease or condition
•
may affect treatments (medicines, etc.) that work for certain diseases in some people, but not in others. 
We will remove direct identifiers (such as your name) and instead code your information before sending it to the repository. NIH 
will never get this code or the identifiers we have removed. 
The repository is a controlled-access repository.  Controlled-access data is only available to researchers and companies who apply 
to the NIH. The NIH will review data requests for scientific merit and for methods to protect data and methods to ensure data will 
be used for the approved purpose.  We will not know what types of health-related research will be done with the data that are 
sent to the repository. 
Expiration of Your Authorization
There is no expiration of your authorization
Revoking Your Authorization
If you sign this form, at any time later you may revoke (take back) your permission to use your information.  If you want to do this, 
you must the study PI at:
Whitney Wharton, PhD
Associate Professor
Emory University
Nell Hodgson School of Nursing
 
At that point, the researchers would not collect any more of your PHI.  But they may use or disclose the information you already 
gave them so they can follow the law, protect your safety, or make sure that the study was done properly and the data is correct.  If 
you revoke your authorization you will not be able to stay in the study. 
Other Items You Should Know about Your Privacy
Not all people and entities are covered by the Privacy Rules.  HIPAA only applies to health care providers, health care payers, and 
health care clearinghouses.  If we disclose your information to people who are not covered by the Privacy Rules, including HIPAA, 
then your information won’t be protected by the Privacy Rules.  People who do not have to follow the Privacy rules can use or 
disclose your information with others without your permission if they are allowed to do so by the laws that cover them.
To maintain the integrity of this research study, you generally will not have access to your PHI related to this research until the study 
is complete.  When the study ends, and at your request, you generally will have access to your PHI that we maintain in a designated 
record set.  A designated record set is data that includes medical information or billing records that your health care providers use to 
make decisions about you. If it is necessary for your health care, your health information will be provided to your doctor. 
IRB00080192
IRB Approved
1/13/2021


Page 11 of 11
Version Date 4/22/2020 
We may remove identifying information from your PHI.  Once we do this, the remaining information will not be subject to the 
Privacy Rules.  Information without identifiers may be used or disclosed with other people or organizations for purposes besides this 
study.  
IRB00080192
IRB Approved
1/13/2021


Page 12 of 11
Version Date 4/22/2020 
Contact Information
Contact the study PI at 
•
if you have any questions about this study or your part in it,  
•
if you feel you have had a research-related injury or a bad reaction to the study drug, or
•
if you have questions, concerns or complaints about the research
Contact the Emory Institutional Review Board at 404-712-0720 or 877-503-9797 or irb@emory.edu:
•
if you have questions about your rights as a research participant.
•
if you have questions, concerns or complaints about the research.
•
You may also let the IRB know about your experience as a research participant through our Research Participant Survey at 
http://www.surveymonkey.com/s/6ZDMW75.
Consent and Authorization
Please print your name and sign below if you agree to be in this study. By signing this consent and authorization form, you will not give 
up any of your legal rights. We will give you a copy of the signed consent to keep.
Name of Subject 
Signature of Subject 
Date              Time
________________________________________________________________
Name of Person Conducting Informed Consent Discussion
Signature of Person Conducting Informed Consent Discussion
Date              Time
IRB00080192
IRB Approved
1/13/2021