Clinical trial NCT02087865
Conditions: Genetic Risk for Alzheimer's Disease
Sponsor: The Cleveland Clinic
Start date: 2014-05-01; Completion date: 2021-12-20
Enrollment: 89 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study examines the sensitivity of functional MRI to detect brain changes caused by donepezil HCL (a cholinesterase inhibitor) in healthy older adults at genetic risk for Alzheimer's Disease.

Detailed description:
This 24-week study will examine the sensitivity of functional MRI to detect brain changes caused by donepezil HCL (a cholinesterase inhibitor) in healthy older adults at genetic risk for Alzheimer's Disease. Participants with a family history of Alzheimer's Disease will be eligible for this study. Participants without a family history of AD will also be enrolled to serve as a control group.

Arms: arm 1: Participants will receive 5mg of donepezil HCL for 4 weeks and then 10mg of donepezil HCL for 20 weeks. arm 2: Participants will receive placebo for 24 weeks. arm 3: Participants without a family history of AD will undergo the study evaluations but will not receive any study drug
Interventions: intervention 1: donepezil HCL intervention 2: Placebo
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_SAP_000.pdf: 
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Effects of Donepezil HCL on Task-Activated fMRI Brain Activation in  
Healthy Older Adults at Genetic Risk for Alzheimer’s Disease 
 
Principal Investigator: Stephen M. Rao, Ph.D. 
Funded by the National Institute on Aging (R01 AG022304) 
 
Introduction   
 
The neuropathological changes associated with Alzheimer’s disease (AD) are thought to begin decades 
prior to the advent of symptoms.  By the time AD is diagnosed, patients have experienced widespread 
cognitive impairment and extensive brain atrophy.  Interventions administered at this stage may be too 
late to alter the disease trajectory.  This recognition has prompted investigators in the field to consider 
prevention trials involving cognitively intact individuals at genetic risk for AD.  The first wave of such 
prevention trials will focus on persons with the autosomal-dominant mutation variant of AD, since it is 
possible to determine with certainty that the participant will develop AD.  Should these prevention trials 
identify an agent that effectively alters the disease course during the preclinical phase, the next step will 
be to enroll cognitively intact elders at risk for the more common, sporadic form of AD. 
 
 
Prior to conducting a prevention trial in sporadic AD, it is essential to validate biomarkers for purposes of 
accurately identifying persons at risk for AD during the preclinical phase and for monitoring treatment 
response since such individuals are by definition asymptomatic. Several candidate biochemical, 
anatomical, and functional biomarkers have shown promise, but vary in their ease of administration, 
availability, safety, accuracy, reproducibility, and invasiveness.  Among these candidate biomarkers, task-
activated functional magnetic resonance imaging (fMRI) is a promising approach that is noninvasive, 
carries little risk, and offers a high potential for identifying persons who may eventually develop AD.  
Our fMRI research program has examined brain circuits involved in semantic memory using a famous 
name recognition test.  We have demonstrated that the presence of the apolipoprotein-E (APOE) ε4 allele 
and a family history of dementia are associated with increased activation in several key AD-related brain 
regions (e.g., hippocampus, posterior cingulate, temporoparietal junction), suggesting its possible role as a 
marker for disease risk and progression during the preclinical stage (Seidenberg et al., 2009). This 
increased activation is believed to serve as a compensatory brain response during the prodromal period.  
We have shown that genetically at risk elders who do not demonstrate hyperactivation at study entry 
develop cognitive dysfunction within 18 months of the fMRI scan (Woodard et al., 2010).  We have also 
demonstrated that genetically at-risk elders who exercise regularly demonstrate hyperactivation, where 
sedentary at-risk elders do not (Smith et al., 2011).  We therefore propose to examine the value of task-
activated fMRI in monitoring drug intervention effectiveness in persons at genetic risk for AD.   
 
Clinical studies suggest that cholinesterase inhibitors (ChEIs), such as donepezil hydrochloride (HCL), 
exert a cognitive benefit with chronic use among MCI and AD patients.  Some studies also demonstrate a 
slight treatment benefit for persons who are APOE ε4 carriers.  We propose to conduct a 24-week, 
randomized, double-blind, placebo-controlled, parallel group study of donepezil HCL (Aricept®) in 60 
elders who have both AD risk factors, a family history of AD and the presence of one or both APOE ε4 
alleles. As noted above, our preliminary analyses indicate that at-risk healthy elders exhibit increased 
fMRI activation on a semantic memory activation task relative to not at-risk healthy elders and that 
increased activation is protective against future declines on neuropsychological testing in at-risk elders.  
For this project, we will extend our preliminary data by using task-activated fMRI as the primary 
biomarker for assessing treatment efficacy in cognitively intact elders at risk for AD; neuropsychological 
testing and brain morphometry will serve as secondary endpoints.  We hypothesize that changes in fMRI 
magnitude will demonstrate greater sensitivity to cholinergic modulation than changes on 
neuropsychological testing. Based on our preliminary longitudinal fMRI data, we also predict that at-risk 


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elders taking donepezil HCL will maintain or enhance the level of activation in response to a semantic 
memory activation task; in contrast, at-risk elders taking placebo will experience a decline in their brain 
activation, indicating a reduction in brain reserve and increased risk for cognitive dysfunction.   
 
For this imaging biomarker validation study, it will also be necessary to include a group of elders who are 
at low genetic risk for developing AD (no family history and non-carrier of APOE ε4 allele).  This group 
will undergo fMRI scanning and neuropsychological testing at entry and at 24 weeks, but will not receive 
medication or placebo.  The purpose of the low risk group is to serve as a reference for interpreting the 
fMRI brain activation response.  We predict that both the drug and placebo at risk elder groups will 
display greater activation than the low risk group at baseline.  At 24 weeks, the disparity in brain 
activation between the low risk group and the high risk group taking donepezil HCL will remain stable or 
increase as compensatory responses are bolstered, whereas the disparity between the low risk group and 
the high risk group taking placebo will decrease as the compensatory response diminishes.   
 
Sample 
Ninety cognitively intact, healthy older adults (60 with and 30 without AD genetic risk factors) will be 
recruited between the ages of 60 and 80 (inclusive). Candidate participants will undergo comprehensive 
screening, including review of medical records, standardized telephone screening, and background history 
questionnaires.  The 60 High Risk participants must have a family history of dementia and have one or 
both APOE ε4 alleles; the 30 Low Risk participants will not have a family history of dementia and not 
possess an ε4 allele.  The Low Risk group will be demographically matched to the High Risk group. 
 
To be included in the study, all participants will have  
 Normal general cognitive function 
 MMSE score  ≥ 27 
 Logical Memory II subscale Delayed Paragraph A score of ≥7 
 Geriatric Depression Score < 6, 
 Hachinski Score ≤ 4 
 Intact activities of daily living 
 Visual and auditory acuity adequate for neuropsychological testing 
 Women must be two years post-menopausal or surgically sterile 
 Stable prescription medication dosages one month prior to testing and participant will agree not to 
change their medication regimen unless cleared by the study physician 
 
Prospective participants will be excluded if they have a history or evidence of: 1) neurological 
illnesses/conditions, such as motor or vocal tics (including a diagnosis of Tourette’s syndrome), head 
trauma with significant loss of consciousness (>30 min), cerebral ischemia, vascular headache, carotid 
artery disease, cerebral palsy, epilepsy, brain tumor, chronic meningitis, multiple sclerosis, pernicious 
anemia, normal-pressure hydrocephalus, HIV infection, Mild Cognitive Impairment, Alzheimer’s disease, 
Parkinson’s disease, and Huntington's disease; 2) medical illnesses/conditions that may affect brain 
function, such as untreated hypertension (blood pressure > 140/100 mm Hg), insulin-dependent diabetes 
mellitus, endocrine disorders, renal disease, glaucoma, and chronic obstructive pulmonary disease; 3) 
current Axis I psychiatric disturbance meeting DSM-IV Axis I criteria; 4) severe depressive symptoms as 
indicated by Geriatric Depression Scale (short form) score greater than or equal to 6;  5) substance abuse 
or dependence meeting DSM-IV Axis I criteria; 6) exclusion criteria specific to MR scanning: pregnancy, 
weight inappropriate for height, ferrous objects within the body, low visual acuity, and a history of 
claustrophobia; 7) use of medications that may affect the hemodynamic response in the scanner; 8) prior 
history of use of any cholinesterase inhibitor; 9) hypersensitivity to donepezil HCL or other carbamate 
derivatives or other components of the formulation; 10) currently taking drugs or over-the-counter 


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preparations that increase cholinergic activity (e.g., sage); 11) body weight below  45 kg; 12) planning to 
undergo surgery requiring general anesthesia during the treatment period; 13) any unstable or severe 
cardiovascular disease or asthmatic condition; 14) history of transient ischemic attack or a score of more 
than 4 on the modified Hachinski ischemic scale 15) Screening laboratory testing indicating any of the 
following; total bilirubin, alanine aminotransferase (ALT) or aspartate aminotransferase (AST) greater 
than two times the upper limit of normal; Renal impairment with a serum creatinine (Cr) greater than 1.2 
times the upper limit of normal; Hematocrit (Hct) less than 37% for males and less than 32% for females, 
absolute neutrophil cell count of less than or equal to 1,500/L, or platelet cell count of less than 
120,000/L. We will also exclude participants whose high-resolution anatomic MR scans reveal the 
presence of a structural abnormality. 
 
Research Procedures  
Telephone Prescreening 
Potential participants will be prescreened over the phone using the Phone Screen questionnaire. If 
determined to be eligible based on this prescreening, participants will then be scheduled for an in person 
screening visit. If a prescreened participant enrolls in the research study, the Phone Screen questionnaire 
will become part of the research record. 
 
Initial Screening Visit (Visit #1) 
At the screening visit demographic information will be collected including age, race, years of education, 
and occupation.  The participant’s medical history as well as family history of dementia will also be 
collected. Participants will undergo a neuropsychological battery including the Mini-Mental State Exam, 
WMS-R Logical Memory, and Geriatric Depression Scale – short form. 
 
All participants will undergo a blood draw for APOE genotyping.  
 
APOE Genotyping 
All potential participants will undergo APOE genotyping. If a participant chooses to not undergo APOE 
genotyping he/she will not be enrolled in the study. If a participant is considered to be ineligible at the 
screening visit (e.g. low cognitive scores, medical exclusion) his/her blood sample will not be sent for 
genotyping. 
 
A blood sample will be collected for the APOE genotyping at the first screening visit. The APOE genotyping 
will be performed by the Cleveland Clinic Genomic Medicine Biorepository lab (GMB) under the direction of 
Lynn Bekris. However, if participants are also enrolled in the CBH Biobank (14-604) the GMB 
confirmatory genotyping will be conducted as part of this study and the additional sample will not need to 
be drawn. If a discrepancy is found between the results, both laboratories will be asked to repeat 
genotyping. 
The results of the APOE genotyping will be stored in the research record and will not be placed in the 
medical record. If a participant chooses not to receive information on his or her genetic status, 
participation in the study will be discontinued.  
 
Genetic Counseling 
All participants will be required to undergo a genetic counseling session to receive the results of the 
genetic testing. Test results will not be released to participants over the phone or to a participant’s 
physician. The results of this genetic testing will not be placed in the medical record. During the genetic 
counseling session, participants will receive a letter stating if they are a carrier of the APOE ε4 allele. The 
decision to share this information with a physician outside of the study is left to the participant. This 
genetic counseling will occur at the beginning of the second screening visit. 
 


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Laboratory Testing 
If a high-risk participant is determined to be eligible based on the screening visit and the genetic testing, 
blood will be drawn for Comprehensive Metabolic Panel (CMP) and Complete Blood Count (CBC) 
laboratory testing. The CMP and CBC will be sent to the Cleveland Clinic Main Laboratory. This blood 
draw will occur at the second screening visit. Participants do not need to fast for this testing. If the CMP 
or CBC were recently completed within a month for a clinical evaluation or another research 
project, the results from that testing will be used to confirm eligibility 
 
iPad Application Testing 
All participants will be required to complete an iPad application test which will include the Processing 
Speed Test. This testing will occur at the second screening visit.  
 
Eligibility Confirmatory Cognitive Testing  
Participants with borderline MMSE and WMS-R Logical Memory scores at screening visit #1 will 
receive the Repeatable Battery of the Assessment of Neuropsychological Status (RBANS) at screening 
visit #2 
 
Electrocardiogram (ECG) 
All high-risk participants will undergo a 12-lead ECG at the second screening visit which will be 
reviewed by the CCF cardiology department to assist the study clinician with determining eligibility. 
Heart rate will be examined after the participant has been on study drug for four weeks before increasing 
the dosage to 10mg. Heart rate observance will be used to confirm the absence of any cardiovascular side 
effect events, most commonly bradycardia. If a participant’s heart rate falls below 55bpm, above 110 bpm 
or experiences a 20 bpm difference from the initial ECG reading, the study clinician will be notified 
immediately to assess the patient before distribution of 10mg dosage.  
 
Comprehensive Cognitive Battery 
Participants in the study will undergo an extensive cognitive battery at the baseline and follow-up visits.  
 
This battery will include: 
 Symbol Digit Modalities Test 
 Rey Auditory and Verbal Learning Test 
 Brief Visuospatial Memory Test – Revised 
 Delis Kaplan Executive Function System Verbal Fluency,  Sorting, and Trail Making Tests 
 Wide Rang Achievement Test-4: Reading  
 Wechsler Adult Intelligence Test-IV: Digit Span, Coding, and Block Design  
 Judgment Of Line Orientation Test 
 Boston Naming Test  
 Processing Speed Test (iPad app) (screening visit #2 and follow-up) 
 Computerized Stroop, Sternberg, Stop Signal and Paced Finger Tapping tests. 
 Measurements of grip strength and finger tapping speed 
 
Self-report measures will include: 
 Lawton Activities of Daily Living 
 Center for Epidemiologic Studies Depression Scale 
 Geriatric Anxiety Scale 
 Emotion Regulation Questionnaire 
 Toronto Alexithmia Scale 
 IQ code 


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 Satisfaction with Life Scale 
 7-Day Physical Activity Scale 
 Stanford Brief Activity Scale 
 Prime Screen 
 SF-12 
 
 
Physical Examination 
A physical and neurological examination will be performed by a physician at the second screening visit to 
verify that the participant does not have any of the medical exclusions for this study.  
 
fMRI Scanning Session 
All participants will undergo a functional magnetic resonance imaging (fMRI) exam at the baseline and 
follow-up study visits. The MRI will be conducted in the Mellen Imaging Center in a 3.0 T Siemens Trio 
scanner. This exam will include high resolution anatomical imaging, task-activated fMRI, resting state 
fMRI, and diffusion tensor imaging (DTI). The Famous Name Recognition (FNR) task will be used for 
the task-activated fMRI. The entire imaging exam will last approximately one hour. A bite bar will be 
used to limit motion artifacts in the imaging data. The bite bar apparatus consists of a plastic platform that 
is placed over the head coil. Prior to placing the coil and platform over the participant’s head, a dental 
impression is taken using dental impression compound. The impression is mounted to a plastic plate that 
is then passed through the coil, placed into the participant’s mouth and bolted to the platform.  The 
process takes around 5 minutes to perform and does not compromise the participant’s safety within the 
scanner. There is a quick release mechanism that allows the bite bar to be removed in seconds in the event 
of emergency. The participant is asked to bite firmly on the bite bar during periods when the scanner is on 
and acquiring images. When the scanner is off, the participant is instructed to relax. Some participants 
will have a sensitive gag reflex that will prevent them from comfortably using this device. The bite bar 
will not be used in these participants. 
 
Dispensing of Study Drug (High Risk group only) 
The High Risk participants will be randomly assigned to either treatment or placebo groups, using a 
double-blind procedure under the supervision of the unblinded P.I.  At the end of Day 1, participants will 
receive a four-week supply of 5mg donepezil HCL capsules or identical placebo.  After the first four 
weeks (Week 4), participants will then receive a 4 week supply of 10 mg capsules, or identical placebo.  
Participants will be dispensed a 4 week supply of 10mg donepezil HCL capsules or identical placebo at 
the Week 8, 12, 16, and 20 visits. Participants will be instructed to take one capsule per day at the same 
time each day. 
 
Safety, side effect tolerability, and compliance will be assessed at each study visit. Participants will be 
encouraged to contact the Treating Physician if they have any questions or experience any adverse events. 
Participants unable to tolerate the higher dose due to side effects will be placed back on the 5mg dosage 
for the remainder of the study. Participants unable to tolerate the initial dose will be discontinued from the 
study and replaced. The study treating physician will monitor adverse events as well as drug tolerability. 
 
The study drug and placebo will be stored and dispensed by the Investigational Drug Service (IDS) 
through the CCF Pharmacy. The IDS will be responsible for the study randomization and will provide the 
randomization information to the unblinded P.I. and study treating physician.  
 
Donepezil HCL is approved by the FDA for clinical use in patients with AD. This drug is not approved 
for the treatment of preclinical AD. As such, donepezil HCL is considered an “off label” drug for the 
treatment of this at-risk population. An IND Exemption request has been submitted to the FDA. 


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Compensation 
Participants will receive $20 for the first screening visit and $10 for the genetic counseling session. 
Eligible High Risk participants will receive an additional $10 for completing the additional blood draw 
and ECG at the second screening visit.  $50 for the baseline visit, and $75 for the follow-up visit. High 
Risk participants will receive $20 for each of the five visits during the treatment period. Low Risk 
participants will receive a total of $155 for completing the study. High Risk participants will receive a 
total of $265 for completing the study. Stipends will be given as cash at the study visit. If cash is 
unavailable a check will be mailed to the address provided by the participant.  
 
7T Add-on Pilot Study 
The purpose of the 7T add-on study is to better understand the brain mechanisms underlying the unique 
protective effect of physical activity (PA) on cognitively intact older adults possessing an APOE e4 allele 
using state-of-the-art 7T MR imaging. We hypothesize that the beneficial effects of PA counteract the 
negative consequences of possessing an e4 allele in cognitively intact, healthy elders.  Specifically, we 
hypothesize that physically active carriers will demonstrate less atrophy, increased brain activation in 
memory regions, better functional and structural connectivity, and less white matter lesions than sedentary 
carriers; the effects of PA will be less pronounced in non-carriers For this add-on study, a subset of 20 
cognitively intact, healthy elders between the ages of 60 and 75 will participate.   Half will be e3/e4 
heterozygotes (carriers); the remaining half e3/e3 homozygotes (non-carriers).  PA levels will be derived 
from a validated self-report questionnaire (SBAS): half will have engaged in moderate PA (high PA) and 
half will be sedentary (low PA).  Thus there will be 4 groups (n=5 each): high PA carriers, low PA 
carriers, high PA non-carriers, and low PA non-carriers. Participants will undergo ultra-high spatial 
resolution anatomical imaging, susceptibility weighted imaging, diffusion tensor imaging [HARDI], and 
T2-weighted imaging [FLAIR]). 
 
Potential Risks and Participant Safety 
There are no known risks associated with magnetic resonance imaging.  
 
All dosages of donepezil HCL proposed for use in the study (including the titration procedure) are 
recommended by the manufacturer, approved by the FDA, and are commonly used in medical practice in 
the United States. The most common side effects (with the proportion of patients in the controlled clinical 
trial titrated to 10mg/day over a six week period who experienced the symptom in parentheses) include 
nausea (6%), diarrhea (9%), insomnia (6%), fatigue (3%), vomiting (5%), muscle cramps (3%), and 
anorexia/decreased appetite (3%). At present, the only known contraindication to the use of donepezil 
HCL is hypersensitivity to the drug or to piperidine derivatives. Prospective participants will be screened 
for pre-diagnosed contraindications and cautionary conditions for donepezil HCL treatment (see 
exclusions above). Weight will be monitored during treatment; participants whose weight drops below 
50kg will stop treatment and be replaced in the trial. Participants will also be advised to inform their 
physicians of their participation in this trial. If a safety concern is identified or a participant reports 
intolerable side effects, a safety visit will be scheduled with the study treating physician. The physician 
will determine if it is safe for the participant to continue in the study at the current dosage, if the dosage 
should be lowered back to 5mg, or if the participant should discontinue the study medication and be 
removed from the study. 
 
Possible risks also include: minor bruising or discomfort from the blood draw, the invasion of privacy 
from the review of medical records, and discomfort and fatigue associated with neuropsychological 
testing. Rest periods or breaks will be offered to the participants.  
 


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There is a possible risk of psychological harm (anxiety, depression) after learning the results of genetic 
testing. All participants will be required to undergo genetic counseling with Dr. Rao or one of the study 
physicians. All physicians involved in this study specialize in dementia and are qualified to provide 
genetic counseling for APOE status.   
 
Data Analysis 
Analysis of the data will be conducted by the study team under the direction of Dr. Rao. Residualized 
change scores will be computed for each of the three principal outcome measures (fMRI, 
neuropsychological testing, anatomical MRI). Groups (placebo vs. donepezil HCL) will be compared on 
each of these residualized change scores. It is expected that group differences will be greater for fMRI 
than for neuropsychological or anatomical MRI change scores. A hierarchical regression will then be used 
to investigate other potential predictors (e.g., AD family history) that may account for additional variance 
in treatment response beyond group membership. 
 
Imaging data analysis will be conducted by the study team at the Cleveland Clinic as well as Sally 
Durgerian at the Medical College of Wisconsin (MCW). Functional images will be generated and 
analyzed using the Analysis of Functional NeuroImages (AFNI) software. Both voxel-wise and ROI 
analyses will be applied to the analysis of the fMRI data.  
 
Power Analysis and Sample Size   
Calculations of the number of participants can be made from preliminary longitudinal fMRI data 
comparing High vs. Low Risk elders.  For the posterior cingulate, the mean change in the AUC (Famous 
minus Unfamiliar Names) from baseline to follow-up was -0.55 percent signal change for the High Risk 
group and +0.20 percent signal change for the Low Risk group (pooled SD = 0.86). Assuming power = 
0.80 and a two-tailed α = 0.05, a sample size of 22 is required.  Thus, assuming that the treated group 
performs similarly to the Low Risk group, we have enough power to discriminate treated (n=30) versus 
placebo (n=30) groups using fMRI as the primary outcome measure.   
 
Data Management 
All participants will be assigned a unique study-specific ID when enrolled. Data will be stored in a 
password protected database (REDCap) with access restricted to the P.I. and designated study staff. Paper 
study records will be stored in a locked file cabinet with access restricted to the P.I. and designated study 
staff. Imaging data will be stored on password protected servers behind the CCF firewall. A Data Use 
Agreement has been put in place to allow Ms. Durgerian at MCW access to this imaging data. 
 
Data shared with co-investigators at other institutions (Marquette University, Rosalind Franklin 
University, Medical College of Wisconsin, and Wayne State University) will be de-identified. No PHI 
will be shared with these collaborators without prior approval from the IRB.  
 
Adverse Events and Data Monitoring 
Dr. Jeffrey Cummings and Dr. Charles Bernick (non-study staff) will review study reports and will submit 
a data and safety monitoring report to the IRB every six months.   Dr. Rao, with the assistance of the 
treating physician, will be responsible for monitoring participant safety and adverse events as these events 
occur. Adverse events will be reported to the IRB as required. If deemed appropriate, serious adverse 
events will also be reported to the FDA and drug manufacturer. 
 
Consent 
A copy of the current informed consent form will be mailed to the participant in advance so that there is 
adequate time to review the document. After arrival at the first visit, the document will be reviewed and 
any participant questions will be answered. After detailed explanation of the study and its potential risks, 


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informed consent will be obtained by a member of the study team prior to the start of any study related 
activity. The informed consent process will be documented in the participant’s medical record. A copy of 
the signed informed consent document will be provided to the participant and the original document will 
be stored in the research record.  
 
 


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References 
 
Seidenberg, M., Guidotti, L., Nielson, K. A., Woodard, J. L., Durgerian, S., Antuono, P., et al. 
(2009). Semantic memory activation in individuals at risk for developing Alzheimer disease. Neurology, 
73, 612-620. 
Smith, J. C., Nielson, K. A., Woodard, J. L., Seidenberg, M., Durgerian, S., Antuono, P., et al. 
(2011). Interactive effects of physical activity and APOE-epsilon4 on BOLD semantic memory activation 
in healthy elders. Neuroimage, 54, 635-644. 
Woodard, J. L., Seidenberg, M., Nielson, K. A., Smith, J. C., Antuono, P., Durgerian, S., et al. 
(2010). Prediction of cognitive decline in healthy older adults using fMRI. J Alzheimers Dis, 21, 871-885.