Therapeutic Effects of Exercise in Adults With Amnestic Mild Cognitive Impairment (MCI)
Phase: NA
Conditions: Mild Cognitive Impairment, Cognitive Decline, Memory Impairment
Sponsor: Alzheimer's Disease Cooperative Study (ADCS)

 
 
 
 
 
 
 
 
 
HOWARD FELDMAN, MDCM, FRCP(C)  
PROFESSOR, DEPARTMENT OF NEUROSCIENCES 
DIRECTOR, ALZHEIMER’S DISEASE COOPERATIVE STUDY (ADCS) 
DEAN, ALZHEIMER’S DISEASE AND NEURODEGENERATIVE RESEARCH 
9500 Gilman Drive     La Jolla, California 92037-0949     TEL: (858) 246-1347   FAX: (858) 246-1414 
 
 
 
 
 
 
 
Protocol Title: 
Therapeutic Effects of Exercise in Adults with 
Amnestic Mild Cognitive Impairment 
 
Protocol Short Title: EXERT 
 
Protocol Number: ADC-041-EX 
 
NCT02814526 
 
Protocol Version 7.0 
18NOV2021 
 
 
 
 

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Version 7.0: 18NOV2021 
 
 
 
 
 
 
 
 
 
 
Protocol Title: 
 
Therapeutic Effects of Exercise in Adults with 
Amnestic Mild Cognitive Impairment 
 
 
Protocol Short Title: 
 
EXERT 
 
 
 
Protocol Number: 
 
ADC-041-EX 
 
Protocol Version 7.0 
18NOV2021 
 
 
 
 
Confidentiality Statement: 
The information in this document is privileged or confidential and may not be disclosed unless 
such disclosure is required by applicable laws and regulations.  It is the property of NIH and 
ADCS and should not be copied by or distributed to persons not involved in the study.  Persons 
to whom the information is disclosed must be informed that the information is privileged or 
confidential and may not be further disclosed by them. These restrictions on disclosure will 
apply equally to all future information supplied to you, which is indicated as privileged or 
confidential. Any unauthorized review, use, disclosure, copying or distribution is strictly 
prohibited. 
 

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SIGNATURE PAGE 
 
(SIGNATURES ON FILE AT ADCS) 
 
 
 
 
____________________________________ 
 
___________________ 
Laura Baker, PhD 
 
 
 
 
 
Date (MM/DD/YYYY) 
Project Director 
Professor of Internal Medicine - Geriatrics 
Wake Forest University School of Medicine 
 
 
 
 
____________________________________ 
 
___________________ 
Carl Cotman, PhD 
 
 
 
 
 
Date (MM/DD/YYYY) 
Project Director 
Professor of Neurology & Neurobiology 
University of California, Irvine 
 
 
 
 
____________________________________ 
 
___________________ 
Howard Feldman, MDCM, FRCP(C)  
 
 
Date (MM/DD/YYYY) 
Principal Investigator  
Alzheimer’s Disease Cooperative Study 
University of California, San Diego 
 
 
 
 
____________________________________ 
 
___________________ 
Gabriel Leger, MD 
 
 
 
 
 
Date (MM/DD/YYYY) 
Medical Monitor 
Alzheimer's Disease Cooperative Study 
University of California, San Diego 
 
 

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Sponsor: 
 
Laurie M. Ryan, PhD 
National Institute on Aging 
7201 Wisconsin Avenue, Suite 350 
Bethesda, MD 20892-9205 
ryanl@mail.nih.gov 
Tel: 301-496-9350  
 
Protocol Number: 
 
ADC-041-EX 
 
Project Directors: 
 
 
 
 
 
 
Laura Baker, PhD 
Wake Forest University Health Sciences 
Medical Center Boulevard 
Winston Salem, NC  27157-1207 
ldbaker@wakehealth.edu 
Tel: 336-713-8831 
 
Carl Cotman, PhD 
University of California - Irvine 
School of Medicine 
1113 Gillespie Building 
Irvine, CA  92697 
cwcotman@uci.edu 
Tel: 949-824-5847 
 
Principal Investigator, 
Coordination & Data  
Management Center 
Coordinating Center: 
 
Howard Feldman, MD 
ADCS Director 
Alzheimer’s Disease Cooperative Study  
University of California, San Diego 
9500 Gilman Drive 
La Jolla, CA 92093-0949 
howardfeldman@health.ucsd.edu 
Tel: (858) 246-1365 
 
Medical Emergencies: 
 
Gabriel Leger, MD 
Medical Monitor 
Alzheimer’s Disease Cooperative Study  
gleger@health.ucsd.edu 
Tel: (858) 246-2539 
 
 
Version:                     
  
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TABLE OF CONTENTS 
 
LIST OF ABBREVIATIONS ......................................................................................................... 9 
PROTOCOL SYNOPSIS ............................................................................................................ 11 
1.0 
INTRODUCTION ........................................................................................................... 13 
 Primary Aim .................................................................................................................... 13 
 Secondary Aims ............................................................................................................. 14 
2.0 
Preliminary Studies ..................................................................................................... 15 
 Summary of Clinical Findings ......................................................................................... 15 
 Safety and Compliance .................................................................................................. 16 
3.0 
Background and significance ..................................................................................... 16 
 Rationale for Aerobic Exercise as a Therapeutic Intervention in Mild Cognitive 
Impairment ..................................................................................................................... 16 
 Rationale for Aerobic Exercise Effects on AD Pathology in the Brain ............................ 17 
 Rationale Supporting Selection of Primary and Secondary Cognitive Outcomes .......... 17 
 Rationale for Length and Design of EXERT ................................................................... 18 
 Rationale for Population Selection ................................................................................. 18 
 Rationale for Selected Exercise Dose ............................................................................ 18 
 Rationale for Intervention Implementation in Community-Based Facilities .................... 18 
 Rationale for Magnetic Resonance Imaging .................................................................. 19 
 Rationale for Inclusion of Actigraphy .............................................................................. 19 
 Rationale for Collection of Biofluids ............................................................................... 20 
4.0 
Potential Risks and benefits associated with Intervention ..................................... 20 
 Potential Benefits ........................................................................................................... 20 
 Potential Risks ............................................................................................................... 20 
5.0 
Sample Size and Statistical Plan ................................................................................ 22 
 Randomization ............................................................................................................... 22 
 Power and Sample Size Determination ......................................................................... 22 
 Selection of Participants to be Used in Analysis ............................................................ 23 
 Efficacy Analysis ............................................................................................................ 23 
5.4.1 Analysis of Primary Outcome ....................................................................................... 23 
5.4.2 Analyses of Secondary Outcomes ............................................................................... 24 
 Safety Analysis ............................................................................................................... 25 
 Termination of the Trial .................................................................................................. 25 

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6.0 
Interventions and implementation ............................................................................. 25 
 Overview ........................................................................................................................ 25 
 Collaboration with the YMCA ......................................................................................... 26 
6.2.1 YMCA Study Team....................................................................................................... 26 
6.2.2 Interface Between the Clinic and the YMCA ................................................................ 27 
6.2.3 Adverse Event Reporting by YMCA Trainers ............................................................... 27 
 Implementation of the Interventions ............................................................................... 28 
6.3.1 Aerobic Training Intervention ....................................................................................... 30 
6.3.2 Stretching, Balance, and Range of Motion Intervention ............................................... 31 
 Adherence ...................................................................................................................... 31 
 Safety During Exercise ................................................................................................... 32 
 Temporary Intervention Discontinuation ........................................................................ 33 
 Reasons for Temporary Discontinuation ........................................................................ 33 
 Timing of Temporary Discontinuation Relative to Assessment of Primary and Secondary 
Outcomes ...................................................................................................................... 34 
 Blinding .......................................................................................................................... 34 
 Breaking the Blind .......................................................................................................... 35 
 Concomitant AD Medications ......................................................................................... 35 
7.0 
Study Population ......................................................................................................... 35 
 Inclusion Criteria ............................................................................................................ 35 
 Exclusion Criteria ........................................................................................................... 36 
 Recruitment and Retention Strategies ........................................................................... 38 
 Inclusion of Women and Minorities ................................................................................ 38 
8.0 
Study Timeline ............................................................................................................. 38 
9.0 
Description of study visits .......................................................................................... 38 
 Screening I (Visit 0) ........................................................................................................ 38 
 Screening II (Visit 1) ....................................................................................................... 39 
 Baseline (Visit 2) ............................................................................................................ 40 
 Month 6 (Visit 3) ............................................................................................................. 42 
 Month 12 (Visit 4) / or Early Termination ........................................................................ 43 
 Month 18 (Visit 5) ........................................................................................................... 45 
10.0 
Early intervention discontinuation ............................................................................. 46 
 Reasons for Early Discontinuation ................................................................................. 47 

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11.0 
Study-Specific Instruments ........................................................................................ 47 
 EXERT Telephone Assessment of Physical Activity ...................................................... 47 
 Cognitive Evaluations ..................................................................................................... 47 
11.2.1 Modified Mental State Examination .............................................................................. 47 
11.2.2 Logical Memory ............................................................................................................ 48 
11.2.3 Auditory Verbal Learning Test ...................................................................................... 48 
11.2.4 ADAS-Cog-Exec Global Composite ............................................................................. 48 
11.2.5 Executive Function Composite ..................................................................................... 49 
11.2.6 Episodic Memory Composite ........................................................................................ 51 
 Behavioral and Functional Evaluations .......................................................................... 51 
11.3.1 Clinical Dementia Rating Scale – Sum of Boxes (described above) ............................ 51 
11.3.2 ADCS-Activities of Daily Living-MCI ............................................................................. 51 
11.3.3 Behavior Rating Inventory of Executive Function – Adult Version ............................... 52 
11.3.4 Neuropsychiatric Inventory ........................................................................................... 52 
11.3.5 Cognitive Change Index ............................................................................................... 52 
11.3.6 Geriatric Depression Scale........................................................................................... 52 
11.3.7 SF-36 ........................................................................................................................... 52 
11.3.8 EQ5D ........................................................................................................................... 53 
11.3.9 Study Partner Self-Assessment Questionnaire ............................................................ 53 
 Modified Hachinski ......................................................................................................... 53 
 Research Satisfaction Survey ........................................................................................ 53 
 Treatment Blinding Questionnaire .................................................................................. 53 
 Heart Rate Monitor ......................................................................................................... 54 
 ActiGraph Link ................................................................................................................ 54 
 Instruments Administered by Trainers at the YMCA ...................................................... 54 
11.9.1 Rating of Perceived Exertion ........................................................................................ 54 
11.9.2 Adverse Event Checklist .............................................................................................. 54 
12.0 
Study–specific procedures ......................................................................................... 54 
 Safety Assessments ....................................................................................................... 54 
12.1.1 Physical and Neurological Examination ....................................................................... 55 
12.1.2 Electrocardiogram ........................................................................................................ 55 
12.1.3 Clinical Laboratory Evaluations .................................................................................... 55 

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 Biofluids .......................................................................................................................... 56 
12.2.1 Genetic Samples, Storage and Future Use .................................................................. 56 
12.2.2 Blood Collection for Biomarker Analyses and Banking ................................................ 56 
12.2.3 CSF Collection for Biomarker Analyses and Banking .................................................. 56 
 Magnetic Resonance Imaging ........................................................................................ 57 
12.3.1 Site Qualification .......................................................................................................... 57 
12.3.2 Data Acquisition ........................................................................................................... 57 
12.3.3 Data Management and Quality Control ........................................................................ 58 
 400 m Walk Test ............................................................................................................ 58 
 Actigraphy Recordings ................................................................................................... 59 
13.0 
Personnel Requirements ............................................................................................ 59 
 Clinic Personnel ............................................................................................................. 59 
 YMCA Study Team (see Section 6.2.1) ......................................................................... 60 
14.0 
Adverse Events ............................................................................................................ 61 
 Definition ........................................................................................................................ 61 
 Follow-Up of AEs ........................................................................................................... 62 
 Reporting of Unanticipated Problems, AEs, Protocol Deviations ................................... 62 
15.0 
Serious Adverse Events .............................................................................................. 62 
 Definition ........................................................................................................................ 62 
 Reporting SAEs .............................................................................................................. 62 
16.0 
Data and Safety Monitoring Board ............................................................................. 63 
17.0 
Recording and collection of data ............................................................................... 63 
 Case Report Form .......................................................................................................... 63 
 Audio / Visual Recording ................................................................................................ 64 
 Study Files and Patient Source Documents ................................................................... 64 
18.0 
Ethics and Regulatory Considerations ...................................................................... 64 
 Good Clinical Practice .................................................................................................... 64 
 Institutional Review Board .............................................................................................. 65 
 Informed Consent and HIPAA Compliance .................................................................... 65 
18.3.1 Participant Confidentiality | HIPAA ............................................................................... 66 
 Genetic Research and Storage of Genetic Material ....................................................... 66 
 Storage of Biospecimen Samples .................................................................................. 66 
 MRI Data Storage .......................................................................................................... 67 

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 Inclusion of Children as Participants in Research Involving Human Subjects ............... 67 
 Study Monitoring ............................................................................................................ 67 
19.0 
Audit .............................................................................................................................. 67 
20.0 
Record Retention ......................................................................................................... 67 
21.0 
Publication Policy ........................................................................................................ 68 
22.0 
Sharing of Final Research Data .................................................................................. 68 
23.0 
Literature Cited ............................................................................................................ 69 
Appendix 1: Schedule of Events ............................................................................................. 77 
 
 

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LIST OF ABBREVIATIONS 
 
3MSE 
Modified Mental Status Exam 
Aβ 
Beta-Amyloid 
AD 
Alzheimer’s Disease 
ADAS-Cog 
Alzheimer’s Disease Assessment Scale – Cognitive Subscale 
ADAS-Cog-Exec 
Alzheimer’s Disease Assessment Scale – Cognitive and Executive 
Function Composite Score  
ADCS 
Alzheimer’s Disease Cooperative Study 
ADCS-ADL-MCI 
Alzheimer’s Disease Cooperative Study – Activities Of Daily Living – 
Mild Cognitive Impairment 
ADNI 
Alzheimer’s Disease Neuroimaging Initiative 
AE 
Adverse Event 
APOE/APOE4 
Apolipoprotein/Apolipoprotein Epsilon 4  
ASL 
Arterial Spin Labeling  
AVLT 
Auditory Verbal Learning Test 
AX 
Aerobic Exercise 
BDNF 
Brain-Derived Neurotrophic Factor 
BRIEF-A 
Behavior Rating Inventory Of Executive Function – Adult Version 
BPSO 
Behavioral Pattern Separation Of Objects (Stark Task) 
CDR 
Clinical Dementia Rating 
CDR-SB 
Clinical Dementia Rating – Sum Of Boxes 
CFR 
Code Of Federal Regulations 
CRF/e-CRF 
Case Report Form/Electronic Case Report Form  
CSF 
Cerebrospinal Fluid 
DET 
Detection Task (Cogstate) 
DCCS 
Dimensional Change Card Sort (NIH Toolbox) 
DNA 
Deoxyribonucleic Acid 
DSMB 
Data And Safety Monitoring Board 
DSST 
Digit Symbol Substitution Test 
ECG 
Electrocardiogram 
EDC 
Electronic Data Capture 
EQ5D 
EuroQol 5-Item Health Questionnaire 
FDA 
Food And Drug Administration 
FNAME 
Face-Name Associative Memory Exam 
fMRI 
Functional Magnetic Resonance Imaging 
GCP 
Good Clinical Practice 
GDS 
Geriatric Depression Scale 
GMLT 
Groton Maze Learning Test (Cogstate) 
HBA1C 
Hemoglobin A1c 
HCY 
Homocysteine 
HIPAA 
Health Insurance Portability And Accountability Act 
HR 
Heart Rate 

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HRR 
Heart Rate Reserve 
ICF 
Informed Consent Form 
ICH 
International Conference On Harmonisation 
IDN 
Identification Task (Cogstate) 
IRB 
Institutional Review Board 
LP 
Lumbar Puncture 
MCI 
Mild Cognitive Impairment  
MEDDRA 
Medical Dictionary For Regulatory Activities 
MMA 
Methylmalonic Acid 
MMRM 
Mixed Effects Model For Repeated Measures 
MMSE 
Mini-Mental State Examination 
MPRAGE 
Magnetization Prepared Rapid Gradient Echo 
MR/MRI 
Magnetic Resonance / Magnetic Resonance Imaging 
NIA 
National Institute On Aging 
NIH 
National Institutes Of Health 
NPI 
Neuropsychiatric Inventory 
NSAID 
Non-Steroidal Anti-Inflammatory Drugs 
OBK 
One Back Task (Cogstate) 
OCL 
One Card Learning (Cogstate) 
OHRP 
Office For Human Research Protections 
PD 
Project Director  
PCP 
Primary Care Provider 
PHI 
Protected Health Information 
PI 
Principal Investigator 
PID 
Participant Identification Number 
RPE 
Rating Of Perceived Exertion 
PT 
Prothrombin Time  
PTT 
Partial Thromboplastin Time  
SAE 
Severe Adverse Event 
SBR 
Stretching/Balance/Range Of Motion 
SD 
Standard Deviation 
SF-36 
36-Item Short Form Health Survey 
sMRI 
Structural Magnetic Resonance Imaging 
T 
Tesla 
TAPA 
Telephone Assessment Of Physical Activity 
TEAE 
Treatment-Emergent Adverse Event 
TSH 
Thyroid Stimulating Hormone 
VEGF 
Vascular Endothelial Growth Factor 
WAIS-R 
Wechsler Adult Intelligence Scale – Revised  
Y-PM 
YMCA Project Manager 
Y-USA 
YMCA Of The United States Of America 
 
 

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PROTOCOL SYNOPSIS 
PROTOCOL TITLE 
 
 
 
Therapeutic Effects of Exercise in Adults with  
Amnestic Mild Cognitive Impairment  
PROJECT DIRECTORS 
Laura Baker, PhD and Carl Cotman, PhD 
STUDY SPONSOR 
National Institute on Aging (NIA) 
STUDY DESIGN  
Phase 3, multicenter, randomized single-blind study to examine the 
effects of aerobic exercise on cognition, functional status, whole 
and regional brain atrophy, whole and regional cerebral blood flow, 
and cerebrospinal fluid biomarkers of Alzheimer’s disease in 300 
adults with amnestic mild cognitive impairment (MCI) 
DURATION OF STUDY 
PARTICIPATION  
• 
Screening period of up to 4 weeks 
• 
Supervised intervention duration of 12 months 
• 
Unsupervised intervention extension of 6 months 
SUMMARY OF 
INVESTIGATIONAL 
INTERVENTION 
• 
Two interventions will be implemented: supervised and 
structured moderate/high intensity aerobic training vs. 
stretching/balance/range of motion for 12 months, followed by a 
6-month unsupervised extension 
• 
Moderate/high intensity aerobic exercise will involve training at 
70-80% heart rate reserve for 30 min, with an additional 10 
minutes for warm-up and 5 minutes for cool-down, 4 times per 
week, for 12 months while supervised twice per week by a 
study-certified YMCA Trainer; participants in the 
stretching/balance/range of motion group will adhere to the 
same timeline, but exercise at an intensity at or below 35% 
heart rate reserve 
SUMMARY OF KEY 
ELIGIBILITY CRITERIA 
• 
Age: 65 to 89 years (inclusive) 
• 
Mini-Mental State Examination at screening: ≥24 for 
participants with 13 or more years of education; ≥22 for 
participants with 12 or fewer years of education 
• 
Clinical Dementia Rating =0.5 with a memory score of 0.5 or 
greater at screening 
• 
Profile of test scores and clinical ratings is consistent with 
amnestic mild cognitive impairment  
• 
Modified Hachinski score ≤4 
PRIMARY OUTCOME 
MEASURE 
 
ADAS-Cog-Exec Global Composite Score: Word Recall, Delayed 
Word Recall, Orientation and Number Cancellation subscales of 
the Alzheimer’s Disease Assessment Scale – Cognitive Subscale, 
version 13 (ADAS-Cog13); tests of executive function including 
Trail-Making Test A and B, Digit Symbol Substitution Test, and 
Category Fluency; and Clinical Dementia Rating (CDR) sum of box 
scores for Memory, Orientation and Judgement and Problem 
Solving.  

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SECONDARY OUTCOME 
MEASURES 
Clinical Dementia Rating – Sum of Boxes, ADAS-Cog13 total 
score, Executive Function Composite, Episodic Memory 
Composite, functional status (Alzheimer’s Disease Cooperative 
Study – Activities Of Daily Living – MCI, Behavior Rating Inventory 
Of Executive Function – Adult Version), mood and health-related 
quality of life (Neuropsychiatric Inventory, 36-Item Short Form 
Health Survey, EuroQol 5-Item Health Questionnaire), brain 
volume and perfusion using structural and functional magnetic 
resonance imaging, biomarkers in blood and cerebrospinal fluid, 
actigraphy-measured total activity and sleep integrity 
 
 

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1.0 
INTRODUCTION  
 
An urgent need exists to find effective treatments for Alzheimer’s disease (AD) that can arrest or 
reverse the disease at its earliest stages. The emotional and financial burden of AD to patients, 
family members, and society is enormous, and is predicted to grow exponentially as the median 
population age increases. Amnestic mild cognitive impairment (MCI), characterized by mild 
memory loss often accompanied by mild executive dysfunction, is presumed early stage AD, 
and the prodrome of clinical dementia. The potential to preserve, or even enhance, cognition in 
adults at high risk of cognitive decline due to neurodegenerative disease clearly has important 
implications not only for the affected individual, but also for the support system that bears the 
social and financial burdens of long-term caregiving. However, prior studies testing interventions 
to prevent or arrest cognitive decline in MCI using a variety of different pharmaceutical 
approaches have been largely negative. Contemporary approaches in modern health care are 
beginning to acknowledge lifestyle modification as a potential potent health-promoting and 
disease-modifying strategy to preserve or improve cognitive function and quality of life for older 
adults. The long prodromal period associated with MCI provides an ideal opportunity for lifestyle 
interventions such as increased physical activity to protect and enhance cognition when 
neuropathologic processes that cause decline can still be prevented or delayed.  
 
To date, no large multi-site study has been carried out to evaluate potential therapeutic effects 
of aerobic exercise on brain function and markers of disease progression in adults with MCI and 
thus at high risk for dementia despite promising evidence from epidemiological and preliminary 
clinical trials. This pivotal study will examine whether moderate-to-high intensity aerobic 
exercise can improve cognition and other measures of brain health in adults with MCI. If 
successful, the results of this study may have large-scale implications for public policy regarding 
standard of clinical care and prescriptive practices for a fast-growing and vulnerable population 
of older adults. The study will also provide information about potential mechanisms through 
which aerobic exercise may benefit brain function by examining key markers of disease 
progression in brain imaging and cerebrospinal fluid (CSF). These results will likely have 
considerable clinical, scientific, and social significance, and may provide therapeutically relevant 
knowledge about the effect of aerobic exercise on AD pathophysiology. 
 
 
Primary Aim 
 
Aim 1: To test the hypothesis that 12 months of supervised moderate/high intensity 
aerobic exercise, relative to a stretching/balance/range of motion control, will improve 
cognitive function, measured using a validated composite score (ADAS-Cog-Exec) that 
includes select subscales (Word Recall, Delayed Word Recall, Orientation, Number 
Cancellation) from the Alzheimer’s Disease Assessment Scale – Cognitive Subscale 
(version 13); tests of executive function including Trail-Making Test A and B, Digit 
Symbol Substitution Test, Category Fluency; and Clinical Dementia Rating (CDR) sum 
of box scores for Memory, Orientation and Judgement and Problem Solving in older 
adults with amnestic MCI. 
 

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Secondary Aims 
 
Aim 2: To test the hypothesis that 12 months of aerobic exercise, relative to the control, 
will reduce clinical ratings of cognitive impairment as measured by the Clinical Dementia 
Rating Scale – Sum of Boxes, and total score on the ADAS-Cog13.  
 
Aim 3: To test the hypothesis that 12 months of aerobic exercise, relative to the control, 
will improve executive function and episodic memory, as measured by domain-specific 
composite scores derived from ADAS-Cog-Exec subtests and other computer-
administered tests (Cogstate, NIH Toolbox).  
 
Aim 4: To test the hypothesis that 12 months of aerobic exercise, relative to the control, 
will improve daily living skills (ADCS–Activities Of Daily Living–MCI, Behavior Rating 
Inventory Of Executive Function–Adult Version), mood and health-related quality of life 
(Neuropsychiatric Inventory, 36-Item Short Form Health Survey, EuroQol 5-Item Health 
Questionnaire), and subjective memory concerns (Cognitive Change Index).  
 
Aim 5: To test the hypothesis that 12 months of aerobic exercise, relative to the control, 
reduces the rate of regional and whole brain atrophy, and increases regional and whole 
brain perfusion assessed using volumetric and functional magnetic resonance imaging 
(fMRI). 
 
Aim 6: To test the hypothesis that 12 months of aerobic exercise, relative to the control, 
will favorably alter AD biomarkers in CSF including beta-amyloid and tau, and to conduct 
exploratory analyses of exercise effects on other markers of brain health and disease in 
CSF and blood (e.g., brain-derived neurotrophic factor, vascular endothelial growth 
factor, measures of inflammation, proteomics/metabolomics). 
 
Aim 7: To examine whether gender, age, baseline AD biomarker profile, apolipoprotein 
epsilon 4 (ApoE4) genotypes, total activity, and sleep integrity predict treatment 
response.  
 
Aim 8: To examine the enduring cognitive and behavioral effects of the intervention 
following a 6-month extension, during which the assigned exercise is continued without 
supervision, to test a model for a community-based exercise prescription in adults with 
MCI. 
 
Aim 9: To assess the impact of the intervention on the study partner’s health, wellbeing 
and quality of life using the Study Partner Self-Assessment Questionnaire.  
 
 
 

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2.0 
PRELIMINARY STUDIES  
 
 
Summary of Clinical Findings  
 
Although not without controversy,1 the majority of cross-sectional and longitudinal epidemiologic 
studies to date,2 including the Canadian Study on Health and Aging,3 the Hisayama Study,4 the 
Cardiovascular Health Cognitive Study,5 the MacArthur Study,6 and the Mayo Clinic Study,7 
indicate reduced risk of cognitive decline with increased physical activity, even among the oldest 
old.8 
 
Exercise benefits on cognition are also supported by the results of controlled trials in normal 
aging. The results of a meta-analysis support an overall benefit of aerobic exercise on episodic 
memory, attention, processing speed, and executive function in non-demented older adults.9 
Short-term aerobic training (e.g., 4-12 months) increases whole brain and hippocampal volume, 
and regional gray and white matter volumes in prefrontal cortex.10,11 Short-term aerobic exercise 
also augments hippocampal perfusion,12 consistent with findings from longitudinal observational 
studies of lifelong fitness training.13 Other exercise effects on brain function include favorable 
changes in neuronal network activity, notably in brain regions supporting higher cognitive 
functions. In a small controlled 4-month trial, Burdette and colleagues12 demonstrated exercise-
induced increases in cerebral blood flow and network connectivity in brain regions that support 
episodic memory and executive function in healthy older adults. In this study, post-intervention 
connectivity exceeded that observed in young adults, and the primary circuit altered by exercise 
was that between the hippocampus and the anterior cingulate, an important region for executive 
control. Positive effects of exercise on resting network activity within the frontal lobe and 
between frontal, posterior parietal, and temporal cortices (default mode network) are also 
reported by others.11 Together, these studies demonstrate that exercise can be a potent 
modulator of brain structure and function in healthy older adults.  
 
While studies of exercise in normal older adults support benefits for cognitive health, the impact 
of aerobic exercise on brain structure and function in adults with amnestic MCI has only recently 
been examined. Conceivably, exercise may not confer the same benefits when brain health is 
compromised by pathological processes associated with more advanced neurodegenerative 
disease. However, in adults with AD, improved cardiorespiratory fitness is associated with less 
whole brain atrophy and increased white matter volume.14 In adults with MCI and presumably 
relatively less AD pathology, increasing fitness is associated with less regional brain atrophy in 
medial temporal (including entorhinal) cortex.15 Although only a few controlled exercise trials in 
MCI have been completed to date, the results thus far provide encouraging support for 
cognition-enhancing effects. In the Baker et al. controlled 6-month pilot trial of supervised 
aerobic exercise versus stretching in MCI, they reported positive effects of exercise on 
cognition, particularly on tasks of executive function.16 Favorable exercise effects on 
glucoregulation and Aβ levels in plasma were also reported. In a larger controlled 6-month trial 
of home-based aerobic exercise (walking) versus usual care in adults with MCI, Lautenschlager 
et al.17 reported exercise benefits on a global test of cognitive function (ADAS-Cog), on delayed 
word list recall, and on a clinician-based assessment, with evidence for persisting benefits at the 

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18-month follow-up. These studies are encouraging, but not without limitations. In the 
Lautenschlager study, the interventions were not tightly controlled (usual care group was 
permitted to exercise), and cognitive abilities that typically improve with exercise in healthy older 
adults were not adequately assessed. In the Baker et al. study, sample size was small. 
Biomarkers in brain were not collected in either study.  
 
In a recent larger 6-month study in MCI that included brain imaging and CSF collection,18 
moderate/high intensity aerobic exercise vs. stretching improved executive function; increased 
blood flow in areas of the brain that are characteristically reduced with aging and with 
progression of AD; and reduced CSF levels of phosphorylated tau protein – a hallmark 
biomarker of disease progression. The multi-site trial of exercise in adults with MCI, referred to 
as “EXERT,” will test whether these promising findings can be confirmed in a larger and longer 
duration study to definitively establish the therapeutic efficacy of moderate/high intensity aerobic 
exercise to slow disease progression in older adults at high risk for AD dementia.   
 
 
Safety and Compliance 
 
Aerobic exercise, at the intensity targeted in EXERT, is well-tolerated even in sedentary older 
adults, is the standard recommendation by the American Heart Association for older adults,19 
and is commonly used in community settings to improve physical fitness. Although aerobic 
exercise intensity in EXERT is described as ‘moderate/high’, this descriptor in no way describes 
intensity of exercise completed by highly trained athletes. Moderate/high intensity of aerobic 
exercise in EXERT is defined as 70-80% of heart rate reserve (HRR), which is similar to 70-80% 
of maximum heart rate (HR) with an adjustment for baseline cardiorespiratory fitness. This 
exercise intensity was successfully achieved in three 6-month studies conducted by Baker et al. 
that enrolled over 130 older adults who were at increased risk for AD dementia. In these 
studies, serious adverse event (SAE) rates were low (<5%) and comparable across intervention 
groups.16,18,20  
 
3.0 
BACKGROUND AND SIGNIFICANCE 
 
 
Rationale for Aerobic Exercise as a Therapeutic Intervention in Mild Cognitive 
Impairment  
 
The study rationale is based on growing evidence that aerobic exercise has numerous health-
restoring effects in the brain, and that a sedentary lifestyle may contribute to AD 
pathogenesis.21,22 Increased physical activity improves cardiovascular health, glucose 
regulation, and lipid metabolism, and has positive effects on mood and stress in older adults.23 
In clinical studies, aerobic exercise is associated with improved cognitive function,16,18 increased 
brain volume,10,11 increased brain perfusion,18 and reduced levels of AD biomarkers in CSF.18,22 
 
 
 

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Rationale for Aerobic Exercise Effects on AD Pathology in the Brain 
 
The identification of biomarkers associated with AD pathogenesis can aid diagnosis, help to 
monitor disease progression, and identify potential underlying mechanisms. Thus, exercise-
induced effects on AD biomarkers represent a key component of this trial. EXERT will examine 
whole brain and regional changes in structure and blood flow as measured by brain magnetic 
resonance imaging (MRI), and chemical biomarkers in CSF and blood. Alzheimer’s Disease 
Neuroimaging Initiative (ADNI) studies provide valuable longitudinal MRI data in adults with MCI 
and early stage dementia versus healthy adults pointing to entorhinal and hippocampal atrophy 
as sensitive markers of disease progression.24,25 New evidence also suggests that aerobic 
exercise may reverse aging- and AD-related changes in cerebral blood flow.18 CSF 
concentration of beta-amyloid (Aβ) 1-42 (Aβ42), the more toxic form of the Aβ peptide, is also 
an important marker of AD risk.25-28 A decrease in CSF Aβ42 is an early event preceding 
hippocampal atrophy, tauopathy, and other degenerative processes,29,30 and thus a valuable 
index of disease progression.  
 
Although reducing rate of progression from MCI to Alzheimer’s dementia is not a primary 
outcome in this study, the use of progression-sensitive biomarkers will be a powerful tool to 
evaluate the impact of exercise on brain health, and on disease progression in future studies. In 
cross-sectional studies, high-levels of physical activity are associated with reduced cerebral Aβ 
deposition (evaluated with brain imaging using positron emission tomography) and increased 
CSF Aβ in older adults,22 and in a controlled 12-month trial of moderate-intensity aerobic 
exercise, hippocampal volume in older adults was increased by 2%, reversing age-related loss 
by 1-2 years.31 Similar aging- and AD-related markers of brain structure and function will be 
measured to provide important information about mechanisms that may account for positive 
exercise effects, including CSF levels of inflammatory markers such as IL-1β, IL-6, IL-8, TNFα,32 
about proteolytic products such as visinin-like protein-1 (a marker of neuronal injury),33 and 
about growth factors such as brain-derived neurotrophic factor (BDNF).34,35 In animal studies, 
exercise increases brain BDNF, reduces peripheral and brain inflammation, and slows 
progression of neurodegeneration.36,37 Other new markers that probe possible mechanisms are 
emerging though the use of proteomics and metabolomics, which will be explored in EXERT.38-
41 Genotype effects on response to exercise will also be examined, including the ε4 allelic 
variant of the apolipoprotein E (ApoE) gene that has independent and synergistic effects on Aβ-
related AD pathogenesis, atherosclerotic changes, cardiovascular disease, and cognitive 
decline.42-48  
 
 
Rationale Supporting Selection of Primary and Secondary Cognitive Outcomes 
 
Recent findings from ADNI indicate that ADAS-Cog scores reliably change over 12 months in 
MCI. A modified version of the ADAS-Cog (version 13) supplemented with other tests, referred 
to as ADAS-Cog-Exec, has been validated49 and will be used as the primary outcome measure 
to assess efficacy in EXERT. This composite includes ADAS-Cog13 subtests shown to be 
maximally sensitive to change over time in MCI (Word Recall, Delayed Word Recall, 
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Test, Digit Symbol Substitution Test [DSST], Category Fluency), and Clinical Dementia Rating 
scale sum of box scores for Memory, Orientation, and Judgement and Problem Solving. 
Although inclusion of supplemental measures may increase variability overall, a heavier 
executive function load in the ADAS-Cog composite will likely add sensitivity given prior 
evidence of beneficial exercise effects on this cognitive domain. The selected secondary 
cognitive measures were either sensitive to aerobic exercise in previous studies of healthy older 
adults20,50,51 or individuals with MCI,16,18,20 or to early hippocampal/medial temporal cortical 
changes in MCI.52  
 
 
Rationale for Length and Design of EXERT 
 
In preliminary studies, beneficial cognitive effects in MCI were observed following 6 months of 
moderate/high intensity aerobic exercise. EXERT includes an extended intervention period of 
one year for the primary analyses, which should only increase power to detect a treatment effect 
on cognition and biomarker endpoints in MCI. A 6-month unsupervised extension of the 
intervention will provide additional information regarding longer-term efficacy and exercise 
adherence that will provide important translational value for future community-based and, 
potentially, therapeutic programs for adults with MCI. 
 
 
Rationale for Population Selection 
 
Adults with a cognitive profile indicating amnestic MCI will be enrolled in EXERT to examine 
potential therapeutic effects on brain structure and function in early stage AD when 
neuropathologic processes that cause decline can still be potentially prevented or delayed. 
Although enrollment will not be restricted to biomarker-positive patients, the trial will collect CSF 
biomarkers and MRI measures of atrophy and blood flow that can be examined relative to 
treatment response and group assignment in secondary analyses.  
 
 
Rationale for Selected Exercise Dose  
 
The selected dose of aerobic exercise was based on previous work showing that the targeted 
frequency, duration, and intensity improved cognitive function both in healthy older 
adults10,11,31,51 and in MCI.16,18 Variability in achieved adherence for the aerobic training (AX) 
group will permit examination of relationships between exercise volume (based on intensity, 
duration, frequency) and magnitude of cognitive and biomarker response. A maximum of 35% 
HRR is targeted in the stretching/balance/range of motion (SBR) group as this level of exertion 
falls well below American College of Sports Medicine (ACSM) guidelines for moderate-intensity 
exercise19 and thus ensures maximal separation in exercise dose between the groups. 
 
 
Rationale for Intervention Implementation in Community-Based Facilities  
 
One aim of EXERT is to test the feasibility of prescriptive aerobic exercise for adults with MCI 
using community-based facilities equipped to successfully provide adequate resources and a 
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Y-USA) and local YMCA branches will provide facilities for exercise and trainer supervision of 
participants as they complete their assigned intervention activities. The Y-USA has worked 
closely with the study leadership to identify suitable YMCA facilities near participating clinic sites 
that will provide oversight of study-related activities carried out at the YMCAs, and ensure 
participant safety and high levels of intervention fidelity. This innovative collaboration between 
academia and a well-established national nonprofit community-based organization will test a 
highly translatable mechanism for delivery of a promising behavioral intervention to slow or 
prevent progression to Alzheimer’s dementia.     
 
 
Rationale for Magnetic Resonance Imaging 
 
Longitudinal data collected in ADNI provides robust evidence that structural MRI can be a 
credible predictor of future cognitive and functional decline, and is sensitive to total and 
hippocampal/entorhinal volume reductions over a 12-month period.24,25,53 Jack et al. examined 
the role of structural MRI outcomes as endpoints for disease progression in therapeutic trials for 
AD and reported that multi-site consistency is feasible.54 Others highlight particular vulnerability 
of the nearby entorhinal cortex to atrophy over the same period of time.55 The results of prior 
normal aging studies show positive effects of exercise on hippocampal, prefrontal, and posterior 
parietal regions;10,11,31 and those of a recent study in MCI indicate increased brain perfusion 
using fMRI in prefrontal and posterior parietal regions.18 EXERT will test whether 12 months of 
supervised aerobic exercise can attenuate disease-related atrophy and increase perfusion in 
hippocampal, prefrontal, and posterior parietal regions that support memory and executive 
function.  
 
 
Rationale for Inclusion of Actigraphy 
 
Actigraphy will be used to collect multiple 24-hour samples of physical activity to test the impact 
of total activity and of sleep quality on treatment response.  
 
Aerobic exercise has favorable effects on multiple neurobiological systems, one of which 
controls sleep. Results from the Baltimore Longitudinal Study of Aging indicate that poor sleep 
may have a neuropathologic signature: in community-dwelling older adults, brain Aβ burden was 
increased in older adults with self-reported shorter sleep duration and quality,56 which may point 
to an important role of sleep in Aβ clearance.57,58 Behaviorally, when sleep is disturbed, memory 
is impaired.59,60 In healthy adults, 6 months of aerobic exercise has been shown to significantly 
improve overall sleep quality,61-63 with downstream benefits on inflammatory processes.63 
EXERT will expand these findings to assess intervention effects on sleep quality in adults with 
MCI. 
 
While regular participation in structured exercise programs may influence quality of nighttime 
activity, short intense bouts of exercise may also impact total quantity of other physical activity 
completed during other times of the day. Controlled trials of structured exercise typically quantify 
activities that occur only during these short bouts. The importance of objective measures of total 
physical activity is underscored by the results of prospective studies showing that increased 

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total physical activity predicts reduced dementia risk,64 and that older adults who engage in 
structured exercise may actually be less active at other times of the day.65 Controlled exercise 
trials that fail to quantify total physical activity may overlook an important mediator of response 
to the intervention. 
 
 
Rationale for Collection of Biofluids 
 
CSF biomarkers associated with AD pathology such as Aβ42, Aβ 1-40 (Aβ40) and total and 
phosphorylated tau protein will be measured, as will relevant biomarkers in blood. Residual 
specimens will be banked in the ADCS biospecimen bank to permit putative and evolving 
biomarkers associated with AD pathology (such as brain-derived neurotrophic factor [BDNF], 
vascular endothelial growth factor [VEGF], insulin, inflammatory markers) to be examined 
later.66,67  
Although some studies suggest that the greatest cognitive benefit may be seen in adults with 
the ε4 allelic variant of the ApoE genotype,68 recent data indicate that exercise may benefit ε4 
carriers and non-carriers alike. Specific Aim 7 will examine whether ApoE4 carriage is a 
predictor of treatment response.  
 
4.0 
POTENTIAL RISKS AND BENEFITS ASSOCIATED WITH INTERVENTION 
 
 
Potential Benefits 
 
There is an urgent need to identify promising treatments for adults with MCI who are at 
increased risk for progression to Alzheimer’s dementia. At present, no large multi-site study has 
evaluated the potential therapeutic effect of 12 months of aerobic exercise in MCI. There are 
significant potential scientific and clinical benefits for the subject population. Although regular 
exercise is the standard of care to maintain optimum physical health and prevent various 
medical conditions such as cardiovascular disease and diabetes, exercise is not prescribed to 
maintain optimum cognitive health or prevent diseases associated with cognitive decline. In 
addition, little is known about the effects of aerobic exercise on AD pathophysiology with 
possible consequences for Aβ regulation and tau phosphorylation, and for structural brain 
integrity characteristically compromised by disease progression. EXERT has the potential to 
identify important mechanisms related to exercise effects on cognition in the earliest stages of 
AD. Participants will receive a free 18-month membership to a participating YMCA, and a 
personal trainer who will oversee their exercise in the first 12 months of the study. The relatively 
minor risks posed by the intervention, cognitive testing, MRI and lumbar puncture (LP) are 
outweighed by the value of the scientific investigations outlined in this proposal that could 
potentially alter widespread practices for standard of care in MCI. 
 
 
Potential Risks  
 
Although regular physical activity and exercise have numerous health benefits on blood 
circulation, metabolism, lipoprotein profile, bone mass, risk of falling and disease,69 high-
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well as orthopedic71 and soft tissue (muscle, tendon, cartilage) injury. High-intensity exercise is 
also associated with lower adherence to a training regimen than lower-intensity exercise.72 
Evidence favoring high-intensity over moderate-intensity exercise, however, is provided by a 
recent joint report by the ACSM and the American Heart Association73 showing greater risk 
reduction for cardiovascular disease and all-cause mortality. The EXERT protocols of 
moderate/high intensity aerobic training are consistent with the latest ACSM exercise 
recommendations for older adults.19 Risk of injury is strongest for overweight and unfit older 
adults.74 When sedentary adults begin to walk or jog, they may develop foot, leg, and knee 
injuries when training is performed more than 3 days per week and for more than 30 minutes 
per session;75 while prolonged exercise may result in overuse-related orthopedic injuries.74 The 
EXERT protocol that includes gradual increments of exercise intensity and duration, under the 
supervision of a trainer and taking into account individual needs and limitations, is in 
accordance with this recommendation and its safety has been established in other community-
based exercise programs.76-78 In previous pilot exercise studies in MCI on which the protocol is 
based, of the 100 enrollees who completed the high-intensity arm (meeting all EXERT inclusion 
criteria),16,20,79 only 3 subjects (3%) were dropped due to a cardiovascular adverse event (AE) 
(follow-up tests indicated chronic disease pre-dating study entry for all 3 adults).  
 
There are no known risks associated with participation in the SBR control group. 
 
400 m Walk Test. Participants will be screened for cardiac or pulmonary disorders to exclude 
those who cannot safely complete this test. Participants will be instructed to walk as quickly as 
possible to complete 10 laps, totaling 400 m. Safety precautions will be taken while 
administering this test by monitoring physical signs and symptoms of fatigue or discomfort, and 
by applying standardized stopping criteria. If the participant reports chest pain, tightness or 
pressure, significant shortness of breath or difficulty breathing, or feeling lightheaded or faint, 
the test will be terminated. The 400 m Walk Test will be performed in settings where a 
defibrillator is available. Clinic staff members are trained to provide immediate care and 
promptly contact medical personnel in the event of a medical emergency. Also, institutional and 
community Emergency Medical Services (EMS) will be engaged (call 9-1-1) if needed. 
 
Brain MRI. All participants will be screened for presence of iron-containing substances near the 
head that can be perturbed by the magnet of the MRI scanner, including pacemakers, cardiac 
defibrillators, or other metal fragments in or near the head. There is a remote risk of external 
injury to the body when metal outside of the magnet is brought close to the scanner. However, 
scanners are located in secure rooms to avoid inadvertent introduction of metals into the 
magnetic field. Other than injuries from unsecured metal materials, there are no known 
longstanding detrimental health effects associated with exposure to high magnetic fields, 
magnetic gradients, or radiofrequency energy used in MRI. Because the procedure requires 
participants to lie still inside a narrow tube, participants may experience claustrophobia or mild 
body position discomfort.  
 
Lumbar Puncture. The risk for serious AE related to LP (e.g., post-LP headache, infection, 
nerve root damage) is very low.80 LP may be associated with pain during the procedure. This is 

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usually temporary and confined to the lower back.  Headache may occur in about 5% of elderly 
adults who receive an LP using the ADCS LP protocol.  Less commonly, in about 1-4% of 
subjects, a persistent low-pressure headache may develop, probably due to leakage of CSF.  
On rare occasions, a blood patch (injection of some of the subject’s blood to patch the CSF 
leak) may be needed.  Potential but rare risks of LP include infection, damage to nerves in the 
back, bleeding into the CSF space, and death. Risk for these events is less than 1%. 
 
General. Blood collection may be associated with transient discomfort and bruising, and a small 
risk of infection. Cognitive testing may produce frustration in some subjects. Questionnaires 
about mood may uncover or potentiate feelings of dysthymia and helplessness.   
 
5.0 
SAMPLE SIZE AND STATISTICAL PLAN 
 
This study is a multisite, randomized, single-blind trial comparing the effects of supervised 
moderate/high intensity aerobic exercise (70-80% HRR) versus stretching/balance/range of 
motion (≤35% HRR) in adults with MCI (N=300). 
 
 
Randomization 
 
In this single-blind study design, eligible participants per site will be randomized using a simple 
1:1 schedule to either the AX or SBR group, and stratified by site, ApoE4 carrier status (yes or 
no), and gender. After 12 months of supervised exercise, all participants will transition to 
independent exercise (without supervision) and will be instructed to continue their assigned 
physical activity regimen for an additional 6 months to test the efficacy of a translational model. 
 
 
Power and Sample Size Determination 
 
Power calculations for EXERT were based on two-sample t-tests.81 Sample sizes were 
estimated using 12-month ADAS-Cog change scores from the ADCS MCI trial, targeting power 
=80%, 2-sided alpha =5%, and SD =4.1. Calculations ranged over effect sizes in ADAS-Cog 
from 1.0–2.0, and dropout rates from between 10-25%, which are similar to other reports, 
including multi-center trials of physical activity interventions in older cohorts.11,16,17,31,82,83 The trial 
is powered to conservatively accommodate 20% attrition. Based on these considerations, and 
an effect size =1.5, 291 total subjects are required. The trial will target enrollment of 300 
participants. The statistical approach that includes analyses of a composite measure rather than 
an individual test score is expected to increase statistical power. In light of evidence showing 
exercise benefits on executive function in other studies, and sensitivity of select CDR and 
ADAS-Cog13 subscales to more subtle changes associated with MCI, use of the ADAS-Cog-
Exec composite, in particular, should also increase sensitivity and power.   
 
To estimate an intervention effect on biomarkers, the difference in hippocampal atrophy 
between ADNI MCI participants versus healthy controls (HCs) without the ApoE4 allele was 
used. With a total sample size of 300, assuming 20% attrition and SD =1.54 (based on ADNI 
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volume between intervention groups as small as 0.56%, is 80% (5% alpha). As a reference, the 
difference in percent change from Baseline to Month 12 in hippocampal volume between ADNI 
MCI and normal controls ApoE4 non-carriers (presumed to be free of disease) is estimated to 
be 1.02%. Thus, the study is powered to detect an improvement equivalent to 0.559/1.02 
=54.8% of this ApoE4 related effect. With regard to entorhinal cortical thinning, assuming SD 
=1.68 (ADNI data), power to detect a difference in percent change from Baseline to Month 12 as 
small as 0.61% between intervention groups is estimated at 80%. Again as a reference, the 
difference in percent change from Baseline to Month 12 between ADNI MCI and normal controls 
ApoE4 non-carriers is estimated to be 1.49%. Thus the study is powered to detect an 
improvement equivalent to 0.61/1.49 =40.9% of this ApoE4 related effect. 
 
The preceding calculation assumes a maximal intervention effect would result in normalization 
of atrophy to the rate seen in healthy controls. However, Erickson et al.31 report hippocampal 
expansion with exercise in non-demented older adults. Here, 120 subjects completed a 
12-month program of aerobic exercise (mean age+/-SD: 67.6yrs+/-5.81yrs) or stretching 
(65.5yrs+/-5.44yrs), and were tested at baseline, and at months 6 and 12. The aerobic group 
had significant increases in left and right hippocampal volumes (2.12% and 1.97% change from 
baseline, respectively) after 12 months. For the stretching group, left and right hippocampal 
volumes decreased (-1.40% and -1.43% change, respectively) after 12 months (all p’s<0.001). 
Assuming an effect as large as that observed in Erickson et al. (~2%) and ADNI estimated 
standard deviation of change (SD =1.7), 20% attrition, and 2-sided alpha =5%, 300 randomized 
participants should provide greater than 99% power. Despite the compelling data described by 
Erickson et al., EXERT is conservatively powered to detect a relatively modest normalization of 
hippocampal atrophy. 
 
 
Selection of Participants to be Used in Analysis 
 
The modified intent to treat (mITT) population will be used for primary analysis. The mITT 
population will include all eligible individuals who, (1) began the exercise intervention and (2) 
completed at least one post-baseline assessment for the primary analysis. Exploratory analyses 
will include a per-protocol population of all eligible participants who, (1) completed the 12-month 
assessments for the primary analysis, (2) participated in at least 60% of the prescribed exercise 
sessions, and (3) met exercise goals in at least 60% of the supervised sessions, and an intent-
to-treat (ITT) population of all eligible individuals who are randomized. 
 
 
Efficacy Analysis 
 
5.4.1 Analysis of Primary Outcome 
 
To address Aim 1 for the primary efficacy analysis, longitudinal scores from baseline through 
the first 12 months will be analyzed using a mixed effects model for repeated measures 
(MMRM) to assess differences in scores between intervention groups. The MMRM model will 
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interaction, baseline ADAS-Cog-Exec by time interaction, plus covariates that include site, 
ApoE4 carrier status, sex, and additional covariates meeting the criteria below.  
 
Time will be treated as categorical. An analysis of covariance model imputing missing data with 
multiple imputation will be used as a sensitivity analysis. As a second sensitivity analysis, a 
similar MMRM model will be fit with time modeled as a continuous factor. If the longitudinal 
patterns over time are markedly non-linear, such as might occur due to learning effects, a 
quadratic term for time will be included in the model. In this case the intervention-by-time linear 
term assesses whether there is a relative difference between intervention groups that grows 
linearly with time. Potential confounders (baseline Walk Test time, age, education, 3MSE 
baseline score, and use of cholinesterase inhibitors) will be included in efficacy analyses as 
covariates if the following two conditions are satisfied: (1) imbalance at baseline (p<0.1) and, (2) 
association between the covariate and the response (p<0.15). Safety data will be analyzed 
using exact contingency table methods by intervention group assignment. 
 
Differences in the primary outcome of change in ADAS-Cog-Exec between intervention groups 
will be tested at the two-sided 5% significance level. No adjustment to the type 1 error level will 
be made for secondary analyses.  
 
5.4.2 Analyses of Secondary Outcomes 
 
Aims 2–4: Similar analyses to that described for the primary analysis will be performed on the 
Clinical Dementia Rating Scale – Sum of Boxes (CDR-SB), ADAS-Cog13 total score, Executive 
Function and Episodic Memory Composites, tests of daily living skills (ADCS–Activities Of Daily 
Living–MCI [ADCS-ADL-MCI], Behavior Rating Inventory Of Executive Function–Adult Version 
[BRIEF-A]), mood and health-related quality of life (Neuropsychiatric Inventory [NPI], 36-Item 
Short-Form Health Survey [SF-36]), EuroQol 5-Item Health Questionnaire [EQ5D]), and 
subjective memory concerns (Cognitive Change Index). 
 
Aim 5: Change in brain volume and inter-regional correlations in brain functional activity will be 
compared between treatment groups. The analysis will be completed separately for each 
volumetric and functional MRI parameter. 
 
Aim 6: CSF biomarkers of brain health and disease will be examined using a similar analytic 
strategy to that described for the analysis of the primary outcome using MMRM and other 
sensitivity models to test for intervention effects. Covariate adjustment, sensitivity analyses, and 
multiple imputation analyses will be carried out as specified under Aim 1.  
 
Aim 7: To examine whether sociodemographic factors, genotype, actigraphy outcomes, or 
baseline cognitive and biomarker profiles predict treatment response, MMRM and sensitivity 
models as described above will be performed using subgroup analyses. Model fitting and 
covariate adjustment will be carried out as specified under Aim 1. 
 
 
 

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Aim 8: To examine the enduring cognitive and behavioral effects of the intervention following 
the 6-month unsupervised exercise extension, MMRM and sensitivity models as described 
above will be performed. Model fitting and covariate adjustment will be carried out as specified 
under Aim 1.  
 
Aim 9: To examine the impacts of the intervention on the study partner, MMRM and sensitivity 
models as described above will be performed on data obtained using the Study Partner Self-
Assessment Questionnaire.  
 
 
Safety Analysis 
 
Safety will be assessed by summarizing and analyzing AEs during the intervention period. 
Adverse events will be coded according to established Medical Dictionary for Regulatory 
Activities (MedDRA) terms and summarized by MedDRA System Organ Class and Preferred 
Term. Treatment-emergent adverse events (TEAE) will be defined as events that first occurred 
or worsened on or after randomization. 
 
An overview of AEs, including the number and percentage of participants who died, suffered 
SAEs, discontinued due to AEs, and who suffered TEAEs, will be provided. A comparison 
between intervention arms will be performed. Summaries of AEs by within system organ class 
will be provided for: (1)   pre-existing conditions, (2) TEAEs, and (3) SAEs. Discontinuations due 
to AEs will also be listed. 
 
 
Termination of the Trial   
 
No criteria for trial termination are specified. If safety or efficacy issues are identified during trial 
conduct, the Data and Safety Monitoring Board (DSMB) may decide to stop the study. 
 
6.0 
INTERVENTIONS AND IMPLEMENTATION 
 
 
Overview 
 
Participants will complete EXERT interventions at participating YMCAs located near the 
selected clinic sites across the U.S. The YMCA will provide 18-month memberships at no cost 
to participants. In the first 12 months, a study-certified YMCA Trainer will supervise all 
participants for the first 8 exercise sessions completed (weeks 1 and 2), and for 2 of 4 weekly 
sessions thereafter through Month 12. At this time, participants will transition to independent 
exercise and continue their assigned exercise programs for the final 6 months of the study 
without supervision. To encourage adherence and optimize cost efficiency, Trainers will provide 
supervision to small groups of participants (2-4 individuals) randomized to the same intervention 
whenever possible. Compliance will be evaluated using multiple mechanisms including HR 
monitoring, participant ratings of perceived exertion, entries in participants’ Physical Activity 
Logs, Trainer assessment of effort, and weekly data review by the YMCA-Project Manager (Y-

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PM) and the Intervention Oversight Team (includes the PDs, Wake Forest team of exercise trial 
specialists, and Y-USA). These mechanisms will provide multiple and regular opportunities to 
discuss participant progress, identify and resolve barriers, and encourage high levels of 
adherence to study protocols. The Intervention Oversight Team has the necessary expertise to 
successfully accomplish this objective in EXERT. 
 
 
Collaboration with the YMCA 
 
EXERT has partnered with the national office of the YMCA (referred to as ‘Y-USA’) to provide 
exercise facilities and trained personnel to supervise participants as they complete their 
assigned intervention protocols. The YMCA Trainers maintain certifications to keep current with 
latest knowledge about fitness and its practice, and have experience supervising older adult 
exercise. This collaboration with the Y-USA will move the field forward in bridging the rift 
between academic research and health care delivery, thus providing additional important 
translational value to the study.  
 
Study-certification of Trainers will involve completion of training regarding the study protocol, 
proper implementation of the interventions, data capture of adherence outcomes, and AE 
recording and reporting.    
 
Intervention adherence data will be recorded by Trainers on Case Report Forms (CRFs) during 
supervised exercise sessions and will include type of exercise completed, HR during exercise, 
ratings of perceived exertion, and exercise duration and intensity. During supervised sessions, 
Trainers will also review participants’ Physical Activity Logs to ensure they are properly 
completed and study goals are met, and complete an AE Checklist that will be faxed to the clinic 
for review and follow-up as per study protocol (see Sections 14 and 15).  The Trainers and Y-
PMs will provide regular updates as requested by the clinic, the Intervention Oversight Team, 
and the ADCS.  All Y-PMs will attend a telephone conference twice per month, attended by 
Clinic YMCA Liaisons, the Intervention Oversight Team, and the ADCS to ensure efficient 
coordination and implementation of the intervention protocols. Trainers will also attend at least 
one telephone conference call per month with members of the Intervention Oversight Team. 
 
6.2.1 YMCA Study Team  
 
The YMCA team will consist of the following: 
 
Y-USA. The Senior Manager of Program Development for Y-USA, and the Y-USA Study 
Manager will serve as the primary interface between the national office of the YMCA, the PDs, 
the Wake Forest team, the ADCS, the participating YMCA Associations, and the Y-PMs.  
  
YMCA Project Manager (Y-PM). The site Y-PM, a senior level staff member will oversee Trainer 
supervision of EXERT participants, review and upload all adherence data to the central data 
repository, respond to adherence data queries as needed, and maintain a close bidirectional 
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management of study-related issues. The site Y-PM will report all AEs to the clinic, maintain 
regular communication with the Clinic YMCA Liaison regarding participant progress, and 
participate in bi-weekly conference calls with other site Y-PMs and Clinic YMCA Liaisons, the 
Intervention Oversight Team, and the ADCS to review study progress and address challenges 
as they arise. 
 
YMCA Trainers. Trainers at each site will supervise participants, providing encouragement and 
exercise-related expertise to help participants achieve the targeted intervention goals and to 
maintain high levels of adherence throughout the trial. During supervised sessions, Trainers will 
record adherence data on CRFs, review participant Physical Activity Logs to identify and 
address challenges and assess adherence, complete the AE Checklist, maintain close 
communication with the Y-PM and the Clinic YMCA Liaison regarding participant progress and, 
as schedule permits, participate in twice per month conference calls to review study progress 
with other Trainers, Y-PMs, Clinic YMCA Liaisons, the Intervention Oversight Team, and the 
ADCS. 
 
6.2.2 Interface Between the Clinic and the YMCA 
 
The clinic will be responsible for recruitment and screening of study candidates, all assessments 
of primary and secondary outcomes, randomization, and AE tracking, management and 
reporting to the site Institutional Review Board (IRB), the Intervention Oversight Team, and the 
ADCS.  
 
Once randomized, the site Y-PM will be notified by the clinic and the participant’s contact 
information will be provided so that the first orientation meeting at the YMCA can be scheduled. 
The sharing of contact information with the YMCA will be covered in the consent form. The 
Y-PM will review all adherence CRFs completed by the Trainers during supervised exercise 
sessions, and will enter and upload all compliance data to the ADCS Electronic Data Capture 
(EDC) and respond to any associated data queries.     
 
6.2.3 Adverse Event Reporting by YMCA Trainers 
 
The AE Checklist will be completed weekly during a Trainer-supervised exercise session. This 
survey will query change in health or physical status in the last week, and will include questions 
to identify potential SAEs (death, life-threatening, hospitalization, disability or permanent 
damage). The AE Checklist will also query TEAEs, which most commonly include muscle or 
joint aches including flare-ups of pre-existing musculoskeletal conditions (e.g., arthritis, foot 
bone spurs or neuromas). The AE Checklist will be faxed to the clinic to permit review by the 
Study Clinician within 24 hours of AE notification by the participant. 
 
Response to emergent serious or life-threatening medical events that occur while the participant 
is exercising at the YMCA will follow standard YMCA protocols that apply to the management of 
these events for any member of the facility. When appropriate, using the best judgment of 
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hospital for treatment. Other standard YMCA protocols may be used in the event of an onsite 
injury or medical event.  
 
 
Implementation of the Interventions 
 
Both intervention groups will complete their assigned exercise at participating YMCA branches 
near the selected clinics. Intensity and duration of exercise in both groups will be gradually 
increased over the first 6 weeks in the study, and then maintained at the intervention-specific 
targeted level (described in Sections 6.3.1 and 6.3.2) for the remainder of the 18-month 
intervention.  
 
All participants will be provided with a digital HR monitor that includes a chest strap and a wrist-
worn monitoring device and watch, and taught to use this device to monitor and record HR while 
exercising. Participants taking medications with HR-lowering effects will be provided with HR 
monitors, but will be taught to rely more heavily on other measures of effort intensity such as 
breathing rate, and ability to talk while exercising. During supervised sessions, effort will also be 
assessed by the Trainers. Participants in both intervention groups will be trained to properly use 
the Rating of Perceived Exertion (RPE) modified Borg scale (ratings range from 1=very mild, to 
10=very, very hard) in the first 2 weeks of the program as a supplemental means of assessing 
exercise effort. Proper use of the RPE scale will be assessed and retrained by the Trainer at 
regular intervals and as needed throughout the study.  
 
During supervised sessions for both intervention groups, the Trainer will record HR and RPE 
every 5-10 minutes, as well as other relevant exercise parameters (e.g., total duration, type of 
exercise completed, treadmill speed and grade). The Trainer will also record any additional 
observations that might assist the Intervention Oversight Team in their weekly review of 
participant progress. These data will be uploaded to the EDC by the Y-PM within 48 hours of the 
exercise session.  
 
For all supervised and unsupervised exercise sessions completed, participants will record the 
following in their Physical Activity Log: date and time, type of exercise, exercise duration, 
average HR, maximum RPE achieved, and other intervention-specific details (e.g., body regions 
stretched, grade/resistance and speed of equipment used). During each supervised session, the 
Trainer will review these entries, discuss and problem-solve issues that are uncovered during 
this review, and confirm the exercise schedule for the next few days. At the Baseline, Month 6, 
and Month 12 clinic assessments, participants will receive a 6-month supply of Physical Activity 
Logs. At the end of each 4-week period, the Trainer will collect completed Logs and store them 
in a locked cabinet until retrieved by the Clinic YMCA Liaison, which will occur monthly. In the 
final 6 months of the study (unsupervised), participants will return the last set of 6 completed 
Physical Activity Logs to the clinic at the Month 18 visit. 
 
Progression through the 18-month intervention will involve transition from one ‘phase’ to 
another. This transition will provide an objective measure of progress for participants, and a 
structure that will facilitate Trainer, Y-PM, and Intervention Oversight Team efforts to anticipate 

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and address participant issues that may characteristically change as they advance through the 
study (e.g., development of mastery, boredom with routines). The phases will also differ with 
regard to study expectations of participants and emphasis in training, which will shift from the 
basics of the prescribed exercise routines in the early part of the study to strategies to support 
and maintain independent exercise later in the program. The phases are defined by months in 
study, where ‘month’ always refers to exactly 4 weeks.   
 
• 
In Phase 1 (months 0-3), participants will receive instruction about the program and any 
equipment to be used, about proper form and technique, attire, exercise facility etiquette 
and symptoms of fatigue and injury, and exercise expectations will be gradually 
increased with the goal of reaching intervention-specific activity goals by the end of week 
6 (i.e., 70-80% HRR for the AX group; ≤35% HRR for the SBR group). Training will also 
focus on participants’ self-efficacy to begin to develop a strong foundation that will 
support adherence to the interventions over long periods of time. Participants will be 
asked to limit travel as much as possible, and will not be permitted to engage in alternate 
exercise activities (classes, outside walking). For all participants, the first 8 sessions of 
exercise will be supervised by a study-certified YMCA Trainer.   
 
• 
In Phase 2 (months 4-6), the goal will be for participants to begin to develop mastery of 
the intervention-specific activities. In Phase 2, participants will be allowed to engage in 
2 alternate activities per month (e.g., aerobic or easy yoga classes). Alternate activities 
must receive prior approval by the Trainer and the Y-PM to ensure that the activity is 
consistent with participant-specific intervention goals. Continued participation in 2 
alternate activities per month in Phase 2 will also be subject to approval by the 
Intervention Oversight Team who will regularly review the participant’s adherence 
record. The opportunity for participants to engage in alternate activities serves as a 
reward and thus an adherence-promoting strategy.   
 
• 
In Phase 3 (months 7-9), participants’ target HR will be re-calculated using the most 
recent resting HR measurement obtained during the Month 6 clinic assessment. This 
reassessment will ensure that the intervention-specific HR training goals are 
appropriately adjusted for current fitness levels (using surrogate measure of resting HR). 
In Phase 3, participants will continue their prescribed activities using the same 
supervision schedule, and will have the opportunity to engage in 1 pre-approved 
alternate activity per week (e.g., aerobic or easy yoga class). As in Phase 2, continued 
participation in alternate activities will be subject to approval by the Intervention 
Oversight Team who will regularly review participant adherence. 
 
• 
In Phase 4 (months 10-12), participants will adhere to the same exercise regimen 
(4 times per week) and supervision schedule (twice per week), and will continue to have 
the opportunity to participate in 1 pre-approved alternate activity per week, subject to 
approval by the Intervention Oversight Team. The supervised sessions will include 
training and discussions to prepare participants for independent exercise.  
 

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• 
In Phase 5 (months 13-18), participants will transition from supervised to unsupervised 
exercise following the Month 12 clinic assessment. During this time, participants will 
continue to complete their assigned exercise interventions as prescribed but without 
supervision other than what is normally provided by YMCA staff to all YMCA members. 
Attendance will be tracked using the YMCA membership card electronic scan records 
and participant-recorded entries in Physical Activity Logs.  
 
6.3.1 Aerobic Training Intervention 
 
The aerobic exercise (AX) will consist of treadmill walking supplemented with use of the elliptical 
trainer or stationary cycle at moderate/high to high levels of cardiorespiratory intensity, defined 
as 70-80% of HRR (HRR =220-age-resting HR) for 30 min, 4 days per week. Each session will 
include an additional 10 minutes of warm-up and an additional 5 min for cool-down. In study 
Phases 2-5, participants will be permitted to attend pre-approved aerobic exercise classes at 
the YMCA to encourage continued participation over the duration of the 18-month trial. High 
levels of retention (>80%) and adherence (>90%) have been achieved in previous exercise 
trials in healthy and memory-impaired older adults.16,20,82,84,85 
 
The following algorithm – previously used in studies of older, sedentary adults16,20,79 – will be 
used to establish AX HR targets and exercise durations during the initial ramp-up period and for 
the remainder of the 18-month program: 
 
Exercise Goals 
Week 
Warm-Up,  
Cool-Down Time 
RPE 
Effort, Time in 
Training HR Zone 
Target HR = 50-60% HRR; 
Total Duration = 15-25 minutes 
1 
3 min, 2 min 
1 – 2 
50%, 10 min 
2 
5 min, 5 min 
3 – 4 
60%, 15 min 
Target HR = 65-70% HRR; 
Total Duration = 30-45 minutes 
 
3 
5 min, 5 min 
4 – 5 
65%, 20 min 
4 
5 min, 5 min 
5 – 6 
65%, 25 min 
5 
5 min, 5 min 
5 – 7  
65%, 30 min 
6 
10 min, 5 min 
6 – 8  
70%, 30 min 
Target HR = 70-80% HRR; 
Total Duration = 45 minutes 
7+ 
10 min, 5 min 
6 – 8 
75%, 30 min 
 
Although the AX algorithm will identify appropriate training HR targets for the majority of older 
adults, the targets may require slight adjustments by the Trainers to meet specific needs of 
participants. Adjustments might include increasing duration of the ramp-up period beyond 
6 weeks if participants have difficulty meeting the exercise intensity and duration goals due to 
physical limitations (e.g., musculoskeletal issues, obesity), or lowering of training HR targets for 
a period of time to permit participants to adjust to the program or recover from injury or 
unanticipated prolonged inactivity. Adjustments to the AX algorithm will be regularly reviewed by 
the Intervention Oversight Team to ensure that study goals are met.  
 
 
 

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6.3.2 Stretching, Balance, and Range of Motion Intervention 
 
The stretching, balance, and range of motion (SBR) intervention will include a rotating and 
varied routine of stretching exercises for large and small muscle groups, and activities to 
improve balance and range of motion. SBR activities will be tailored so that participants are able 
to maintain HR at or below 35% HRR during each session, which will be completed 4 days per 
week for 45 min per session.  
 
The SBR algorithm described below will be used to establish HR targets and exercise duration 
during the ramp-up period and for the remainder of the 18-month program. The algorithm serves 
as a guideline and can be adjusted by the Trainer when study goals are not met. For example, 
adjustments to the SBR regimen may be required if achieved HR consistently exceeds the 
maximum allowable target. If HR continues to rise even under very low exercise demands (e.g., 
cardiac response to gentle stretches may be greater for obese or severely deconditioned 
adults), new maximum HR targets may be set, subject to revision as participants become 
accustomed to physical activity. Adjustments to the SBR algorithm will be regularly reviewed by 
the Intervention Oversight Team to ensure that study goals are met.  
 
Exercise Goals 
Week 
Warm-Up, 
Cool-Down Time 
RPE 
Total Exercise 
Duration 
Target HR ≤ 35% HRR 
1 
3 min, 2 min 
1 – 2 
15 min 
2 
5 min, 5 min 
1 – 3 
20 min 
3 
5 min, 5 min 
1 – 3 
25 min 
4 
5 min, 5 min 
1 – 3 
30 min 
5 
5 min, 5 min 
1 – 3 
35 min 
6 
5 min, 5 min 
1 – 3 
40 min 
7+ 
5 min, 5 min 
1 – 3 
45 min 
 
 
Adherence 
 
Adherence will be assessed using several strategies, including Physical Activity Log entries, 
and adherence outcomes obtained during the supervised sessions that include attendance, type 
of activity completed, exercise duration, time in target HR zone, subjective ratings of perceived 
effort, and achieved HR.  
 
The Intervention Oversight Team has extensive experience implementing behavioral 
management strategies to support a positive exercise environment. The goal in EXERT will be 
for participants to complete at least 80% of the prescribed exercise sessions. Participants who 
miss a supervised exercise session will be contacted by the Trainer to confirm that the 
participant will attend the next scheduled supervised session. Participants who miss 2 
consecutive supervised sessions for any reason will be contacted by the Trainer or Y-PM to 
problem-solve issues that obstruct attendance, provide encouragement, and schedule the next 
supervised session. For these cases, the Intervention Oversight Team may contact the Y-PM 
and Clinic YMCA Liaison to discuss strategies to increase adherence. Participants who do not 

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attend at least 10 supervised or unsupervised sessions per month will be counseled to improve 
attendance, and motivational strategies to increase adherence and limit obstacles to study 
participation will be implemented if necessary (e.g., goal setting, reinforcers identified and 
scheduled, etc.). In the first 12 months of the intervention, participants without an excused leave 
of absence who miss 48 exercise sessions within a 3-month period will be dropped from the 
intervention due to non-compliance.  
 
If a participant misses a supervised exercise session for reasons that are unplanned (excludes 
missed visit for holiday closure, weather, and other anticipated reasons), a Missed Visit CRF will 
be completed by the Trainer and uploaded to the EDC by the Y-PM to permit tracking of these 
events.  
 
For planned travel, total time away must be no more than a total of 2 months over the course of 
the study, and no more than 1 month at any one time to be considered for study entry. 
Participants must be willing to continue the assigned exercise unsupervised if travelling out of 
the area for more than 1 week. For all planned absences, the Trainer will meet with the 
participant in advance to develop an acceptable program for continued exercise.  
 
Although high levels of adherence will be stressed at all times, adherence will be particularly 
important in the 4 weeks preceding the Month 6 and Month 12 assessment clinic visits. At the 
Intervention Oversight Team’s discretion and in consultation with the site Principal Investigator 
(PI), the acceptable window for completion of these visits may be expanded by up to 6 weeks if 
this shift would permit participants to resume exercise at the targeted dose for at least 3 weeks 
following a temporary discontinuation and prior to assessment of primary study outcomes. 
Assessment window expansions will not impact the overall duration of the 18-month trial. 
 
 
Safety During Exercise 
 
While completing the intervention, participants will be instructed as to best-practice exercise 
guidelines including warm-up and cool-down activities, positioning and shifting of body weight, 
proper form, safety around exercise equipment, exercise quantity (intensity, duration frequency) 
and attire to minimize risk of discomfort and injury. These discussions between the Trainer and 
participant will be initiated on Day 1 of the intervention, and will continue throughout the 
12 months of supervised exercise. Physical activities will be gradually increased in intensity and 
duration in the initial stages of the intervention period to reduce likelihood of injury and to 
promote self-efficacy regarding completion of the assigned activities. Regular oversight by 
Trainers will provide numerous opportunities for encouragement, minor adjustments to the 
routine or program as needed to meet study goals and to address participant challenges, 
education about the importance of exercise and adherence to study protocols, and early 
identification of practices that could ultimately lead to injury if not corrected. Frequent contact 
between the participant and the Trainer also affords numerous opportunities to query AEs, 
opportunities that would not otherwise be available for participants in clinical trials that include 
minimal staff contact between assessment visits. 
 

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During supervised sessions, the Trainer will monitor HR, breathing rate, and other signs of 
physical effort. Sessions will be terminated and clinic staff immediately notified if any of the 
following symptoms become apparent:  
 
• 
Resting HR is <40 beats per minute (bpm) or >120 bpm  
• 
Unusual or severe shortness of breath 
• 
Chest pain, including chest discomfort or pressure, left arm pain, report of indigestion or 
stomach discomfort 
• 
Palpitations 
• 
Fainting, light headedness, dizziness   
 
A supervised session may also be terminated if participants complain of musculoskeletal pain 
that contraindicates continued safe exercise. 
 
 
 
Temporary Intervention Discontinuation 
 
There may be situations that arise that will warrant temporary discontinuation of the intervention 
for a participant. When these events occur, the Intervention Oversight Team, Y-PM, Trainer, 
and Clinic YMCA Liaison will develop a plan during twice per month meetings to keep the 
participant engaged in the study while ‘on hold’ and to reengage the participant once the 
situation has resolved. The decision to remove a participant from the study in the event of a 
prolonged Temporary Intervention Discontinuation will be made by the Intervention Oversight 
Team, in consultation with the site PI and the ADCS, on a case-by-case basis.  
 
A participant will be classified as being medically ‘on hold’ if 4 or more consecutive exercise 
sessions are missed due to self-reported hospitalization, injury or other health issue (vacations 
excluded), or is withdrawn from physical activity as per primary care provider (PCP) orders. If a 
participant is on hold, the Trainer, Y-PM, or Clinic YMCA Liaison will contact the participant 
weekly to obtain updates about status and expected schedule when exercise can be resumed.  
 
Restart following soft tissue injuries without surgery can occur when the participant self-reports 
an ability to continue the intervention. Restart following other medical complications will require 
prior approval by the Study Clinician. The site PI may choose to obtain the participant’s PCP 
approval for re-start as well. Communication with participants on medical leave regarding their 
status in the study should always emphasize that they are ‘on hold’ rather than ‘temporarily 
suspended’ or ‘on leave’ to encourage continued psychological/emotional commitment to the 
study, which will likely expedite restart when appropriate to do so.  
 
 
Reasons for Temporary Discontinuation 
 
Reason(s) for temporary intervention discontinuation will be captured in the appropriate CRF 
and coded as follows: 
 
• 
Adverse experience: The participant has experienced an AE that, in the opinion of the 

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investigator, requires temporary intervention discontinuation; this may include abnormal 
laboratory values. 
• 
Safety risk: Any participant who is deemed a safety risk by the investigator due to a 
temporary condition. 
• 
Study temporarily suspended by the ADCS. 
• 
Investigator judgment that it is in the participant’s or study’s best interest to temporarily 
discontinue the intervention until ongoing personal or medical issues no longer interfere 
with participation, including unanticipated prolonged travel or medical issues (e.g., 
surgery, accidents, development of new medical conditions), and family matters. 
• 
Intervention Oversight Team judgment that it is in the participant’s or study’s best 
interest to temporarily discontinue the intervention until ongoing personal or medical 
issues no longer interfere with participation, including unanticipated prolonged travel or 
medical issues (e.g., surgery, accidents, development of new medical conditions), and 
family matters. 
 
 
Timing of Temporary Discontinuation Relative to Assessment of Primary and 
Secondary Outcomes 
 
If a temporary intervention discontinuation occurs near the time of the scheduled Month 6 or 
Month 12 clinic assessment, the acceptable window within which to complete this visit may be 
expanded by up to 6 weeks if this would allow participants to resume the intervention at the 
prescribed dose for at least 3 weeks prior to the assessment. If longer delays are required to 
meet this goal, the assessment visit will be completed according to the original schedule. The 
decision to postpone an assessment visit will be made by the Intervention Oversight Team, in 
consultation with the site PI and the ADCS, on a case-by-case basis.  
 
 
Blinding   
 
The Study Clinician and the Clinic YMCA Liaison will be unblinded to intervention group 
assignment; all other clinic staff will remain blinded. The Study Clinician will be responsible for 
reviewing and following up on all AEs. The Clinic YMCA Liaison serves as the primary interface 
between the participating YMCA and the clinic, and thus will be exposed to intervention-specific 
details for participants. The description of TEAEs may relate to physical activities completed as 
part of the assigned intervention. Disclosure of randomization assignment will occur in the clinic 
by either the Clinic YMCA Liaison or the Study Clinician. 
 
It will be critically important that the clinic staff member(s) who administer the cognitive and 
functional assessment instruments to participants (referred to as ‘Raters’) remain blinded. 
Unblinded staff will not discuss any details about a participant’s intervention or progress with the 
Rater, and the Rater will not have access to any intervention-related data, including AEs, 
supervised exercise adherence data, or participant Physical Activity Logs. Participants will be 
instructed by the Clinic YMCA Liaison at the start of each clinic visit to refrain from sharing any 
information about their assigned intervention with the Rater or other clinic staff (other than the 
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share information about their assigned exercise program, and Raters will also remind 
participants to keep this information to themselves at frequent intervals. These procedures to 
ensure that the Rater remains blinded to intervention assignment have been used with success 
in other randomized clinical trials of aerobic exercise in non-demented older adults.16,86  
 
The Wake Forest team and the Y-USA will remain unblinded so that they may assist the 
Trainers, Y-PMs, and Clinic YMCA Liaisons with intervention-specific challenges as they arise. 
The Project Directors will remain blinded to primary and secondary outcomes by intervention 
group assignment.  
 
 
Breaking the Blind   
 
Decisions regarding breaking the blind for clinic personnel other than the Clinic YMCA Liaison 
and Study Clinician must be made in consultation with the PDs and the ADCS Medical Director. 
If the blind is broken for other clinic staff members in any instance, the site PI must document 
the following information on a Blind Break Notification Form for the participant: date, personnel 
exposed, and why/how blind was broken. An alternate plan for assessment of primary outcomes 
at future clinic visits may be requested by the PDs and the ADCS.    
 
 
Concomitant AD Medications  
 
Stable use of memantine or cholinesterase inhibitors at study entry will be permitted (3 or more 
months at a consistent dose with no plans to modify). Participants who start AD medications 
after enrollment will be permitted to continue in the study. 
 
7.0 
STUDY POPULATION 
 
A total of 300 adults diagnosed with test scores and clinical ratings consistent with amnestic 
MCI will be enrolled into EXERT. To determine eligibility, all participants will undergo cognitive 
assessment, physical and neurological examination, electrocardiogram (ECG), clinical/safety 
laboratory assessment, and interviews of the participant and study partner. 
 
 
Inclusion Criteria  
 
1. Age between 65 and 89 years old, inclusive 
2. MMSE: ≥24 for participants with 13 or more years of education; ≥22 for participants with 12 
or fewer years of education  
3. Global CDR score of 0.5 with a memory score of at least 0.5 
4. Profile of test scores and clinical ratings is consistent with amnestic mild cognitive 
impairment  
5. Speaks English fluently 
6. Visual and auditory acuity adequate for cognitive testing 
7. Completed at least 6 years of formal education or work history sufficient to exclude mental 
retardation 

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8. Has an informant who knows the participant well, has regular contact, and is available to 
accompany the participant to clinic visits or complete study partner assessments remotely.   
9. Sedentary or underactive, determined by responses to the staff-administered EXERT 
Telephone Assessment of Physical Activity (TAPA) survey 
10. Willing to be randomized to either intervention group and to complete the assigned activities 
as specified for 18 months 
11. Willing and able to reliably travel to the identified YMCA, 4 times per week for 18 months 
12. Ability to safely participate in either intervention and complete the 400 m Walk Test within 
15 min without sitting or use of any assistance 
13. Plans to reside in the area for at least 18 months 
14. For planned travel, total time away must be no more than 2 months over the course of the 
study, and no more than 1 month at any one time; participants must be willing to continue 
the assigned exercise program if travelling out of the area for more than 1 week 
15. In overall good general health with no disease or planned surgery that could interfere with 
study participation 
16. Modified Hachinski ≤4 
17. Stable use of cholinesterase inhibitors, memantine, vitamin E, estrogens, aspirin (81-300 mg 
daily), beta-blockers, or cholesterol-lowering agents for 12 weeks prior to screening 
(important for biomarker analyses) 
18. Stable use of antidepressants lacking significant anticholinergic side effects for 4 weeks 
prior to screening as long as the participant does not meet DSM V criteria for major 
depression currently or in the last 12 months; GDS scores are to be used to inform clinical 
decisions but there is no specified cut-off score for inclusion 
19. When applicable, willing to complete 4-week washout of psychoactive medications, 
including disallowed antidepressants, neuroleptics, chronic anxiolytics or sedative hypnotics, 
and willing to avoid these medications for the duration of the trial 
20. Able to complete all baseline assessments 
 
 
Exclusion Criteria  
 
1. Any significant neurologic disease, other than MCI, including any form of dementia, 
Parkinson’s disease, Huntington’s disease, normal pressure hydrocephalus, brain tumor, 
progressive supranuclear palsy, seizure disorder, subdural hematoma, multiple sclerosis, or 
history of significant head trauma with persistent neurologic sequelae or known structural 
brain abnormalities 
2. Sensory or musculoskeletal impairment sufficient to preclude successful and safe 
completion of the intervention or assessment protocols; must be able to walk safely and 
unassisted on a treadmill 
3. Contraindications for MRI studies, including claustrophobia, metal (ferromagnetic) implants, 
or cardiac pacemaker  
4. Brain MRI at screening shows evidence of infection, infarction, or other clinically significant 
focal lesions, including multiple lacunes in prefrontal or critical memory regions; inconclusive 
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5. History of major depression or bipolar disorder (DSM V criteria), psychotic features, agitation 
or behavioral problems within the last 12 months 
6. History of schizophrenia, as per DSM V criteria 
7. History of alcohol or substance abuse or dependence within the past 2 years, as per DSM V 
criteria 
8. Currently consumes more than 3 alcoholic drinks per day 
9. Clinically significant or unstable medical condition, including uncontrolled hypertension or 
significant cardiac, pulmonary, hematologic, renal, hepatic, gastrointestinal, endocrine, 
metabolic or other systemic disease in the opinion of clinic medical personnel that may put 
the participant at increased risk, influence the results or compromise the participant’s ability 
to participate in the study (treated atrial fibrillation for more than 1 year or occasional 
premature ventricular contractions on ECG are not exclusions) 
10. History in the last 6 months of myocardial infarction, coronary artery angioplasty, bypass 
grafting, or STENT placement 
11. History in the last 3 months of transient ischemic attack or small vessel stroke (if more than 
3 months, small vessel stroke with no residual effects are permitted) 
12. Expected joint replacement surgery within the next 18 months 
13. History within the last 5 years of a primary or recurrent malignant disease with the exception 
of non-melanoma skin cancers, resected cutaneous squamous cell carcinoma in situ, basal 
cell carcinoma, cervical carcinoma in situ, or in situ prostate cancer with normal prostate-
specific antigen posttreatment 
14. Hemoglobin A1c >7.0  
15. Clinically significant abnormalities in screening laboratory blood tests: low B12 is 
exclusionary, unless follow-up labs (homocysteine [HCY] and methylmalonic acid [MMA]) 
indicate that it is not physiologically significant 
16. Current or past use of insulin to treat type 2 diabetes (other diabetes medications are 
acceptable if hemoglobin A1c ≤7) 
17. Current use (within 60 days of screening) of psychoactive medications including tricyclic 
antidepressants, antipsychotics, mood-stabilizing psychotropic agents (e.g. lithium salts), 
psychostimulants, opiate analgesics, antiparkinsonian medications, anticonvulsant 
medications (except gabapentin and pregabalin for non-seizure indications), systemic 
corticosteroids, or medications with significant central anticholinergic activity. Limited use of 
antipsychotics (quetiapine ≤ 50mg/day or risperidone ≤ 0.5mg/day), and non-chronic use of 
opiate analgesics on an as needed basis is permitted; such medications must be avoided for 
8 hours before clinic assessments 
18. Chronic use of anxiolytics or sedative hypnotics except as follows: use of benzodiazepines 
for treatment on an as-needed basis for insomnia or daily dosing of anxiolytics is permitted; 
medications must be avoided for 8 hours before clinic assessments 
19. Previous or current treatment involving active immunization against amyloid  
20. Previous treatment with approved or investigational agents with anti-amyloid properties or 
passive immunization against amyloid are prohibited 12 months prior to screening and for 
the duration of the trial; treatment with other investigational agents are prohibited 3 months 
prior to screening and for the duration of the trial 
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22. For LP, current blood clotting or bleeding disorder, or significantly abnormal prothrombin 
time (PT) or partial thromboplastin time (PTT) at screening 
23. For LP, presence of physical distortions due to spinal surgery, severe degenerative joint 
disease or deformity, or obesity that could interfere with CSF collection (as per investigator 
judgment) 
24. Participants whom the PI deems otherwise ineligible 
 
 
Recruitment and Retention Strategies 
 
A recruitment plan will be developed in coordination with the ADCS and its study partners. The 
plan will include national media releases and EXERT-specific study materials that can be used 
by the clinics to recruit participants upon receipt of local IRB approval to do so. Multiple 
strategies will be used to promote high rates of retention, including twice weekly meetings with 
the Trainer, opportunities to participate in group exercise activities, and by providing tangible 
reinforcers as participants advance through the study (e.g., quilts, T-shirts, exercise 
accomplishment reports).  
 
 
Inclusion of Women and Minorities 
 
No subject will be excluded for reasons of sex, race, or ethnic group. There are currently no 
studies that definitively support or negate differences in response to aerobic exercise within 
these subgroups. Consistent with the aims of the ADCS Minority Recruitment Core, EXERT will 
target a minimum of 20% racial/ethnic minority representation in the sample of 300 older adults. 
 
8.0 
STUDY TIMELINE  
 
Study participation will include up to 6 weeks between Screening II (Visit 1) and Baseline (Visit 
2), 12 months of supervised exercise at a local YMCA facility, and 6 months of unsupervised 
exercise at the YMCA.  
 
9.0 
DESCRIPTION OF STUDY VISITS 
 
The schedule of events is provided in Appendix 1.  
 
 
Screening I (Visit 0) 
 
Prior to the in-person screening evaluation, the investigator will identify potential participants 
through routine clinical contact or an additional screening process. Prospective participants will 
have a subjective memory complaint and/or demonstrate memory impairments during 
screening, will be considered ‘sedentary’ as assessed by the EXERT TAPA, will meet all other 
inclusion/exclusion criteria, and will agree to be randomized to either the SBR or AX group. 
Study candidates may provide verbal consent over the telephone to complete the EXERT TAPA 
and other screening questions regarding demographics, medical history, and medications to 
assess eligibility for continued screening, if permitted by the local IRB. Study candidates and 

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their collaterals will not be considered as EXERT participants until the core study consent form 
is signed at an in-person screening visit. 
 
 
Screening II (Visit 1) 
 
This assessment will determine eligibility to enroll in EXERT, and may be conducted over 
multiple days. Potential participants and their study partners must sign an informed consent 
form (ICF) and Health Insurance Portability and Accountability Act (HIPAA) authorization prior to 
administration of any procedures for this assessment. Screening II procedures will include the 
following:  
 
• 
ICF/HIPAA: participant and study partner 
• 
Review of inclusion/exclusion criteria (includes review of EXERT TAPA responses) 
• 
Demographics review 
• 
Medical history 
• 
Medication review 
• 
Brief physical examination, vital signs, weight, height 
• 
Brief neurological examination 
• 
Modified Hachinski  
• 
Blood collection for ApoE genotyping, and DNA banking  
• 
Blood collection for clinical labs  
• 
12-lead resting ECG 
• 
Cognitive assessment  
o 3MSE/MMSE 
o Logical Memory I and II 
o Auditory Verbal Learning Test (AVLT) 
• 
Behavioral/functional assessment 
o CDR 
o Cognitive Change Index (self-administered) 
o GDS (self-administered) 
• 
400 m Walk Test 
• 
Brain MRI 
o For participants meeting all other eligibility criteria (as determined by site 
investigator) 
o Participants may be excluded from enrollment if safety concerns are identified  
o At approved sites, protocol will include EXERT fMRI sequences  
• 
Dispense ActiGraph Link for actigraphy data collection 
o Dispense following completion of screening procedures to participants who meet 
eligibility criteria and thus are at high probability of randomization 
o Device should be placed on the participant’s non-dominant wrist at the clinic to 
initiate the recording period 
o Device should continuously remain on the participant’s wrist for the duration of 
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o Retrieve ActiGraph Link device 10 days later during a baseline visit or by mail 
(with a reminder call on Day 10), and upload data  
o Data collection should be completed prior to randomization 
 
The participant will be permitted to proceed to the baseline visit if all inclusion/exclusion criteria 
are met, results from all screening procedures are reviewed, and eligibility have been approved 
by the site investigator. The PDs, in consultation with the ADCS Medical Director, must approve 
any exceptions or questions regarding possible exclusionary medications, medical conditions, or 
laboratory tests.  In addition, the PDs must approve any exceptions to cognitive eligibility criteria 
in cases where there is compelling evidence for MCI but not all cognitive eligibility criteria are 
met.  
 
The baseline visit should be scheduled within 6 weeks of Screening II. A re-screen is allowed in 
the event of a screen failure, but must occur more than 90 days later. If the baseline visit is 
scheduled more than 6 weeks from Screening II (i.e., out-of-window), approval to proceed to the 
baseline visit must be obtained from the ADCS and a rescreen may be required.  
 
 
Baseline (Visit 2) 
 
Baseline procedures may be completed over multiple days, but all assessments should be 
completed within 14 days, with the condition that cognitive and behavioral assessments should 
not be administered while participants are fasting. Cognitive testing conducted after an LP must 
be administered at least 48 hours following the procedure. All baseline assessments must be 
completed before randomization and start of exercise, and include: 
 
• 
Review of inclusion and exclusion criteria 
• 
Medication review 
• 
Vital signs, weight 
• 
Fasting blood collection for banking 
• 
AE query 
• 
Cognitive assessment 
o Primary outcomes assessment (administer the following tests before 
administering other cognitive/behavioral instruments) 
 ADAS-Cog13 
 Trail-Making Test 
 DSST 
 Category and Letter Word Fluency  
o Secondary outcomes assessment (iPad computer tests) 
 Cogstate: Detection task (DET), Identification task (IDN), One Card 
Learning (OCL), One Back task (OBK), Groton Maze Learning Test 
(GMLT), Face Name Associative Memory (FNAME), Behavioral 
Pattern Separation of Objects (BPSO)  
 NIH Toolbox: Flanker, Dimensional Change Card Sort (DCCS) 
• 
Behavioral/functional and other outcomes assessments 

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o Staff-administered questionnaires 
 ADCS-ADL-MCI 
 BRIEF-A 
 NPI 
o Self-administered questionnaires 
 By participant 
 SF-36 
 EQ5D 
 Research Satisfaction Survey 
 By study partner 
 Study Partner Self-Assessment Questionnaire (SF-36, 
Pittsburgh Sleep Quality Index, Insomnia Severity Index, 
questions regarding healthcare utilization) 
 EQ5D (as it relates to participant)  
• 
LP 
o For participants who agree to the LP 
o Follow-up telephone call by staff within 24 hours to query AEs 
• 
Randomization 
o Eligible participants will be randomized to either the SBR or AX group centrally 
by the ADCS using a real-time web-based randomization system 
o Designated unblinded clinic staff member will disclose this assignment to the 
participant, in person, when all baseline assessments have been completed 
o Participants will be provided with a packet of materials describing their assigned 
intervention, their responsibilities to the study, and what the study will provide for 
them. At a YMCA appointment, Trainers will provide participants with a HR 
monitor, the first Physical Activity Log, and the appropriate Activity Resource 
Guide. 
o Participants will be instructed to maintain their regular diet and other activities for 
the duration of the study  
o At time of disclosure, and once the provided materials have been carefully 
reviewed with the participant, the participant will be asked to sign a document 
indicating his/her willingness to complete the assigned programs as instructed, 
for the duration of the 18-month trial 
o Participants will be provided with the name and contact information of the site 
Y-PM who will follow-up within 3 weekdays to schedule the first appointment at 
the YMCA, which should be completed within 2 weeks of the last baseline visit 
o Participants will be instructed to withhold all information about intervention group 
assignment from all other clinic staff members throughout study participation; the 
importance of keeping this ‘secret’ will be emphasized and discussed 
• 
At Site PI discretion, an optional letter can be provided to notify the participant’s primary 
care physician of participant enrollment in the study. 
 

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Beginning in Month 1, Clinic YMCA Liaison will complete a monthly telephone call to query AEs, 
obtain medication updates, provide encouragement, and problem-solve challenges to continued 
participation.  
 
 
Month 6 (Visit 3) 
 
The Month 6 assessment should be completed 6 months (+/- 2 weeks) from the participant’s 
first appointment at the YMCA that initiated the intervention. Participants will be asked to bring 
their HR monitor to the appointment and to refrain from exercise for 24 hours prior to cognitive 
testing, which should not be completed while participants are fasting. Month 6 procedures 
include: 
 
• 
Fasting blood collection for banking 
• 
Medication review 
• 
Brief physical exam, vital signs, weight 
• 
Brief neurological exam 
• 
AE query 
• 
Briefly review adherence with participant using report provided through EDC and entries 
in the Physical Activity Logs (adherence will be regularly monitored by the YMCA 
Trainer, the Y-PM and the Intervention Oversight Team as well) 
• 
Cognitive assessment 
o Primary outcomes assessment (administer the following tests before 
administering other cognitive/behavioral instruments) 
 ADAS-Cog13 
 Trail-Making Test 
 DSST 
 Category and Letter Word Fluency  
o Secondary outcomes assessment (iPad computer tests) 
 Cogstate: DET, IDN, OCL, OBK, GMLT, FNAME, BPSO  
 NIH Toolbox: Flanker, DCCS 
• 
Behavioral/functional and other outcomes assessments 
o Staff-administered questionnaires 
 CDR 
 ADCS-ADL-MCI 
 BRIEF-A 
 NPI 
o Self-administered questionnaires  
 By participant 
 Cognitive Change Index 
 SF-36 
 EQ5D 
 Research Satisfaction Survey 
 By study partner 

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 Study Partner Self-Assessment Questionnaire (SF-36, 
Pittsburgh Sleep Quality Index, Insomnia Severity Index) 
 EQ5D (as it relates to participant) 
• 
400 m Walk Test 
• 
Dispense ActiGraph Link for actigraphy data collection 
o Place device on the participant’s non-dominant wrist to initiate recording period 
o Device should continuously remain on the participant’s wrist for the duration of 
the 10-day recording period 
o Retrieve device from participant 10 days later by return mail (with a reminder call 
on Day 10), and upload data when device is received 
• 
Replace battery in HR monitor 
• 
Provide participant with 6-month supply of Physical Activity Logs  
 
The Clinic YMCA Liaison will continue to complete monthly telephone calls to query AEs, obtain 
medication updates, provide encouragement, and problem-solve challenges to continued 
participation.  
 
 
Month 12 (Visit 4) / or Early Termination 
 
The Month 12 assessment will provide the primary endpoints to evaluate trial efficacy, and 
should be completed 12 months (+/- 2 weeks) from the participant’s first appointment at the 
YMCA that initiated the intervention. The following procedures may be completed over multiple 
days, but within a 7-day window. Participants will be instructed to bring their HR monitor to the 
appointment and to refrain from exercise for 24 hours prior to cognitive testing, fMRI (for 
approved sites), and the LP. Cognitive testing should not be completed while participants are 
fasting, and if conducted after an LP, testing must be administered at least 48 hours following 
the procedure. Month 12 procedures include: 
 
• 
Fasting blood collection for clinical labs  
• 
Fasting blood collection for banking 
• 
Medication review 
• 
Brief physical exam, vital signs, weight 
• 
Brief neurological exam 
• 
AE query 
• 
Briefly review adherence with participant using report provided through EDC and entries 
in the Physical Activity Logs (adherence will be regularly monitored by the YMCA 
Trainer, the Y-PM and the Intervention Oversight Team as well) 
• 
Cognitive assessment 
o Primary outcomes assessment (administer the following tests before 
administering other cognitive/behavioral instruments) 
 ADAS-Cog13 
 Trail-Making Test 
 DSST 
 Category and Letter Word Fluency  

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o Secondary outcomes assessment 
 3MSE/MMSE 
 iPad computer tests 
 Cogstate: DET, IDN, OCL, OBK, GMLT, FNAME, BPSO 
 NIH Toolbox: Flanker, DCCS 
• 
Behavioral/functional and other outcomes assessments 
o Staff-administered questionnaires 
 CDR 
 ADCS-ADL-MCI 
 BRIEF-A 
 NPI 
o Self-administered questionnaires  
 By participant 
 Cognitive Change Index 
 SF-36 
 EQ5D 
 Research Satisfaction Survey 
 By study partner 
 Study Partner Self-Assessment Questionnaire (SF-36, 
Pittsburgh Sleep Quality Index, Insomnia Severity Index) 
 EQ5D (as it relates to participant) 
• 
400 m Walk Test 
• 
Brain MRI 
o At approved sites, protocol will include fMRI sequences  
• 
LP 
o CSF may be collected at this visit, even if not successfully collected at Baseline  
o Follow-up telephone call by staff within 24 hours to query AEs 
• 
Dispense ActiGraph Link for actigraphy data collection 
o Place on the participant’s non-dominant wrist to initiate recording period 
o Device should continuously remain on the participant’s wrist for the duration of 
the 10-day recording period 
o Retrieve device from participant 10 days later by return mail (with a reminder call 
on Day 10), and upload data when device is received 
• 
Replace battery in HR monitor 
• 
Provide participant with 6-month supply of Physical Activity Logs  
• 
Site PI and Raters to complete Treatment Blinding Questionnaire  
 
All participants will transition to unsupervised exercise during the last 6 months of the study. 
Participants will be instructed to continue their assigned intervention at the specified frequency, 
duration, and intensity, and to continue to track their exercise using their Physical Activity Log. 
During this phase of the study, the Clinic YMCA Liaison will continue to contact participants by 
telephone, once per month to query AEs, obtain medication updates, provide encouragement, 
and problem-solve challenges to continued participation.   
 

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Month 18 (Visit 5) 
 
The Month 18 assessment should be completed 18 months (+/- 2 weeks) from the participant’s 
first appointment at the YMCA that initiated the intervention. Participants will be instructed to 
bring their HR monitor to the appointment and to refrain from exercise for 24 hours prior to 
cognitive testing, which should not be completed while fasting. Participants should also be 
asked to return all Physical Activity Logs for review and data entry, as this will be their final 
EXERT assessment. Month 18 procedures include: 
 
• 
Fasting blood collection for clinical labs 
• 
Fasting blood collection for banking  
• 
Medication review 
• 
Brief physical exam, vital signs, weight 
• 
Brief neurological exam 
• 
AE query 
• 
Review returned Physical Activity Logs to ensure that they were completed and 
accurately reflect YMCA attendance records (provided in advance) and the participant’s 
self-report  
• 
Dispense ActiGraph Link for actigraphy data collection 
o Send device and instructions to participants 14 days before the Month 18 
assessment; confirm with participant that the device was received and in place 
with a phone call at the start of the recording period  
o At the clinic visit, remove the device from the participant’s wrist and upload data  
• 
Cognitive assessment 
o Primary outcomes assessment (administer the following tests before 
administering other cognitive/behavioral instruments) 
 ADAS-Cog13 
 Trail-Making Test 
 DSST 
 Category and Letter Word Fluency  
o Secondary outcomes assessment (iPad computer tests) 
 Cogstate: DET, IDN, OCL, OBK, GMLT, FNAME, BPSO  
 NIH Toolbox: Flanker, DCCS 
• 
Behavioral/functional and other outcomes assessment 
o Staff-administered questionnaires 
 CDR 
 ADCS-ADL-MCI 
 BRIEF-A 
 NPI 
o Self-administered questionnaires  
 By participant 
 Cognitive Change Index 
 SF-36 
 EQ5D 

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 Research Satisfaction Survey 
 By study partner 
 Study Partner Self-Assessment Questionnaire (SF-36, 
Pittsburgh Sleep Quality Index, Insomnia Severity Index) 
 EQ5D (as it relates to participant) 
• 
400 m Walk Test 
• 
Provide study close-out materials 
o Summary of progress in intervention 
o Fasting clinical blood test results from all visits 
o Color printout of single brain MRI image if available 
o Study completion certificate 
o ‘Thank-you’ gift or payment for participation 
o Participant’s HR monitor (change battery) 
o Contact information for a YMCA staff member who will provide a personal 
coaching session at the YMCA, at no cost 
• 
Site PI and Raters to complete Treatment Blinding Questionnaire  
 
10.0 
EARLY INTERVENTION DISCONTINUATION 
 
Investigators at each site will make every effort to maximize participant retention. If a participant 
expresses a desire to stop the intervention, the Intervention Oversight Team will be notified and 
will hold a conference call with the Clinic YMCA Liaison and/or site investigator, and Y-PM 
and/or Trainer to discuss the participant’s existing challenges and possible approaches to 
reduce burden to encourage continued participation if at all possible (e.g., adapt exercise 
routine to reduce pain or increase interest, problem-solve regarding transportation issues, etc.).  
 
If a participant continues to decline further participation, or if an investigator discontinues the 
intervention, an Early Discontinuation Visit should be completed as soon as possible just prior to 
or immediately following intervention discontinuation. The Early Discontinuation Visit will include 
all Month 12 assessments to permit collection of primary and secondary outcome measures. If 
this Early Discontinuation Visit occurs before the start of Month 4, then the MRI and LP (when 
applicable) should not be completed. Alternatively, if an in-person Early Discontinuation Visit 
cannot be completed, site personnel should complete, by telephone, as many of the Month 12 
procedures as possible (e.g., medication review, AE query, request return of Physical Activity 
Logs for review and data entry, CDR, Cognitive Change Index, SF-36, ADCS-ADL-MCI, BRIEF-
A, NPI, Research Satisfaction Survey, EQ5D, Study Partner Self-Assessment Questionnaire). 
 
All early intervention discontinuation participants will be strongly encouraged to complete not 
only the Early Discontinuation Visit, but also all regularly scheduled clinic assessments through 
Month 18.  
 
 
 

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Reasons for Early Discontinuation 
 
Reason(s) for intervention discontinuation will be coded as follows: 
 
• 
Perceived lack of efficacy by participant 
• 
Adverse experience by participant that, in the opinion of the investigator, requires 
early termination; this may include abnormal laboratory values 
• 
Participant becomes a safety risk   
• 
Death 
• 
Participant is unwilling or unable to participate 
• 
Participant is not able to adhere to protocol requirements as per judgment of the 
Intervention Oversight Team or site investigator 
• 
Study partner unwilling or unable to participate, and new appropriate study 
partner cannot be identified 
• 
Lost to follow up: Participant could not be recalled to the clinic for follow-up 
assessments 
• 
Participant enrolls in another intervention trial 
• 
EXERT is terminated  
• 
Investigator judgment that it is in the participant’s best interest to discontinue 
participation 
• 
ADCS request: the ADCS determines that it is in the participant’s best interest to 
discontinue participation in the study 
• 
Intervention Oversight Team request: the Intervention Oversight Team determines 
that it is in the participant’s best interest to discontinue participation in the study 
 
11.0 
STUDY-SPECIFIC INSTRUMENTS  
 
 
EXERT Telephone Assessment of Physical Activity  
 
The TAPA is a brief, validated, and commonly administered telephone-based measurement tool 
to assess physical activity in older adults.87 This protocol uses a modified version, adapted for 
EXERT with permission of the original authors.  
 
 
Cognitive Evaluations  
 
11.2.1 Modified Mental State Examination  
 
The 3MSE, an expanded version of the MMSE, has been widely used in epidemiologic cohort 
studies to assess global cognitive function.88 The 3MSE consists of items assessing 8 domains 
of cognitive function (remote memory, recent memory, mental control, time and space 
orientation, abstract thinking, verbal abilities, verbal comprehension and spatial cognition) and is 
scored on a 100-point scale with higher scores indicating better performance. The MMSE89 is a 

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brief, frequently used screening instrument for AD drug studies and includes several shared 
items with the expanded version.  
 
11.2.2 Logical Memory  
 
Logical Memory I and II (immediate and delayed recall) is a modification of the episodic memory 
subtest from the Wechsler Memory Scale-Revised (WMS-R).90 In this version, free recall of one 
short story consisting of 25 bits of information will be elicited immediately after it is read aloud to 
the participant and again after a 20-30 minute delay. Total bits of information from the story that 
are recalled immediately (maximum score = 25) and after the delay (maximum score = 25) are 
recorded.  
 
11.2.3 Auditory Verbal Learning Test 
 
The AVLT is a list learning task with multiple outcomes to assess encoding, consolidation, 
storage, and retrieval of verbal information.91 On each of 5 learning trials, 15 unrelated nouns 
are presented orally at the rate of one word per second and immediate free recall of the words 
is elicited. Number of correctly recalled words on each trial is recorded. A distractor list is then 
presented, after which participants are asked to recall words from the first list (Trial 6). Following 
a 20-30minute delay filled with unrelated testing, free recall of the first 15-item word list (Trial 7) 
is again elicited.  
 
11.2.4 ADAS-Cog-Exec Global Composite  
Select subscales of ADAS-Cog13, tests of executive function, CDR sum of select box scores.49 
 
ADAS-Cog13. The ADAS-Cog92 is a structured scale that evaluates memory (word recall, word 
recognition), reasoning (following commands), language (naming, comprehension), orientation, 
ideational praxis (placing letter in envelope) and constructional praxis (copying geometric 
designs). Ratings of spoken language, language comprehension, word finding difficulty, and 
ability to remember test instructions are also obtained. The test is scored in terms of errors, with 
higher scores reflecting poorer performance and greater impairment. Scores can range from 0 
(best) to 70 (worse) and then number of items not recalled ranging from 0-10 is added for a 
maximum score of 80. The 13-item version of the ADAS-Cog will be administered in EXERT. 
Different Raters should administer the ADAS-Cog13 and the CDR. The ADAS-Cog-Exec global 
composite includes ADAS-Cog13 Word Recall, Delayed Word Recall, Orientation, and Number 
Cancellation. 
 
Trail-Making Test (Trails A and B). Trails A89 consists of 25 circles numbered 1 through 25 
distributed over a white sheet of paper. The participant is instructed to draw a line to connect the 
circles in ascending numerical order as quickly as possible (150 second maximum). Trails B 
consists of 25 circles containing either numbers (1 through 13) or letters (A through L) that are 
randomly distributed across the page, and participants are instructed to connect the circles in 
alternating and ascending order (e.g., 1 to A; 2 to B). Time to complete Trails B (300 second 
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of the task, is a sensitive measure of executive function and working memory, and the effects of 
aerobic exercise.16,20 The ADAS-Cog-Exec global composite includes time to completion for 
parts A and B of the Trail Making Test.  
 
Digit Symbol Substitution Test. The DSST89 is a subset from the Wechsler Adult Scale of 
Intelligence-Revised (WAIS-R). The test consists of 110 small blank squares presented in 7 
rows with 1 of 9 numbers (1-9) randomly printed directly above each blank square. A legend is 
printed above the rows of blank squares, at the top of the page. The legend pairs each of the 
numbers with an abstract symbol. Following a few practice trials, the participant is asked to use 
the legend to fill in the blank squares in consecutive order, working from left to right across the 
rows, with the symbol that is paired with each number and as quickly as possible for 90 
seconds. Number correct is recorded (maximum score =110). This test engages multiple 
abilities including attention, psychomotor speed, visual scanning and tracking, and working 
memory. The ADAS-Cog-Exec global composite scale includes the total score for the Digit 
Symbol Substitution Test.  
 
Word Fluency. This 2-part task assesses word fluency by letter and by category, and thus 
involves planning, organization, and cognitive flexibility. Participants are asked to generate as 
many words as possible in 60 seconds that begin with different letters of the alphabet (f and L), 
in 2 separate trials. Participants are then asked to generate as many words as possible in 60 
seconds that belong to a given semantic category (animals, vegetables). Reduced word fluency 
is associated with AD onset and progression,93 and was sensitive to the effects of aerobic 
exercise in preliminary studies.16,20 The ADAS-Cog-Exec global composite includes the score 
for Category Fluency (mean of Animal and Vegetable Fluency).  
 
Clinical Dementia Rating Scale – Sum of Boxes. The CDR89 is a clinical scale that rates the 
severity of dementia as absent, questionable, mild, moderate, or severe (CDR score of 0, 0.5, 1, 
2, or 3, respectively). The score is based on interviews with the participant and study partner, 
using a structured interview that assesses 6 domains: memory, orientation, judgment and 
problem solving, community affairs, home and hobbies, and personal care. The ratings of 
degree of impairment for each of the 6 domains are synthesized into one global rating of 
dementia (ranging from 0 to 3), with more refined measure of change available with the Sum of 
Boxes. At screening, the CDR global and memory scores will be used to assess eligibility. For 
all other administrations, scores across the 6 domains will be summed to obtain the Sum of 
Boxes score. Different Raters should administer the CDR and the ADAS-Cog13. The ADAS-
Cog-Exec global composite includes the box scores for CDR Memory, Orientation, and 
Judgement and Problem Solving.  
 
11.2.5 Executive Function Composite 
 
The Executive Function Composite will combine 8 measures of executive control using 
performance outcomes on paper-and-pencil tests (described above: Trails B, DSST, Word 
Fluency, Number Cancellation), and iPad tests from the NIH Toolbox (Flanker, DCCS), and 

A D C -0 4 1 -E X  
 
P a g e 5 0  of 7 8  
 
 
V er si o n 7. 0: 1 8 N O V 2 0 2 1 
 
 
 
 
C o g st at e ( G M L T, O B K ). NI H T o ol b o x a n d C o g st at e t e st s will b e l o a d e d o n t h e s a m e i P a d a n d 
a c c e s s e d t hr o u g h diff er e nt i c o n s  o n t h e s cr e e n . 
 
NI H T o ol b o x  Fl a n k er.9 4  T h i s s p e e d e d t e st m e a s ur e s att e nti o n a n d i n hi bit or y c o ntr ol. T h e 
p arti ci p a nt i s a s k e d t o f o c u s o n o n e sti m ul u s ( arr o w i n t h e c e nt er of t h e s cr e e n ) w hil e i n hi biti n g 
at t e nti o n ot h er sti m uli (fl a n ki n g arr o w s). S o m eti m e s t h e c e ntr al sti m ul u s i s p oi nti n g i n t h e s a m e 
dir e cti o n a s t h e fl a n k er s ( c o n gr u e nt) a n d s o m eti m e s i n t h e o p p o sit e dir e cti o n (i n c o n gr u e nt). 
S c ori n g i s b a s e d o n a c o m bi n ati o n of r e a cti o n ti m e  a n d a c c ur a c y. T h e t e st t a k e s a p pr o xi m at el y 
3 mi n ut e s t o a d mi ni st er.   
 
NI H T o ol b o x  Di m e n si o n al C h a n g e C ar d S ort .9 4  T h e D C C S  h a s b e e n v ali d at e d i n ol d er a d ult s, 
i s s e n siti v e t o t h e eff e ct s of a gi n g, a n d p erf or m a n c e i s hi g hl y c orr el at e d wit h s c or e s o n 
st a n d ar di z e d t e st s of c o g niti v e fl e xi bilit y ( i. e., C ol or-W or d I nt erf er e n c e I n hi biti o n  of t h e D eli s -
K a pl a n E x e c uti v e F u n cti o n S c al e s). I n t hi s s p e e d e d t e st, 2 t ar g et pi ct ur e s ar e pr e s e nt e d t h at 
v ar y al o n g 2 di m e n si o n s ( i. e., s h a p e, c ol or). P arti ci p a nt s ar e a s k e d t o m at c h a s eri e s of bi v al e nt 
t e st pi ct ur e s ( e. g., y ell o w b all s, bl u e tr u c k s) t o t h e t ar g et pi ct ur e s, fir st a c c or di n g t o o n e 
di m e n si o n ( e. g., c ol or) a n d t h e n, aft er a n u m b er of tri al s, a c c or di n g t o t h e ot h er di m e n si o n ( e. g., 
s h a p e). “ S wit c h” tri al s ar e al s o i n cl u d e d, i n w hi c h t h e p arti ci p a nt m u st c h a n g e t h e di m e n si o n 
b ei n g m at c h e d. F or e x a m pl e, aft er 4 tri al s m at c hi n g o n s h a p e, t h e p arti ci p a nt m a y b e a s k e d t o 
m at c h o n c ol or f or t h e n e xt tri al a n d t h e n m at c h o n s h a p e  a g ai n  f or s u b s e q u e nt tri al s. S c ori n g i s 
b a s e d o n a c o m bi n ati o n of r e a cti o n ti m e  a n d a c c ur a c y. T h e t e st t a k e s a p pr o xi m at el y 4 mi n ut e s 
t o a d mi ni st er.  
 
C o g st at e  Gr ot o n M a z e L e ar ni n g T e st  (P e di atri c V er si o n ).9 5 ,9 6  T h e G M L T i s a t e st of e x e c uti v e 
f u n cti o n a s s e ssi n g vi s u al/ s p ati al  w or ki n g m e m or y, l e ar ni n g, a n d err or m o nit ori n g.  T h e t e st 
c o n si st s of a n 8 x 8 gri d of gr e y til e s pr e s e nt e d o n a n i P a d s cr e e n. T o fi n d t h e hi d d e n p at h fr o m 
o n e c or n er of t h e gri d t o a n ot h er, t h e p arti ci p a nt t o u c h e s o n e til e at a ti m e  st a rti n g i n t h e t o p l eft 
c or n er,  a n d r e s p o n d s t o f e e d b a c k a b o ut w h et h er t h e t o u c h e d til e b el o n g s t o t h e p at h, w hi c h i s 
i n di c at e d b y a ‘�’ if c orr e ct, a n d a n ‘X ’ if i n c orr e ct. If t h e m o v e i s c orr e ct, t h e �r e m ai n s vi si bl e o n 
t h e til e a n d t h e p arti ci p a nt t o u c h e s  a n ot h er a dj a c e nt s q u ar e. If t h e t o u c h i s i n c orr e ct, t h e X  o n 
t h e til e di s a p p e ar s a n d p arti ci p a nt s m u st t o u c h t h e l a st c orr e ct til e i n t h e p at h  b ef or e c o nti n ui n g. 
T h e tri al e n d s o n c e t h e p arti ci p a nt s u c c e s sf ull y t o u c h e s all til e s i n t h e hi d d e n p at h t h at l e a d s t o 
t h e fl a g i n t h e b ott o m ri g ht c or n er of t h e gri d. T ot al ti m e f or t e st a d mi ni str ati o n i s a p pr o xi m at el y 7  
mi n ut e s.  
 
C o g st at e  O n e B a c k. 5 7  T h e O B K i s a t e st of att e nti o n a n d w or ki n g m e m or y. I n t hi s t a s k, a 
pl a yi n g c ar d i s pr e s e nt e d f a c e u p i n t h e c e nt er of t h e s cr e e n  a n d st arti n g wit h tri al 2, t h e 
p arti ci p a nt m u st d e ci d e w h et h er it i s i d e nti c al t o t h e c ar d pr e s e nt e d i n t h e pr e vi o u s tri al b y 
r e s p o n di n g wit h a fi n g er t o u c h. P erf or m a n c e o n t h e C o g st at e D E T a n d I D N t a s k s will b e u s e d t o 
a dj u st O B K p erf or m a n c e f or si m pl e a n d c h oi c e r e a cti o n ti m e.  Ti m e t o a d mi ni st er all 3 t a s k s i s 6 
mi n ut e s ( 2 mi n ut e s p er t a s k). 
 
 

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11.2.6 Episodic Memory Composite 
 
The Episodic Memory Composite combines several measures of short-term memory including 
Delayed Word Recall from the ADAS-Cog13 and four Cogstate tasks administered via iPad 
(FNAME, BPSO, OCL, GMLT-Delayed Recall). 
Cogstate Face-Name Associative Memory Exam. FNAME pairs 180 pictures of unfamiliar faces 
with common first names (5 lists of 36 trials), and engages memory networks, including the 
hippocampus and default network regions as per fMRI findings.97-99 During encoding, 
participants are instructed to remember each face-name pair presented on the screen and to 
rate how well the name ‘fits’ the face using a Likert scale. During retrieval, participants are 
asked to recall the correct name associated with each face, and subsequently, to select the 
correct name per face from options presented on the screen. For both tasks, accuracy is 
recorded. Test performance is sensitive to physical activity in older adults.100  
 
Cogstate Behavioral Pattern Separation of Objects.101 This visual recognition memory test 
displays pictures on the iPad screen of common objects interspersed with highly similar “lures” 
that vary in levels of mnemonic and visual similarity with target items. During encoding, 
participants indicate whether pictures were of “indoor” or “outdoor” objects by touching a ‘button’ 
on the screen. During the test phase, participants view objects that include exact replicas of 
previously viewed objects, similar but not identical objects, and new objects, and are asked to 
judge whether each object is “old,” “similar,” or “new” using a ‘button’ press. Higher accuracy 
reflects better separation of the visual patterns, and thus better memory. The BPSO robustly 
activates the hippocampus in fMRI studies, and is sensitive to early dysfunction in the 
hippocampus in aging,102-104 and to therapeutic effects in adults with amnestic MCI.105,106 
 
Cogstate One Card Learning.57 The OCL is a test of short-term memory that is sensitive to 
early changes associated with AD.107,108 In this task, a playing card is presented in the center of 
the iPad and starting with Trial 2, the participant must decide whether or not the same card was 
seen before in this task by responding with a finger touch. Administration time is 5 minutes. 
Performance on DET and IDN will be used to adjust OCL performance for simple and choice 
reaction time.  
 
Cogstate GMLT-Delayed Recall. Free recall of the previously learned hidden path will be 
assessed following a delay of approximately 15 minutes. 
 
 
Behavioral and Functional Evaluations  
 
11.3.1 Clinical Dementia Rating Scale – Sum of Boxes (described above) 
 
11.3.2 ADCS-Activities of Daily Living-MCI 
 
The ADCS-ADL-MCI scale is a questionnaire assessing ability to perform everyday tasks, and is 
used to detect functional decline in adults with MCI.109 It was adapted from an inventory 
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interview, study partners are queried as to whether participants attempted each item in the 
inventory during the prior 4 weeks and at what ‘level’ of performance. The questions focus 
predominantly on instrumental activities of daily living (e.g. shopping, preparing meals, using 
household appliances, keeping appointments, reading).  
 
11.3.3 Behavior Rating Inventory of Executive Function – Adult Version  
 
The BRIEF-A is a standardized and validated questionnaire that captures subjective report of an 
adult’s executive function or self-regulation in an everyday environment. The questionnaire can 
be administered to obtain self- or informant-report.  
 
11.3.4 Neuropsychiatric Inventory  
 
The NPI is a well-validated, reliable, multi-item instrument to assess psychopathology in MCI 
and AD dementia based on the results of an interview with the study partner.111 The NPI 
evaluates both the frequency and severity of 10 neuropsychiatric features, including delusions, 
hallucinations, agitation/aggression, dysphoria, anxiety, euphoria, apathy, disinhibition irritability 
and lability, and aberrant motor behavior, as well as evaluates sleep and appetite/eating 
disorders. Frequency assessments range from 1 (occasionally, less than once per week) to 4 
(very frequently, once or more per day or continuously). Severity assessments range from 1 
(mild) to 3 (severe). The score for each subscale is the product of severity and frequency and 
the total score is the sum of all subscales. 
 
11.3.5 Cognitive Change Index  
 
The Cognitive Change Index, adapted from Saykin et al.,112 is a self-report questionnaire listing 
common experiences (e.g., “recalling conversations a few days later”, “remembering names and 
faces of new people I meet”) and participants indicate amount of perceived change over the 
past 5 years using a Likert scale. Only the first 12 questions that address subjective memory 
concerns will be administered. The same 12-item subscale is used in the large multicenter 
ADNI-2 study.  
 
11.3.6 Geriatric Depression Scale  
 
The GDS is a well-validated, self-administered questionnaire used to assess mood in geriatric 
populations.113  
 
11.3.7 SF-36  
 
The Short Form Health Survey is a well-validated, commonly used self-administered survey of 
health status that includes questions about mood, pain, physical functioning, and overall 
health.114 
 
 
 

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11.3.8 EQ5D  
 
The EQ5D is a brief questionnaire about health-related quality of life that queries 5 dimensions 
of everyday experience (mobility, self-care, usual activities, pain/discomfort, anxiety/depression) 
that are each rated using a 5-point scale (no problems/slight problems/moderate 
problems/severe problems/extreme problems). The EQ5D is a well-validated instrument that 
provides a single index for overall health status.115 
 
11.3.9 Study Partner Self-Assessment Questionnaire 
 
This self-administered questionnaire assesses the study partner’s mood, physical functioning, 
sleep, and overall health status, and includes the SF-36 (described above) and 2 well-validated 
brief assessments of sleep quality (Pittsburgh Sleep Quality Index) and duration (Insomnia 
Severity Index116). 
 
 
Modified Hachinski 
 
This brief questionnaire, conducted by a clinician,  incorporates information regarding medical 
history, cognitive symptoms and features of stroke, reported by a study partner as well as the 
neurological examination, and neuroimaging studies.117 
 
 
Research Satisfaction Survey 
 
A Research Satisfaction Survey will be administered to the participant and study partner to 
evaluate satisfaction with the study. The survey may reveal specific aspects of the study that 
participants dislike, which can inform efforts to improve their experiences when participating in 
future studies. Past studies show that participant input and feedback is important for 
retention.118,119 
 
 
Treatment Blinding Questionnaire 
 
Following the Month 12 and 18 clinic assessments, the site PI and Raters will complete a 
Treatment Blinding Questionnaire to document knowledge of intervention group assignment per 
participant.   
 
 
 

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Heart Rate Monitor 
A HR monitor that includes a watch-like device and a chest 
strap will be provided to all participants to wear during exercise, 
which will permit HR monitoring to assess effort and exercise 
intensity.  
 
 
ActiGraph Link 
 
The ActiGraph Link is a validated 3-axis accelerometer and 
watch-like device (ActiGraph™) with a low profile case and 
high-resolution liquid crystal display window (see picture on 
right). The device contains a gyroscope, magnetometer, and 
secondary accelerometer to record movement, rotation, and 
body position data. The ActiGraph Link will be configured to 
display only the time, not activity information.  
 
 
Instruments Administered by Trainers at the YMCA 
 
11.9.1 Rating of Perceived Exertion  
 
The RPE modified Borg scale is a validated and accepted supplemental method for assessing 
exercise intensity in older adults. The rating scale ranges from 1 to 10 (1 =very mild, to 10 
=very, very hard), and participants are trained to self-assess their cardiorespiratory effort using 
this tool.  
 
11.9.2 Adverse Event Checklist 
 
The AE Checklist will be administered once per week by the Trainer prior to a supervised 
exercise session. The checklist will query change in health or physical status in the last week, 
and will include questions to identify SAEs (death, life-threatening, hospitalization, disability or 
permanent damage). 
 
12.0 
STUDY–SPECIFIC PROCEDURES 
 
 
Safety Assessments 
 
Physical and neurological examinations will occur every 6 months while participants are enrolled 
in the study. An MRI will be conducted during screening and repeated at Month 12 for safety 
assessment and study outcomes. Participants receiving an LP will receive a follow-up telephone 
call 24 hours later from the clinic to confirm the participant’s well-being and to query AEs, which 
will be reported to the ADCS DSMB. Safety reports will be prepared by the Medical and Safety 
Core and submitted to the DSMB for periodic review.  
 

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Participants will exercise at YMCA facilities staffed by trained personnel who ensure the safety 
of all YMCA members. Twice per week, a study-certified YMCA Trainer will supervise the 
participant while exercising to ensure safe practices are consistently used.   
 
12.1.1 Physical and Neurological Examination 
 
A brief physical examination will be performed by a medically qualified professional every 6 
months. A review of the major body systems will be performed and vital signs will be assessed. 
A brief neurological examination will include assessment of motor strength, sensory, deep 
tendon, tremor, cerebellar, cranial, and mental status. 
 
12.1.2 Electrocardiogram  
 
A standard 12-lead resting ECG will be performed during screening. The ECG report will be 
reviewed, signed, and dated by the investigator. Those with clinically significant ECG findings 
will be referred for follow-up as deemed appropriate by the investigator, and may be excluded 
from the study. 
 
12.1.3 Clinical Laboratory Evaluations 
 
All routine laboratory samples will be analyzed by a central laboratory, which will provide a 
procedures manual and supplies. Lab reports will be reviewed, signed and dated by the Study 
Clinician. If a value is outside of the laboratory’s normal range, the Study Clinician will indicate if 
it is clinically significant. If clinically significant, lab tests may need to be repeated and/or follow-
up with the participant’s PCP may be required.    
 
Clinical laboratory assessments include: 
• 
Chemistry Panel (Screening II, Month 12) 
• 
Fasting glucose and hemoglobin A1c  
• 
TSH (Screening II) 
• 
CBC | Differential (Screening II, Month 12) 
• 
Vitamin B12 (Screening II); Note: HCY & MMA reflex tests will be run only if the B12 
level is ≤211 pg/ml; additional blood draw will not be required for reflex testing 
• 
PT, PTT Coagulation Panel (Screening II, Month 12) 
 
 
 

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Biofluids 
 
Biofluid collection schedule, quantities, and assessments are summarized in the table below.  
 
12.2.1 Genetic Samples, Storage and Future Use 
 
DNA will be extracted from participant blood samples to determine ApoE genotypes, which will 
be examined with regard to their roles on cognitive and biomarker response to the interventions. 
Participants will be asked to consent to optional DNA banking for future research studies. ApoE 
genotyping will be performed and DNA will be banked using established ADCS Biomarker Core 
protocols.  
 
12.2.2 Blood Collection for Biomarker Analyses and Banking 
 
Blood will be collected to extract plasma and peripheral blood mononuclear cells (PBMCs) in the 
morning after a minimum 10-hour overnight fast, and shipped to the ADCS Biomarker Core at 
UCSD for banking and analysis.  
 
12.2.3 CSF Collection for Biomarker Analyses and Banking 
 
It is expected that most participants will receive LPs pre- and post-treatment. Coagulation and 
platelets will be examined in blood before an LP is performed. All CSF samples will be collected 
after an overnight fast. Participants who are taking anticoagulants, warfarin (Coumadin) and 
dabigatran (Pradaxa) should not be screened for an LP, as these are prohibited medications. 
Based on clinician judgment and depending on the clinical indication, it may be suitable to 
discontinue participants from their anti-platelet agent (e.g., aspirin, Plavix, NSAIDs) for 5-7 days 
prior to the LP and until at least 24 hours after the procedure. It is not required that participants 
be discontinued from their anti-platelet agent in order to screen and enroll in EXERT.  
 

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The baseline LP must be conducted prior to randomization. At Month 12, the LP should be 
performed after the MRI or at least 72 hours before the MRI, and at least 24 hours after the last 
bout of exercise.  
 
A total of 20 ml of CSF will be collected during each LP. To clear any blood from minor trauma 
associated with needle insertion, the first 1-2 mL of CSF are discarded (or more if needed). 
Collected CSF will be aliquoted into sterile microtubes. Approximately 2 mL of CSF or volume 
per local laboratory requirements will be sent at ambient temperature to the local laboratory for 
protein, glucose and cell count. The remaining CSF will be shipped to the ADCS Biomarker 
Core at UCSD for storage and analysis. 
 
 
Magnetic Resonance Imaging   
 
12.3.1 Site Qualification  
 
Structural MRI. All sMRI procedures will be overseen by the ADCS Imaging Core. Each site’s 
scanner will have an identifying number, which will be appended to the image header of all MRI 
data. Each scanner will be subjected to a qualifying process that includes an evaluation for 
excessive vibration or other image artifact revealed through submitted magnetic resonance 
(MR) images obtained through a standard protocol of an American College of Radiology 
phantom. In addition, 3D T1 MPRAGE or IR-FSPGR images of a human brain obtained through 
a standardized imaging protocol of a volunteer at each site will be submitted to the ADCS 
Imaging Core for automated segmentation, and the resulting segmentations will be examined by 
ADCS Imaging Core for anatomical accuracy. Once the phantom and volunteer scan pass 
quality control by the ADCS Imaging Core, the scanner will be considered certified for EXERT. 
Because longitudinal analysis of brain volumetry will be used in this study, sites will be required 
to use the same scanner for both scans (Baseline, Month 12) of a particular participant. 
 
Functional MRI. Arterial Spin Labeling (ASL) is a contrast-free, resting-state fMRI approach to 
quantify regional blood flow in the brain. Sites that are able to perform ASL will be asked to work 
with the Imaging Core and collaborators at Wake Forest to establish a qualified ASL protocol, 
which can be appended to the sMRI protocol. ASL will be evaluated and approved centrally in a 
manner similar to the sMRI qualification procedures described above. Unlike sMRI qualification 
for safety and volumetric outcomes, ASL qualification will not be required for initiating study 
procedures.  
 
12.3.2 Data Acquisition  
 
The same MRI protocols will be administered at screening and Month 12, which will include a 
localizer scan, followed by a high-resolution 3D T1 structural series (MPRAGE or IR-SPGR), a 
T2-weighted series (FLAIR), a diffusion weighted scan, and a gradient recalled echo scan. Sites 
with access to approved 3.0 Tesla (3T) scanners will be asked to include a resting-state ASL 
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12.3.3 Data Management and Quality Control 
 
Images will be checked for image quality and adherence to scanning protocols. 3D T1-weighted 
datasets passing quality checks will be corrected for spatial distortion and for intensity variation. 
Baseline and follow-up datasets for each participant will be spatially registered to one another 
using rigid-body registration followed by nonlinear registration and neuroanatomic parcellation to 
quantify whole-brain and subregional volumetric change on a participant-by-participant basis.  
 
Sites will use a scanner expected to be available for the duration of the study. Scanners used 
successfully in prior ADCS studies, or are likely to have convenience of scheduling and 
participant experience, are preferred, regardless of field strength for sites collecting only sMRI 
data. For approved sites that will also collect fMRI, 3T machines must be used. Scanners must 
pass the study’s qualification procedures, and participants must be scanned by the same 
scanner at Baseline and Month 12. The analysis procedure will include corrections for gradient 
nonlinearities and intensity non-uniformity.120-122 
 
Sites will be required to procure a clinical read of each participant’s MRI to confirm eligibility 
based on image-derived inclusion and exclusion criteria. Inconclusive findings will be subject to 
review by the ADCS Imaging Core. All imaging data will be de-identified through a numerical 
coding system and submitted to the ADCS EDC.  
 
 
400 m Walk Test  
 
The Walk Test is a low-cost and safe means of assessing walking speed and endurance that 
correlates with peak oxygen consumption in older adults,123 and provides community-based 
translational relevance. The timed walk covers 10 laps totaling 400 m. The will be administered 
by trained personnel using a standardized protocol that has been validated in a large trials of 
older adults (e.g., LIFE).78,86 In EXERT, participants will not undergo exercise stress testing. The 
American Heart Association and the ACSM joint position statement advised that “apparently 
healthy persons of all ages and asymptomatic persons at increased risk may participate in 
moderate-intensity exercise without first undergoing a medical examination or a medically 
supervised, symptom-limited exercise test”.124 Exercise stress testing, although clinically useful 
to assess symptomatic coronary heart disease, does not add predictive value for asymptomatic 
community-dwelling older adults before the start of a supervised and individualized program, 
particularly when exercise intensity and duration are gradually ramped up over time.11 Older 
persons have a high prevalence of ECG abnormalities,125 which diminish the diagnostic 
accuracy of treadmill exercise testing.126 Participants with potential cardiac contraindications for 
participation in either intervention will be excluded during screening.  
 
 
 

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Actigraphy Recordings 
 
Accelerometry data will be collected over a 10-day period at Baseline, and at Months 6, 12, and 
18. Participants will continuously wear the ActiGraph Link, a watch-like device, for the entire 
recording period – even while showering and bathing. It is also important that participants wear 
the device while sleeping.  
 
During Screening II after the MRI and when the majority of eligibility requirements have been 
confirmed, a clinic staff member will initialize the device and place it on the participant’s non-
dominant wrist to start the 10-day recording period. Ten days later (at a minimum), the device 
should be retrieved from the participant during a baseline visit (preferable) or by mail (with a 
reminder call on Day 10), and the data uploaded using the provided ActiGraph hub. The 
baseline actigraphy recording is to be completed prior to randomization (highly preferable), but 
most certainly before intervention initiation at the YMCA.  
 
For the Month 6 and 12 assessments, the ActiGraph Link should once again be placed on the 
participant’s non-dominant wrist during the clinic visit to initiate the recording. Participants 
should be reminded to continuously wear the device, even in the shower and while sleeping, for 
the entire 10-day period. The device should be retrieved from the participant 10 days later (at a 
minimum) by return mail, with a reminder call on Day 10, and the data uploaded using the 
provided ActiGraph hub.  
 
For the Month 18 assessment, the device should be sent to the participant 14 days before the 
visit, with instructions to place on the non-dominant wrist and wear continuously until their 
scheduled clinic appointment. A staff member should call the participant to confirm that the 
ActiGraph Link was received and is in place at the start of the recording period. At the Month 18 
visit, the device will be removed from the participant’s wrist and the data uploaded using the 
ActiGraph hub. 
 
13.0 
PERSONNEL REQUIREMENTS 
 
Personnel roles and requirements to carry out the protocol are listed below. Additional details 
are provided in the procedures manual. 
 
 
Clinic Personnel  
 
At a minimum, 4 clinic staff members (Site PI/Study Clinician, Study Coordinator/Clinic YMCA 
Liaison, Rater 1, Rater 2) and will be required to carry out the protocol at each site. Additional 
functions are outlined below that may be covered one staff member at some sites, or multiple 
staff at other sites.  
 
• 
Site Protocol Principal Investigator: The Protocol PI is responsible for the overall 
conduct of the study at the site. The PI will perform or supervise clinical evaluation of all 
participants and ensure protocol adherence. The PI will supervise project personnel and 

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ensure that the Raters maintain a high level of skill and accuracy in conducting 
assessments. If the PI does not also serve as the Study Clinician (unblinded), the PI 
may complete certain rating scales. 
 
• 
Study Clinician: The Study Clinician will be responsible for conducting and supervising 
the medical evaluation (physical and neurological examinations), ensuring medical 
eligibility for the study, reviewing AEs, interpreting laboratory results, and supervising 
study-related clinical care provided to the participant. This person will also perform, or 
supervise trained medical staff to perform, the LPs. The Study Clinician may be a 
physician, or if consistent with local practice and regulations, a nurse practitioner or 
physician’s assistant. The Study Clinician will be reviewing AEs and thus will be 
unblinded to intervention group assignment. 
 
• 
Study Coordinator: This person will be responsible for managing the day-to-day 
conduct of the trial. Duties may include tracking recruitment, ensuring accurate 
administration of all instruments at the site, maintaining CRFs, processing of laboratory 
samples, serving as liaison with the ADCS clinical monitor, coordinating clinic visits, 
administering cognitive assessments, and data entry of outcomes other than those 
associated with intervention adherence. If the Study Coordinator also serves as the 
Clinic YMCA Liaison (unblinded), this person may not be involved in outcomes collection 
or data entry at any time during the study.   
 
• 
Clinic YMCA Liaison: This person will serve as the primary liaison between the clinic 
and the participating local YMCA to facilitate bi-directional information exchange 
regarding study and participant progress, and to assist in resolving participant issues as 
they arise. Thus, this person will be unblinded to intervention group assignment. Duties 
will include monthly visits with the YMCA study team; monthly telephone calls to 
participants to query progress, AEs, and new medications; and attendance on twice per 
month calls with the Intervention Oversight Team. This person must not have access to 
cognitive or functional data, and thus may not serve as a Rater or be involved in data 
entry of these outcomes at any time during the study. 
 
• 
Raters 1 and 2: Raters will be blinded to intervention group assignment, and will be 
responsible for administering the cognitive and functional assessments, and maintaining 
all appropriate certifications. The same individual should not administer both the ADAS-
Cog13 and the CDR. The Raters must be certified to administer the 400 m Walk Test if 
the Study Coordinator is unblinded and thus unable to collect study outcomes.  
 
 
YMCA Study Team (see Section 6.2.1) 
 
 
 

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14.0 
ADVERSE EVENTS 
 
Potential AEs for study-related activities and interventions are described to each participant by 
trained clinic staff during the informed consent process. Participants are instructed to report the 
occurrence of an AE to the Clinic YMCA Liaison or Study Clinician. Participants will also be 
instructed to report AEs to the YMCA Trainers during supervised exercise sessions.  
 
Trainers will complete the AE Checklist with participants once per week during a supervised 
exercise session. The AE Checklist will be faxed to the clinic to permit review and data entry of 
Study Clinician-verified AEs within 24 hours of reporting, and AE medical management as 
needed. AEs will also be queried at each clinic assessment visit, and during the monthly 
telephone call by the Clinic YMCA Liaison.  
 
 
Definition 
 
An AE is defined as per the Code of Federal Regulation Title 21 Part 312, 
http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/cfrsearch.cfm?fr=312.32, and refers to 
any health-related unfavorable or unintended medical event that occurs after the informed 
consent is signed. An AE includes but is not limited to: (1) worsening or change in nature, 
severity, or frequency of conditions or symptoms present at the start of the study; (2) participant 
deterioration due to primary illness; (3) intercurrent illness; and (4) physical incapacity to carry 
out the intervention. An abnormal laboratory value will only be reported as an AE if the 
investigator considers it to be an AE, or if it leads to the discontinuation or termination of the 
intervention.  
 
Minor AEs are defined as conditions that may be unpleasant and bothersome to the participant 
such as sore muscles, but do not require intervention discontinuation. Examples of minor AEs 
include but are not limited to the following: anxiety, fatigue, decreased appetite, insomnia, 
dizziness, muscle or joint stiffness, muscle strain or soreness, ankle or knee pain, foot pain, and 
other minor symptoms that may have restricted the participant’s usual activities for at least ½ 
day like a head cold, flu or allergy problems. Minor AEs should be reported on an annual basis 
to the site IRB.  
 
The investigator should attempt to establish a diagnosis of the event based on signs, symptoms, 
and or other clinical information. In such cases, the diagnosis should be documented as the AE 
and not the individual signs or symptoms. Symptoms and conditions present at the beginning of 
the study will be characterized, so that AEs can be defined as any new symptom, or any 
increase in frequency or severity of an existing symptom. Adverse events should be described 
with medical terminology so that the event can be matched against a medical coding dictionary, 
such as MedDRA. 
 
 
 

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Follow-Up of AEs 
 
The Study Clinician will be responsible for review of all AEs. Following questioning and 
evaluation, all AEs, whether determined to be related or unrelated to the intervention by the 
Study Clinician, must be documented in the participant’s medical record in accordance with the 
investigator’s normal clinical practice, and on the AE Case Report Form (e-CRF). Adverse 
events will be rated as mild, moderate or severe, and for duration, severity, seriousness and 
causal relationship to the intervention. This will also pertain to abnormal laboratory values 
deemed clinically significant by the Study Clinician.  
 
The Study Clinician is obliged to follow participants with AEs until the events have subsided, the 
conditions are considered medically stable, or the participants are no longer available for follow 
up. Participants who discontinue the study due to adverse experiences will be treated and 
followed according to established medical practice. All AEs will be reported to the ADCS DSMB.  
 
 
Reporting of Unanticipated Problems, AEs, Protocol Deviations 
 
Any unanticipated problems, serious and unexpected AEs, deviations or protocol changes will 
be promptly reported by the PI or a designated member of the research team to the site IRB, the 
ADCS DSMB, and the sponsor (NIA) if appropriate. 
 
15.0 
SERIOUS ADVERSE EVENTS 
 
 
Definition  
 
A SAE is defined as per the Code of Federal Regulation Title 21 Part 312, 
http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/cfrsearch.cfm?fr=312.32, and includes: 
death, a life-threatening adverse experience, inpatient hospitalization or prolongation of existing 
hospitalization, a persistent or significant disability/incapacity, or a clinically significant laboratory 
or clinical test result. Important medical events that may not result in death, be life-threatening, 
or require hospitalization may be considered as SAEs if they have the potential to jeopardize 
participant safety or to require medical or surgical intervention to prevent a more serious 
outcome listed above, such as an injurious fall resulting in a fracture that occurred while 
completing one of the exercise interventions. 
 
 
Reporting SAEs 
 
Any SAE due to any cause that occurs during the course of the investigation (i.e., anytime after 
informed consent, regardless of study intervention exposure) must be reported to the clinic and 
the ADCS within 24 hours of learning of the event. All SAEs will be reported to the DSMB, with 
the blind maintained and in summary format (i.e., Group A, Group B).  
 
 
 

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16.0 
DATA AND SAFETY MONITORING BOARD 
 
The ADCS DSMB reviews the safety of all participants enrolled in trials on an ongoing basis. 
The initial task of the DSMB will be to review the protocol to identify any necessary 
modifications. If modifications are necessary, revisions will be reviewed by the DSMB prior to its 
recommendation on initiation of the project. The DSMB, based on its review of the protocol, will 
work with the Medical and Safety Core personnel to identify the study-specific data parameters 
and format of the information to be regularly reported. The DSMB will initially be provided with 
data blinded to treatment status, but they may request unblinded data if there is a safety 
concern. The DSMB and NIA representative will meet in person or by conference call on a 
quarterly basis. 
 
Additionally, the DSMB will be informed of the occurrence of any SAEs within 7 days of being 
reported to the ADCS. The DSMB may at any time request additional information from the 
ADCS.  
 
Based on the review of safety data, the DSMB will make recommendations regarding the 
conduct of the study. These may include amending safety monitoring procedures, modifying the 
protocol or consent, terminating the study or continuing the study as designed. Using the ADCS 
Safety Review Process and the DSMB, there is substantial oversight and case review to alert 
the investigators, in a timely manner, to any safety issues that may arise.  For further details 
please refer to the DSMB charter. 
 
17.0 
RECORDING AND COLLECTION OF DATA  
 
 
Case Report Form 
 
The site PI or designee will record all data collected (either written or electronic record of data). 
Written or electronic data of record must be entered on the electronic version of the CRF 
(e-CRF) provided for that purpose. In some instances no prior written or electronic record of 
data may exist and data recorded directly on the e-CRF is considered source data. The site will 
be suitably trained on the use of the e-CRF and appropriate site personnel will be authorized to 
provide electronic signatures. The PI is responsible to verify the integrity of the data and 
acknowledge as such by signature. 
 
All site entries will be made in a secured web site and the PI or designee will review the record 
for completeness. If corrections are necessary to the e-CRFs, the PI or designee will update the 
e-CRF and document the reason for change.  
 
Completed e-CRFs will be submitted according to ADCS protocols, and reviewed by the ADCS 
to determine their acceptability. If necessary, data correction requests will be generated for 
resolution by the study site.  
 
 
 

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Audio / Visual Recording 
 
It is the site PI’s responsibility to ensure that any audio or visual recording conducted as part of 
the protocol are completed according to locally applicable laws and regulations. 
 
 
Study Files and Patient Source Documents 
 
Participant confidentiality is strictly held in trust by the investigators, research staff, and the 
ADCS and/or sponsoring institution and their agents. This confidentiality is extended to cover 
testing of biological samples and genetic tests, and participant clinical information.  
 
The study protocol, documentation, data and all other information generated will be held in strict 
confidence. No information concerning the study or the data will be released to any 
unauthorized third party, without prior written approval of the sponsoring institution. Authorized 
representatives of the sponsoring institution may inspect all required documents and records 
maintained by the investigator, including but not limited to, medical records (office, clinic or 
hospital) and pharmacy records for participants. The study site will permit access to such 
records. Any data, specimens, forms, reports, video/audio recordings, and other records that 
leave the site will be identified only by a participant identification number (PID) to maintain 
confidentiality. All records will be kept in a locked file cabinet. All computer data entry will 
include only PIDs. Information will not be released without written permission of the participant, 
except as necessary for monitoring by the IRB, the Intervention Oversight Team, the Food and 
Drug Administration (FDA), the NIA, and the Office for Human Research Protections (OHRP). 
 
18.0 
ETHICS AND REGULATORY CONSIDERATIONS 
 
 
Good Clinical Practice 
 
This study will be conducted in accordance with Good Clinical Practice (GCP) guidelines, as 
defined by the International Conference on Harmonisation (ICH) Guideline, Topic E6, the United 
States Code of Federal Regulations, Title 21, Part 50 (21CFR50) – Protection of Human 
Subjects and Part 56 – IRBs, HIPAA, State and Federal regulations and all other applicable 
local regulatory requirements and laws.    
 
Study personnel involved in conducting this study will be qualified by education, training and 
experience to perform their respective task(s) in accordance with GCP.   
 
No study document shall be destroyed without prior written agreement between the ADCS and 
the investigator. Should the investigator wish to assign study records to another party or move 
them to another location, he/she may do so only with the prior written consent of the ADCS.  
 
 

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Institutional Review Board 
 
Each participating institution must provide for the review and approval of this protocol and the 
associated informed consent documents and recruitment material by an appropriate IRB 
registered with the OHRP. Any amendments to the protocol or consent materials must also be 
approved before they are placed into use. In the United States, only institutions holding a 
current US Federal-wide Assurance issued by OHRP may participate. Refer to: 
http://www.hhs.gov/ohrp/assurances/. 
 
The investigator must obtain approval from the IRB for all subsequent ADCS protocol 
amendments and, when warranted, changes to the informed consent document. Protocol and 
informed consent form amendments can be made only with the prior approval of the ADCS.  
The investigator may not implement any protocol deviation without prior notification to the ADCS 
and prior review and documented approval of the IRB, except where necessary to eliminate an 
immediate hazard to study participants, or when change(s) involve only logistical or 
administrative aspects of the trial (ICH 4.5.4). The investigator shall notify the IRB of deviations 
from the protocol or SAEs occurring at the site, in accordance with local procedures.  
 
 
Informed Consent and HIPAA Compliance 
 
In obtaining and documenting informed consent, the investigator should comply with the 
applicable regulatory requirement(s), and should adhere to GCP and to the ethical principles 
that have their origin in the Declaration of Helsinki. Prior to the beginning of the trial, the 
investigator should have IRB approval of the written ICF and any other written information to be 
provided to participants. Participants, their relatives, guardians, or authorized representatives 
and study partners will be given ample opportunity to inquire about the details of the study. Prior 
to a participant’s participation in the trial, the written ICF should be signed and personally dated 
by the participant and by the person who conducted the informed consent discussion. 
Participants should be provided a copy of the signed ICF. 
 
The informed consent will not only cover consent for the trial itself, but also for the genetic 
research, biomarker studies, biological sample storage and brain imaging. The consent for 
storage will include consent to access stored data, biological samples, and imaging data for 
secondary analyses. Consent forms will specify that DNA and biomarker samples are for 
research purposes only; the tests on the DNA and biomarker samples are not diagnostic in 
nature and participants will never receive results. MRI scan findings of clinical significance, 
determined by the site radiologist, can be shared with participants per Study Clinician discretion.  
 
Consent forms will be developed by the ADCS Regulatory Affairs in collaboration with the PDs. 
The sample consent form provided to sites will include all of the required elements of informed 
consent required by the FDA. The sample consent form will be sent to participating sites where 
it should be tailored to include site-specific information to meet local IRB regulations. Each site 
PI, under the guidance of the local IRB, is responsible for ensuring that all applicable state laws 
are met with regards to judgment of competency and the consent form process. Each 

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participating site must submit a letter of IRB-approval and the approved consent form to 
Regulatory Affairs at the ADCS, along with other required regulatory records and essential 
documents in order to be approved to enroll participants into EXERT. During the first monitoring 
visit following participant enrollment, the ADCS clinical monitors will review the consent forms 
and verify that the proper signatures have been obtained.  
 
18.3.1 Participant Confidentiality | HIPAA 
 
Information about study participants will be kept confidential and managed according to the 
requirements of HIPAA. HIPAA regulations require a signed HIPAA Authorization informing the 
participant of the following:  
 
• 
What protected health information (PHI) will be collected from participants in this study 
• 
Who will have access to that information and why 
• 
Who will use or disclose that information 
• 
The rights of a research participant to revoke their authorization for use of their PHI 
 
In the event that a participant revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of participant 
authorization. Each site PI, under the guidance of the local IRB, is responsible for ensuring that 
all applicable HIPAA regulations and State laws are met. 
 
 
Genetic Research and Storage of Genetic Material  
 
The DNA is banked in locked freezers in the ADCS Biomarker laboratory at UCSD. Sample 
tubes are bar-coded and linked to PID only and banked without personal identifiers. The 
presence of the sample is recorded into a computerized inventory database that is managed by 
ADCS Informatics and is encrypted and password-protected. 
 
Only DNA from consenting participants will be banked and used to facilitate future research on 
aging and dementia, particularly in the discovery of genetic polymorphisms that may influence 
risk of developing AD. Collection of DNA will permit ADCS investigators to probe candidate 
genetic polymorphisms as predictors of outcome in future studies. The samples will be stored by 
the ADCS as long as funding is available from the NIH. If funding should lapse completely, the 
UCSD ADRC will provide responsible custodianship of the ADCS biospecimen bank. 
 
 
Storage of Biospecimen Samples  
 
All biospecimens banked for future AD biomarker research will be shipped to and stored by the 
ADCS Biomarker Core at UCSD. Sample tubes are bar-coded and linked to PID only and 
banked without personal identifiers. The presence of the sample is recorded into a 
computerized inventory database that is managed by ADCS Informatics and is encrypted and 
password-protected. 
 

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MRI Data Storage  
 
MRI scans will be labeled according to each site’s imaging machine capabilities using  
PID and scanner specific series descriptions as detailed in the Technical Manual. All imaging 
data will be de-identified using participant identifiers as detailed in the Technical Manual and 
checked by the ADCS Imaging Core to confirm the absence of participant identifying 
information. 
 
 
Inclusion of Children as Participants in Research Involving Human Subjects 
 
Children will not be included. 
 
 
Study Monitoring  
 
The ADCS clinical monitors are responsible for inspecting the e-CRFs and source documents at 
regular intervals throughout the study to verify adherence to the protocol, completeness and 
accuracy of the data, and adherence to local regulations on the conduct of clinical research. An 
unblinded monitor will inspect documents pertaining to randomization, intervention 
implementation, and AEs. A blinded monitor will inspect all other source documents.  
 
The monitoring visits must be conducted according to the applicable ICH and GCP guidelines to 
ensure protocol adherence, quality of data, drug accountability, compliance with regulatory 
requirements and continued adequacy of the investigational site and its facilities. The site 
investigator will cooperate in the monitoring process by ensuring the availability of the e-CRFs, 
source and other necessary documents at the time of the monitoring visits. The site PI will 
promptly address any matters brought to his/her attention by the monitor, and may be asked to 
meet in-person with the site monitor during monitoring visits. 
 
19.0 
AUDIT 
 
In accordance with ICH GCP, representatives of the ADCS and/or sponsor and/or regulatory 
agency may select this study for audit. The site PI and study staff are responsible for 
maintaining the site master file containing all study-related regulatory documentation as outlined 
by ADCS Regulatory Affairs that will be suitable for inspection at any time by ADCS, sponsor, its 
designees, and/or regulatory agencies. Inspection of site facilities (e.g., pharmacy, laboratories, 
YMCAs) to evaluate the trial conduct and compliance with the protocol may also occur.  
 
20.0 
RECORD RETENTION 
 
Essential documents and study records must be retained for a minimum of 7 years following 
primary publication of study results. The ADCS will notify sites when retention of such 
documents is no longer required. 
 
 

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21.0 
PUBLICATION POLICY 
 
The results of this study will be published. To coordinate dissemination of data from this study, a 
publication committee will be formed. The committee will consist of the PDs, the Protocol 
Committee, interested site PIs, and appropriate ADCS personnel. The publication committee will 
solicit input and assistance from other investigators as appropriate and adhere to all ADCS 
Publications Policies. 
 
22.0 
SHARING OF FINAL RESEARCH DATA 
 
Data from this research will be shared with other researchers pursuant to the 02/26/2003 “Final 
NIH Statement on Sharing Research Data.” The ADCS grant contains a data sharing policy 
consistent with the goals of the NIH that also respects the rights of commercial partners. The 
NIH policy can be found at: http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-
032.html.  
 
The NIH endorses the sharing of final research data to serve these and other important 
scientific goals. To protect participants’ rights and confidentiality, identifiers will be removed from 
the data before they are shared. 
 
 
 

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23.0 
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APPENDIX 1: SCHEDULE OF EVENTS 
Visit Number 
0 
1 
2 
3 
4 
5 
Visit Name / Month 
Screen I 
Screen II 
Baseline 
6 
121 
18 
Visit Window (weeks) 
 
 
 
+/- 2 
+/- 2 
+/- 2 
Brief Informed Consent for Screen I 
(screening for Screen II) 
X 
 
 
 
 
 
Informed Consent for Enrollment, HIPAA 
 
X 
 
 
 
 
EXERT TAPA (to confirm sedentary 
status) 
X 
 
 
 
 
 
Review Inclusion & Exclusion Criteria 
X 
X 
 
 
 
 
Demographics 
X 
X 
 
 
 
 
Medical History 
X 
X 
 
 
 
 
Medication Review 
X 
X 
X 
X 
X 
X 
Brief Physical Exam 
 
X 
 
X 
X 
X 
Vital Signs 
 
X 
X 
X 
X 
X 
Height 
 
X 
 
 
 
 
Weight 
 
X 
X 
X 
X 
X 
Brief Neurological Exam 
 
X 
 
X 
X 
X 
Modified Hachinski 
 
X 
 
 
 
 
Fasting Clinical Blood Labs 
 
X 
 
 
X 
X 
Blood Collection for ApoE Genotyping, & 
DNA Banking 
 
X 
 
 
 
 
Fasting Blood Collection for Banking 
 
 
X 
X 
X 
X 
AE Monitoring at Clinic 
 
 
X 
X 
X 
X 
12-Lead Resting ECG 
 
X 
 
 
 
 
3MSE/MMSE 
 
X 
 
 
X 
 
Logical Memory I and II 
 
X 
 
 
 
 
Auditory Verbal Learning Test 
 
X 
 
 
 
 
ADAS-Cog13 
 
 
X 
X 
X 
X 
Trail-Making Test, DSST, Category and 
Letter Word Fluency 
 
 
 
X 
 
X 
 
X 
 
X 
Computer Tests: NIH Toolbox (Flanker, 
DCCS), Cogstate (DET, IDN, OCL, OBK, 
GMLT, FNAME, BPSO) 
 
 
 
X 
 
X 
 
X 
 
X 
CDR 
 
X 
 
X 
X 
X 
ADCS-ADL-MCI, BRIEF-A, NPI (staff-
administered questionnaires) 
 
 
 
X 
 
X 
 
X 
 
X 
GDS (self-administered questionnaire) 
 
X 
 
 
 
 
Cognitive Change Index 
(self-administered questionnaire) 
 
X 
 
X 
X 
X 
SF-36, EQ5D (self-administered) 
 
 
X 
X 
X 
X 
Research Satisfaction Survey 
(self-administered) 
 
 
X 
X 
X 
X 
Study Partner Self-Assessment 
Questionnaire2 
 
 
X 
X 
X 
X 
400 m Walk Test 
 
X 
 
X 
X 
X 
Structural/Functional MRI3 
 
X 
 
 
X 
 
LP for CSF Collection and Banking4 
 
 
X 
 
X 
 

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Visit Number 
0 
1 
2 
3 
4 
5 
Visit Name / Month 
Screen I 
Screen II 
Baseline 
6 
121 
18 
Visit Window (weeks) 
 
 
 
+/- 2 
+/- 2 
+/- 2 
Post-LP Safety Telephone Follow-Up4 
 
 
X 
 
X 
 
Replace Battery in Heart Rate Monitor 
 
 
 
X 
X 
X 
Dispense Physical Activity Logs 
 
 
X 
X 
X 
 
Retrieve/Review Physical Activity Logs5 
 
 
X 
X 
X 
X 
Actigraphy Recording Initialization 
(dispense device)6 
 
X 
 
X 
X 
X 
Actigraphy Device Retrieval (10 days 
later)6 
 
 
X 
X 
X 
X 
Telephone Call to Participant by Clinic 
YMCA Liaison (query AEs, obtain 
medication updates)7 
 
 
 
X 
 
X 
 
X 
 
 
Trainer-Supervised Exercise Sessions8 
 
 
X 
X 
X 
 
Trainer-Administered Rating of 
Perceived Exertion9 
 
 
X 
X 
X 
 
Trainer-Administered AE Checklist10 
 
 
X 
X 
X 
 
Randomization 
 
 
X 
 
 
 
Treatment Blinding Questionnaire 
 
 
 
 
X 
X 
Provide Study Close-Out Materials 
 
 
 
 
 
X 
 
1   Following Month 12 assessment, participants continue with their assigned exercise program but without 
supervision in Months 13-18 
2  The Study Partner Self-Assessment Questionnaire is comprised of the SF-36, the Pittsburgh Sleep 
Quality Index, the Insomnia Severity Index, the EQ5D, and questions about healthcare utilization  
3   Screening MRI to be conducted following site PI confirmation that participant has met all other 
inclusion/exclusion criteria; fMRI sequences added to protocol for approved sites 
4   To be completed for fasting participants who agree to LP at Baseline and Month 12 
5   Logs reviewed by Trainers weekly (in months 1-12), and by Clinic YMCA Liaison monthly when 
 retrieved from YMCA (months 1-18) to identify potential adherence issues 
6   See Section 9.0 for visit-specific instructions  
7   Telephone call to be completed monthly (months 1-18) 
8   Supervision provided by study-certified YMCA Trainers, beginning after randomization through Month 
 12; data collected include type of exercise completed, exercise duration, HR, RPE, and other 
 intervention-specific details (e.g., body parts stretched, treadmill speed and grade) 
9  Rating scale administered as part of every supervised exercise session (months 1-12) to assess effort 
 and estimate exercise intensity 
10Administered once per week by YMCA Trainer during supervised sessions to query change in health 
 status in the preceding 7 days; faxed to clinic for triage and data entry within 24 hours of the session