Effect of Aerobic Exercise on Pathophysiology of PreClinical Alzheimer's Disease
Phase: NA
Conditions: Alzheimer's Disease
Sponsor: University of Kansas Medical Center

 
Protocol 
 
Date of Issue 4/22/2016 
 
Alzheimer’s Prevention Through Exercise (APEx) 
 
ClinicalTrials.gov: NCT02000583 
 

APEX Protocol 22 April 2016 
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Effect of Aerobic Exercise on Pathophysiology of PreClinical Alzheimer’s Disease 
Principal Investigator: Jeffrey Burns, MD 
Amendment 4 
Version 5.0 
Date 22 April 2016 
 
[Note: This document contains the Research Protocol, Plan, and Human Subjects Protection 
information submitted as part of the overall RO1 grant application initially submitted to the NIH and 
reviewed by the HSC in August of 2012.] 
 
 
SPECIFIC AIMS 
Our long-term research goal is to develop and test strategies to prevent Alzheimer’s disease (AD). There is 
an increasing interest in the role of exercise in the prevention and treatment of AD given the growth of the 
elderly population and subsequent increase in age-related disorders. Until disease-modifying AD therapies are 
available, risk factor reduction will remain the cornerstone of dementia prevention.1 Accumulating evidence 
suggests that aerobic exercise may protect against cognitive decline and dementia.2-14 Additionally, animal 
studies suggest exercise may modify AD neuropathological burden.15-19 Our NIH-funded work has 
demonstrated that aerobic fitness is positively associated with brain volume and cognitive performance in early 
AD.20, 21 Moreover, we have extensive experience conducting rigorous NIH-funded clinical trials to test the 
effects of aerobic exercise on the brain (R01AG034614, R01AG033673).   
The advent of amyloid imaging creates an opportunity for identifying individuals in the presumptive 
presymptomatic phase of the disease, when interventions are likely to have the greatest impact.22 
Approximately 30% of cognitively normal older adults have asymptomatic cerebral amyloidosis and thus meet 
the NIA and Alzheimer’s Association research criteria for “preclinical AD.”  The concept of preclinical AD posits 
that cerebral amyloid deposition in cognitively normal adults represents a presymptomatic stage of AD and 
individuals with preclinical AD currently represent the earliest feasible stage for trials of AD prevention.   
This study examines the effects of aerobic exercise on AD pathophysiology (amyloid burden) and 
associated “downstream” neurodegeneration (regional atrophy) and cognitive decline in preclinical AD. The 
proposal extends our ongoing work on the role of exercise to promote a healthier brain and capitalizes on our 
new status as an AD Center (KU ADC; P30AG035982). We will examine the effects of a 52-week aerobic 
exercise program in 120 individuals, 70 with preclinical AD and 50 with nonelevated amyloid. We will use 
existing clinical research infrastructure of the KU ADC to recruit 400 sedentary, cognitively normal (CDR 0) 
individuals age 65 and older for screening with Florbetapir PET imaging to enroll 70 preclinical AD participants 
(defined as cognitively normal participants with elevated cerebral amyloid) and 50 individuals with non-elevated 
cerebral amyloid. Participants will be randomized in a 2:1 ratio to either aerobic exercise or control. Exercise 
training will occur in a community setting through the network of KUMC approved facilities.  
Aim 1: Determine the effect of aerobic exercise on amyloid burden in individuals with preclinical AD 
(cognitively normal with elevated cerebral amyloid) and those without elevated amyloid. We 
hypothesize that 52 weeks of aerobic exercise will be associated with lower amyloid burden as 
measured by Florbetapir PET imaging. Our primary amyloid burden measure will be mean change from 
baseline to 52 weeks in Florbetapir cortical-to-cerebellar ratio averaged across 6 regions of interest 
(frontal, temporal, parietal, anterior cingulate, posterior cingulate, and precuneus).  
Aim 2: Determine if aerobic exercise attenuates structural brain changes in preclinical AD and 
those without elevated amyloid. We hypothesize that aerobic exercise will attenuate hippocampal 
atrophy (1° imaging outcome measure), an area of accelerated atrophy in preclinical AD.  Additionally, 
we will examine the effect of exercise on secondary measures of precuneal and whole-brain atrophy.   
Aim 3: Determine the effects of aerobic exercise on cognition in individuals with preclinical AD and 
those without elevated amyloid. We hypothesize that aerobic exercise will provide cognitive benefits 
in our primary outcome measure of executive function and in secondary measures of memory and 
visuospatial function.  Additionally, we expect that improvements in memory will correlate with structural 
preservation in hippocampus.  
Exploratory Aim: Examine potential underlying mechanisms relating exercise with brain health. Our 

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findings suggest that AD-related cognitive impairment and brain atrophy are associated with systemic 
changes, including accelerated sarcopenia and bone loss,23-26 which are responsive to physical activity 
interventions. Thus, we will explore exercise-related changes in serum markers that may mediate these 
systemic manifestations including BDNF, anabolic hormones (insulin, insulin-like growth factor) and 
inflammatory markers (c-reactive protein, interleukin-6, TNF-alpha). We will explore exercise-related 
change in these markers and their relationship with changes in AD biomarkers and body composition.  
The unprecedented growth of the elderly population27 and increasing prevalence of AD28 underscores the 
need for addressing AD prevention strategies.29 Delaying the onset of AD by 5 years could cut AD incidence by 
50% and reduce the US health care burden by $50 billion annually. This proposal will provide important 
preliminary data assessing potential disease-modifying benefits of exercise on AD pathophysiology in the 
putative earliest stages of disease and inform the design of more definitive studies of exercise as an AD 
prevention strategy. Our experience in community-based exercise trials, new status as an ADC, and 
partnership with Avid Radiopharmaceuticals provides a unique opportunity to efficiently achieve these aims. 
 RESEARCH STRATEGY 
 
 
 
Significance / Background 
 
Preclinical AD: A New Target for AD Prevention Strategies  
In 2011, the NIA and Alzheimer's Association defined research criteria to provide a common rubric to 
advance the study of the preclinical stages of AD and stimulate studies in early intervention.30 These criteria 
define preclinical AD as the presence of cerebral amyloid (measured by amyloid imaging or low CSF Aß42) in 
individuals without cognitive or clinical evidence of dementia.  The concept of preclinical AD postulates AD 
neuropathology accumulates in the brain for years before the emergence of cognitive deficits and that 
progressive deterioration will culminate in dementia if the individual continues to live. Studies supporting the 
concept of preclinical AD demonstrate cerebral amyloid in nondemented individuals is associated with AD-like 
endophenotypes of progressive cognitive decline, brain atrophy, and altered brain function (reviewed below). 
Thus, preclinical AD represents an important therapeutic target for AD prevention strategies.  
 
AD Pathophysiological Cascade 
AD is defined neuropathologically as the presence of cerebral beta-amyloid (Aβ) deposits and 
neurofibrillary tangles.  Biomarker studies suggest AD pathophysiologic changes likely begin years prior to the 
emergence of clinical symptoms and follow a temporal ordering of events beginning with cerebral amyloid 
deposition, followed by elevations in CSF tau, and later the development of “downstream” AD-related 
neurodegeneration (reduced temporo-parietal metabolism and brain atrophy).  Amyloid deposition alone may 
not be sufficient to produce AD clinical symptoms and may require the presence of concomitant tau-based 
pathology or neurodegenerative processes (i.e., atrophy) to produce clinical symptoms.31 Convergent evidence 
from AD biomarker studies suggests amyloid deposition may be a necessary and early component of the AD 
pathophysiological process.32 Further research is necessary to define the precise role of amyloid in the 
pathoetiology of AD, although amyloid imaging allows the identification of key early AD pathophysiological 
events in individuals who remain without functional or cognitive impairments.    
 
Amyloid Imaging 
The molecular imaging of amyloid deposits has promise as a potential biomarker for AD and may allow the 
identification of individuals in the preclinical stages of the illness. Pittsburgh compound-B (PIB) is the most 
widely studied radioligand although its use is restricted by its short half-life. Other molecular imaging agents 
have been developed using longer-lived F18 radiolabels (such as FDDNP, Florbetapir, and Florbetaben) 
making this technology more widely available. The current proposal will use Florbetapir PET imaging, which 
has been validated at autopsy as reflecting the presence and quantity of amyloid pathology.33 We have 
extensive experience with the use of Florbetapir PET through national multi-site trials (Bapineuzumab, ADNI, 
IGIV). Additionally, we have a close working relationship with Avid Pharmaceuticals (see letter of support) and 
Avid will provide the costs of 200 PET scans and 485 Florbetapir doses.  
 
Amyloid Imaging as Biomarker for Preclinical AD 
The clinical significance of cerebral amyloid plaques remains imprecisely defined although early studies 
suggest asymptomatic cerebral amyloid is not benign. Autopsy,34-36 CSF,37 and amyloid imaging studies38-41 
suggest cerebral amyloid is present in 20 – 40% of cognitively normal older adults at levels similar to those 

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seen in AD.  The presence of cerebral amyloid is predictive of AD risk in individuals with MCI42-45 and higher 
mean cortical binding values of PIB predicted progression to AD in a cohort of 159 cognitively normal older 
adults.46 Although studies of the relationship of cerebral amyloid and cognition in nondemented individuals 
have been mixed,44 multiple studies have reported that elevated cerebral amyloid is associated with modest 
differences in cognitive performance47, 48 and more robust longitudinal decline in cognition39, 49, 50 and function.51  
Additionally, neuroimaging suggest cerebral amyloid is associated with structural and functional brain 
changes in areas implicated early in AD. Analyses from the ADNI dataset suggest that lower CSF amyloid52 
and increased PIB retention44 are associated with greater whole brain atrophy and regional atrophy in the 
medial temporal lobe and precuneus.31, 44, 52 Studies in other cohorts have observed elevated PIB retention is 
associated cross-sectionally with lower brain volume39, 53 and with longitudinal rates of global brain atrophy.54, 55 
Additionally, increased cerebral amyloid in nondemented older adults is associated with atrophy in specific 
regions involved early in the AD process,48, 56-60 most commonly the hippocampus48, 59 and the posterior 
cingulate / precuneus.56, 57, 60 Asymptomatic amyloid elevated individuals have also demonstrated evidence of 
disrupted functional connectivity.61-63  Thus, substantial data suggests preclinical AD is associated with 
cognitive decline, brain atrophy, and altered brain function, supporting the concept of preclinical AD as a novel 
target population for testing AD prevention strategies.   
 
 
Rationale for Exercise as an AD Prevention Strategy 
Exercise and physical activity have a biologically plausible and temporal relationship with coronary heart 
disease,64 atherosclerosis,65 stroke,66 type 2 diabetes, some cancers, and all-cause mortality.67 As described 
below, a wealth of data indicates exercise also positively impacts brain health.  
Exercise and Cognition: Cross-sectional studies suggest physical activity is positively associated with 
cognition, particularly in executive and visuospatial function.68-70 Additionally, epidemiologic studies suggest 
that exercise may prevent cognitive decline and dementia. Physical activity in midlife is associated with a 
reduced risk of developing AD in late-life.71 Multiple longitudinal studies report a relationship between self-
reported exercise and cognitive decline.5-7, 13, 72, 73 We found greater baseline levels of aerobic fitness are 
associated with slower dementia progression in AD (n=37) and a trend to less cognitive decline in 
nondemented older adults (n=53).74  
Neuroimaging Evidence: Evidence from MRI studies suggests that exercise, and associated aerobic fitness 
levels, may attenuate age- and AD-related brain changes. Higher levels of aerobic fitness are associated 
cross-sectionally with mitigation of age-related declines in brain density.75 In randomized controlled trials, 
aerobic exercise promotes brain plasticity76 and attenuates hippocampal atrophy while improving spatial 
memory.77 Our studies suggest aerobic fitness in individuals in the earliest stages of AD (n=57) is associated 
with whole brain volume (r=0.54, p<0.001),78 most strongly in the hippocampus and parietal regions, areas 
implicated in early AD.79 Our longitudinal analyses suggest that decline in aerobic fitness is associated with 
greater atrophy in the parahippocampus in early AD (n=37) and greater frontal and basal ganglia atrophy in 
nondemented controls (n=53).74  These results suggest physical exercise may have disease-modifying effects 
on AD pathophysiology.  
Additionally, we have performed studies demonstrating associations of body composition (BMI, lean mass, 
bone density) with AD biomarkers, brain atrophy and cognition, providing additional support for exercise in 
delaying the functional onset of AD. AD is associated with weight loss in the preclinical stages of the disease.80 
Using the ADNI cohort, we found that lower BMI was associated with the presence and burden of cerebral 
amyloid and CSF tau in nondemented and MCI participants.81 Using more sensitive measures (DEXA), we 
found that AD is predominantly associated with loss of lean mass23 and bone density,25, 26 which in turn are 
related to measures of AD progression (cognitive performance and brain atrophy). Physical activity has 
systemic effects on anabolic signaling and inflammation, which are shared pathophysiologic factors associated 
with AD, sarcopenia, and osteoporosis. Although the causal relationship of these variables remains unclear, 
this data supports the hypothesis that systemic effects of exercise may modify the co-varying AD-related 
declines in body composition and measures of neurodegeneration.  
 
Potential Mechanisms  
There are a number of potential mechanisms that may relate exercise with brain health. Increased physical 
activity may have a trophic effect on the brain, particularly the hippocampus. For instance, exercise is 

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associated with increased brain-derived neurotrophic factor (BDNF)82 and other important neurochemicals83 
supporting brain growth and survival. Exercise stimulates neurogenesis,84 enhances resistance to brain insults, 
85-87 increases synaptic plasticity,88 and promotes brain vascularization.89, 90  Additionally, exercise reduces  
vascular risk factors (heart disease,64 atherosclerosis,65 stroke,66 diabetes91-96) that place an individual at risk 
for dementia, vascular dementia, and AD.  
Exercise and Amyloid: In addition to the wealth of data on the positive effects of exercise on the brain, 
animal studies indicate exercise may reduce amyloid burden and modify AD pathophysiology through direct 
effects on amyloid precursor protein metabolism15-17 and indirect effects on neurotrophic factors, 
neuroinflammation, and oxidative stress. Multiple transgenic mouse models of AD have shown that physical 
activity in mice reduces neuropathological burden,15 increases neuronal plasticity,82 improves spatial learning 
and memory, 18, 82, and modulates inflammatory processes. 19, 83. Taken together, animal studies suggest that 
voluntary exercise may reduce the production of beta-amyloid and modify the AD pathophysiological cascade.   
Studies in humans assessing the effect of physical activity on AD pathophysiology are sparse, although 
exercise in cognitively normal older adults is associated with lower cerebral amyloid deposition (as assessed 
by both PIB imaging and CSF AB).97 Additionally, exercise may interact with ApoE4 to influence amyloid 
deposition whereby increased physical activity is associated with lower amyloid deposition in E4 carriers.98 
These findings are consistent with longitudinal studies reporting physical activity may have greater benefits on 
cognition in ApoE4 carriers,99-104 although similar studies have been mixed.105-108 Thus, limited human data 
suggests physical activity is associated with lower cerebral amyloid deposition although these findings need 
confirmation in rigorous controlled trials.  
 
KU ADC Exercise Trial Experience   
We have extensive experience with performing rigorous exercise trials in older adults with and without 
dementia, including two ongoing randomized controlled trials to be completed in early 2013. As of February 
2012, we have enrolled a total of 100 individuals into these 6-month intervention trials including individuals with 
AD (n=28) and cognitively normal older adults (n=72).  
The Trial of Exercise on Aging and Memory (TEAM) study (R01AG034614) is a 6-month dose-response 
study assessing the cognitive benefits of 50%, 100%, and 150% of the recommended exercise dose (150min / 
week) in nondemented older adults. As of February 2011, we have enrolled 72 participants (goal 100) and 
study enrollment will be completed in mid 2012. Adherence to the weekly exercise duration goal has been high 
(89%) and retention excellent (51 of 53 [96%] completed the 6-month intervention). Of the 51 individuals who 
have completed the intervention, aerobic fitness as measured by peak oxygen consumption (VO2peak) 
increased following a dose-response function (F=11.5,p<.001): VO2peak decreased in the no exercise group (-
1.1ml/kg/min, -5.0%) and increased in the 50% group (1.6ml/kg/min, +6.8%), 100% group (1.5ml/kg/min, 
+7.3%) and the 150% group (+2.48ml/kg/min, +13.0%).  Preliminary cognitive analyses indicate benefits in the 
executive domain (composite score of Stroop Test, Digit Symbol, Trails B, and Category Fluency; F=4.08, 
p<.05) in a dose response pattern. Standardized scores in the no exercise group were unchanged (-.08), 
improved slightly in the 50% group (+.17), and were not statistically different in the 100% and 150% groups 
(.27 and .25).  Our preliminary results suggest that physiologic adaptations to exercise increase in a dose 
response pattern while the cognitive benefits appear to plateau at the 100% dosage. Thus, 150 minutes a 
week optimally balances physiologic effects, cognitive benefits and participant burden.  
We have also adapted our exercise protocols for AD. In 2007 we piloted a 4-month aerobic exercise 
program in 6 individuals with AD using a community exercise facility. Exercise was tolerated well in this group 
of older adults with AD. In 2010, we began the Alzheimer’s Disease Exercise Program Trial (ADEPT), a 6-
month randomized trial of aerobic exercise vs. stretching control assessing cognitive and structural MRI 
outcomes (R01AG033673).  Currently, we have enrolled 28 participants and anticipate reaching 60 participants 
by January 2013. Ten participants have completed the 6-month intervention with one drop out.  
Exercise trials in older adults are complex, burdensome (to participants and the study team), and require a 
well-coordinated multi-disciplinary approach. Our record for recruiting, characterizing, and exercising older 
adults is excellent. Overall adherence to 6 months of exercise or a rigorous control intervention has been high: 
of 100 participants (n=72 nondemented and 29 with AD) enrolled into aerobic exercise interventions, 61 have 
completed the intervention, 36 are actively exercising, and 3 have dropped out (5% of completers). This history 

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combined with our extensive experience performing longitudinal imaging studies74,109,110 uniquely positions us 
to rigorously measure the biological impact of aerobic exercise on AD pathophysiology in preclinical AD.    
 
 
 

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 INNOVATION 
In 2010, an NIH State-of-the-Science Conference examined data on AD prevention111 and concluded the 
current data is insufficient to draw firm conclusions on the association of modifiable risk factors, including 
physical exercise, with cognitive decline and AD. The greatest limitation of the data is the largely observational 
nature of the studies, limiting the ability to discern association from causation. No randomized controlled trials 
(RCT) were identified by the panel evaluating the effect of physical activity on delaying AD onset. The panel 
reinforced the critical need for RCTs to investigate strategies to maintain cognitive function in at-risk adults.   
The advent of amyloid imaging creates an opportunity for identifying individuals in the presumptive 
presymptomatic phase of the disease, when interventions are likely to have the greatest impact.22 Moreover, 
amyloid imaging provides an opportunity to examine how exercise impacts the pathological hallmark of AD, 
cerebral amyloid deposition. Additionally, our use of structural neuroimaging biomarkers will provide additional 
proof-of-concept data regarding potential disease modifying benefits of aerobic exercise (i.e., atrophy). While 
larger clinical trials with standard clinical trial endpoints (i.e., dementia / AD onset) will be essential for definitive 
proof of the role of exercise in AD prevention, this study will provide important data on the biological effects of 
aerobic exercise in high-risk individuals and provide a foundation for more definitive multi-site trials.  
Until disease-modifying therapeutics are available, risk reduction strategies will remain the cornerstone of 
AD prevention strategies. Aerobic exercise offers a low-cost, low-risk intervention that is widely-available and 
may have disease modifying effects. There is a need for rigorous data demonstrating and defining the efficacy 
of exercise in slowing age-related cognitive decline and enhancing functional independence. Demonstrating 
aerobic exercise alters AD pathophysiology in preclinical AD would have enormous public health implications. 
The study’s implications may impact public health policy by encouraging the public to adapt more active 
lifestyles and stimulate the development of effective exercise delivery programs to enhance initiation and 
maintenance of physical activity interventions in at-risk older adults.    
 
 
 

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APPROACH 
The current proposal extends our ongoing efforts of the KU Alzheimer’s Disease Center (KU ADC) to 
determine the role of aerobic exercise in brain health. This project also advances the KU ADC’s larger mission 
of understanding the role of metabolism in aging and AD. Dr. Burns initiated the AD program in 2004 and has 
been supported by NIH funding to assess the role of fitness in brain aging and AD progression 
(R03AG026374, K23NS058252, R21AG029615) and two ongoing clinical trials assessing how aerobic 
exercise influences cognition in healthy aging (R01AG034614) and the progression of AD (R01AG033673).  
Sample and Recruitment History: The KU ADC has established a history of excellent recruitment for 
investigator-initiated studies and ADCS-sponsored clinical trials drawing on our extensive experience with 
outreach efforts, recruitment databases and advertising. The greater Kansas City area (Missouri and Kansas) 
is home to 2.3 million people with 2004 estimates indicating over 11% of the population is 65 years and older. 
Since 2004, the KU AD clinical research program has recruited and characterized over 500 participants using 
the standard UDS Registry assessment for a variety of investigator-initiated studies. Within five months of 
being funded as an ADC in August 2011, we have enrolled and characterized 108 participants into our 
longitudinal ADC cohort. We will extend our well-developed recruitment and clinical infrastructure for screening 
400 nondemented older adults over 3 years to meet our enrollment goal of 70 individuals with preclinical AD 
and 50 with nonelevated amyloid.    
 
Study Procedures 
This is a randomized controlled trial of 52 weeks of aerobic exercise on sedentary individuals with 
preclinical AD (n=70) and those with non-elevated cerebral amyloid (n=50) The KU ADC will screen a total of 
400 cognitively normal older adults with Florbetapir PET to achieve our enrollment goal. Participants will be 
randomized in a 2:1 ratio to active aerobic exercise vs. control using randomization sequences generated by 
the study statistician (Mahnken). Exercise interventions will be rigorously controlled and supervised in a 
community-based network of KUMC approved facilities across the Kansas City area. Given our history of 5% 
drop out over a 6-month exercise trial, we are projecting a 15% annual dropout rate. Participants will have 
Florbetapir PET and MRI before and after 52 weeks of exercise. Cognitive testing will be completed at 
baseline, 26-, and 52 weeks. Figure 1 provides an overview of the screening and study events described in 
more detail below.    
 
 
 
Timeline and Overview of Study Events 
Timeline: We anticipate initiating screening of participants within 2 months of funding and beginning 
enrollment and the intervention within 4 months. Enrollment will be ongoing with screening of 400 participants 
occurring over three years (~ 3 participants a week) with enrollment completed in the middle of the 4th year of 
the grant. The final participants will complete the 52-week intervention in the middle of the 5th year, allowing 
time to complete data analyses and prepare manuscripts.  
Screening: The KU ADC will screen a total of 400 participants 65 years of age and older to establish a 
sufficient cohort (n~120 given an estimated 30% will have evidence of cerebral amyloid) to enroll 70 preclinical 
AD and 50 amyloid nonelevated participants into the intervention. Screening will include a standard clinical and 
cognitive evaluation (KU ADC Registry or similar cognitive impairment screening) and Florbetapir PET.  
Baseline
(3 visits)
1° Measures
•
Cognitive Testing
•
MRI
2° Measures
•
VO2 Peak  
•
Physical Function 
•
Physical Activity
•
Phlebotomy
26-Week s
(1 visit)
1° Measures
•
Cognitive Testing
2° Measures
•
Physical Activity
Fig. 1  Study Flow and Events
KU ADC 
Screening
Registry Evaluation
•
CDR 0
•
Sedentary / Underactive
Amyloid Imaging
•
Florbetapir PET 
•
n ˜ 120 Aß+
52-Weeks
(4 visits)
1° Measures
•
FlorbetapirPET
•
Cognitive Testing
•
MRI
2° Measures
•
VO2 Peak  
•
Physical Function 
•
Physical Activity
•
Phlebotomy
Enroll 
n=100
n=
400

APEX Protocol 22 April 2016 
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Baseline Evaluation: The baseline evaluation will consist of the following outcome assessments 
(methodological details provided below) : brain MRI, cognitive testing, physical function assessment (aerobic 
fitness testing for VO2 peak, DEXA scan for body composition, and physical function), , physical activity, and 
phlebotomy.  
26-Week Evaluation: At 26 weeks (+/- 1 week),, participants will return for an in-person evaluation to 
repeat cognitive testing and assessments of physical activity.    
52-Week Evaluation: At 52 weeks (+/- 1 week), participants will return to complete Florbetapir PET, brain 
MRI, cognitive testing, physical function assessment (VO2 peak, DEXA, physical function), physical activity 
assessment, and phlebotomy.   
Telephone Checks: Participants will be contacted by phone for formal review of medication changes, 
medical history, and adverse events in the first week of initiating the exercise intervention and again at 
approximately weeks 6, 12, 18, 32, 39, and 46 during the intervention. These formal assessments will 
complement the routine assessments performed by exercise instructors that briefly assess new medical or 
exercise-related adverse events. Additionally, the telephone checks will encourage communication between 
the study team and the participants and encourage compliance with the intervention.   
 Blinding: Raters (psychometrician, exercise physiologist) who are blinded to the participant’s intervention 
group (exercise vs. control) will perform outcome assessments. Dr. Burns will be unblinded and perform safety 
assessments and address safety concerns or adverse events. 
See the Study Timeline below for procedures and timing of visits. 
 
 
 
 
 
 
 
 
 
 

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Detailed Methodology 
Screening Procedures 
The KU ADC infrastructure will support screening using standard IRB-approved procedures currently in 
use. The KU ADC was funded in August 2011 and is establishing a longitudinal cohort of 200 nondemented 
and 200 MCI / AD participants. By February 2012, the KU ADC enrolled a total of 108 participants (53 
nondemented, 21 MCI, 31 AD, 3 non-AD participants). As the KU ADC is charged with maintaining a cohort of 
200 nondemented participants, funding for this protocol will augment the ADC infrastructure to support 
recruitment and characterization (clinical, cognitive, Florbetapir PET, described below) of an additional 200 
participants to meet the screening goal of 400 nondemented participants.   
We expect the need to screen 400 participants to identify approximately 120 individuals (30% of the 
screening population) who meet the following inclusion / exclusion criteria.  Consenting to participate in the 
exercise trial will occur after the screening process, although participants will be well-informed of the primary 
purpose of the screening procedures.  Although we do not expect all potential participants (n=120) to agree to 
participate, we expect that a majority (100 of the 120; 83%) will participate in the 52 week exercise trial.   
Inclusion criteria include  
 
• 
CDR 0 (nondemented) 
• 
Age 65 or older 
• 
Florbetapir PET evidence of cerebral amyloidosis 
• 
Non-elevated Florbetapir PET scan algorithm computerized measuring a mean quantitative 
standard uptake value ratio equal to or greater than 1.0 for 6 regions of interest.   
• 
Sedentary or underactive by the Telephone Assessment of Physical Activity  
• 
Stable doses of medications for 30 days.   
• 
Clinician judgment regarding subject’s health status and likelihood  to successfully complete the 
1-year exercise intervention 
 
Exclusion criteria include  
• 
Clinically significant major psychiatric disorder (e.g., Major Depressive Disorder) according to 
DSM-IV criteria or significant psychiatric symptoms that could impair the completion of the study 
• 
Clinically-significant systemic illness that may affect safety or completion of the study   
• 
History of clinically-evident stroke 
• 
Clinically-significant infection within the last 30 days 
• 
 Active cardiac condition (e.g. angina, myocardial infarction, atrial fibrillation) or pulmonary 
condition in the past 2 years that, in the investigator’s opinion, could pose a safety risk to the 
participant—unless cleared for exercise by the participant’s primary care physician or 
cardiologist. 
• 
Uncontrolled hypertension within the last 6 months 
• 
History of cancer in the last 5 years (except non-metastatic basal or squamous cell carcinoma) 
• 
History of drug or alcohol abuse as defined by DSM-IV criteria within the last 2 years   
• 
Insulin-dependent diabetes mellitus  
• 
Significant pain or musculoskeletal disorder prohibiting participation in an exercise program 
• 
Unwillingness to undergo or contraindication to brain MRI scan. 
• 
History within the last 5 years of primary or recurrent malignant disease with the exception of 
resected localized cutaneous squamous cell carcinoma, basal cell carcinoma, cervical 
carcinoma, or prostate cancer.  
 
Non-elevated Amyloid Group:  We will recruit individuals with non-elevated amyloid PET scans who have 
a mean SUVR (in 6 regions of interest) of 1.0 and greater to be enrolled into the trial as part of the non-
elevated amyloid group.  Based on our first 84 non-elevated participants screened for the study, this 
represents about 1/3rd of those with non-elevated amyloid PET scans.  Participants will be recruited by letter or 
phone calls to those who have been previously screened and meet the criteria or during in-person screening 

APEX Protocol 22 April 2016 
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visits until a total of 50 nonelevated participants are enrolled.   
SUVR (Standard Uptake Value Ratio) represents a ratio of the retention of radiotracer in the brain 
compared to the patient’s control region of the cerebellum.  A higher is believed to reflect higher levels of 
amyloid in the brain although in this group of individuals who do not evidence of amyloid deposition given their 
non-elevated status, the relevance of the SUVR value remains uncertain.  Nevertheless, this group is of 
scientific interest given some early data suggesting the group may be enriched with individuals who 
accumulate amyloid over time.   
Rationale for not disclosing SUVR values:  Participants will be informed that they are in a group 
representing 1/3rd of those with non-elevated scans that have been selected as eligible to participate based on 
computer algorithm.  Our current practice is not to communicate information on patient’s SUVR values and we 
believe this continues to be important until more data is available to suggest that SUVR values are shown to be 
clinically relevant. There is currently no consensus or evidence that within non-elevated participants SUVR 
values have clinical relevance.  It remains unclear that an SUVR value, especially in the non-elevated range, 
provides any predictive information on risk.  Additionally, it remains unclear whether the sensitivity and 
precision of the measure influences how these values can be interpreted.  Not disclosing SUVR values to 
participants is the current practice for the national Alzheimer’s Disease Neuroimaging Initiative.  We have a 
scientific interest in the group of individuals in the top third of SUVR measures as there is early evidence that 
those with higher amyloid burdens may accumulate amyloid at a more rapid rate than others.  Whether 
individuals who accumulate amyloid are at higher risk of cognitive change is not yet known although given that 
our primary aim is to assess the impact of aerobic exercise on amyloid accumulation.   
Given the burden and expense of amyloid scanning, MRI scanning, and a one-year exercise program, it is 
not feasible to enroll a sample of all non-elevated participants.   
 
Clinical and Cognitive Evaluation: All participants will have completed a standard cognitive screening by a 
trained rater.  A neuropsychological test battery is performed by a psychometrician. Clinical and cognitive data 
are reviewed at a consensus diagnostic conference attended by ADC clinicians, neuropsychologist, and 
nurses. Participants without evidence of functional or cognitive decline who are sedentary (Telephone 
Assessment of Physical Activity114) will next be evaluated with a Florbetapir PET scan. If more than 90 days 
have elapsed between enrollment and PET scanning, the participant will have to be rescanned.  Eligibility is 
determined based on the initial screening PET scan (not a repeat amyloid PET). 
 
Florbetapir PET: Florbetapir PET scans will be obtained and visually read by a trained radiologist and two 
trained clinicians using quantitative analyses performed as an adjunct to the visual read. This technique 
combines a visual and quantitative assessment into one read referred to as VisQ (i.e., Visual and Quantitative 
reading).  The final determination of amyloid elevated vs. non-elevatedis based on the majority of the three 
independent VisQ results. 
Given estimates of cerebral amyloid deposition in approximately 30% of nondemented older adults, we 
expect to identify approximately 120 of the 400 screened participants will have elevated amyloid. Of these with 
elevated amyloid, we anticipate 85% will be interested in participating in the aerobic exercise protocol. We 
expect 70% to be nonelevated (~280 of the total 400 planned to be screened) and of these 1/3rd will be eligible 
for enrollment in the nonelevated group.  We will enroll 50 of these participants into the nonelevated group.   
 
Rationale for Exercise Dose and Duration: Aerobic exercise is a mainstay of all public health 
recommendations. Walking at moderate intensity is the most common form of exercise for older adults and is 
easily adopted and widely prescribed. Thus it is highly relevant to public health recommendations. The current 
exercise protocol is built on the success of our ongoing Trial of Exercise for Aging and Memory 
(R01AG034614). 150 minutes a week represents the recommended weekly duration by the American College 
of Sports Medicine and therefore has important “real-world” implications.115 Further, based on our preliminary 
results, this dose achieved our best balance between fitness, cognitive benefits, and participant adherence 
The study duration of 52 weeks was chosen for three reasons: 1) feasibility, 2) to maximize physiologic 
benefits of exercise, and 3) evidence from natural history studies suggesting individuals with preclinical AD 
have measurable changes in brain atrophy and cognition over 52 weeks.  First, our experience suggests 12 
months is achievable based on high retention and adherence rates to our 6-month intervention.  Second, 
physiologic adaptations to exercise (VO2, muscle mass) occur at 3-4 months consistently116 but it remains 

APEX Protocol 22 April 2016 
11 
 
unclear how long is needed for brain benefits. A meta-analysis of exercise 3 suggests durations greater than 6 
months are associated with more cognitive benefits and 52 weeks of exercise is associated with structural and 
functional brain change.77, 117 Third, early preclinical AD studies have observed decline in cognition and brain 
structure in 52 week longitudinal studies.77 These expected changes in controls will enhance the study’s power 
to observe exercise-related effects on AD pathophysiology and cognition. Thus, a 52 week intervention is 
feasible and will enhance the likelihood of observing exercise-related biological changes in the brain.  
 
Aerobic Exercise Intervention 
Upon successful completion of baseline evaluations, participants randomized to the aerobic intervention 
group will exercise 150 minutes over 3 to 4 days per week for 52 weeks with supervision in a local KUMC 
approved facility. Through our current trials, we have a strong relationship with the 14 greater Kansas City 
YMCAs (see letter of support) and several additional facilities with which we have a memorandum of 
understanding concerns conducting research. Each center is staffed by trained exercise personnel with 
experience in the older adult population and personal training certification through the National Commission for 
Certifying Agencies.  
Aerobic exercise will consist primarily of walking on a treadmill, although participants can choose to 
exercise on a separate aerobic modality to reduce repetitive stress and boredom. Participants will gradually 
increase their aerobic exercise duration from 60 minutes in the first week to 150 minutes by the sixth week 
(increasing 21 minutes in duration a week). This progressive duration increase allows previously sedentary 
participants to become accustomed to increased activity and minimizes injury. All sessions include 5-minute 
warm-up and cool-down periods. Each subject will wear a heart rate monitoring chest strap during each 
exercise session. Beginning at  40 – 55% of Heart Rate Reserve (% of difference between maximal and 
resting), target heart rate zones will be increased by 10% of HRR every 3 months. Subjects unable to exercise 
continuously on the treadmill will perform intermittent training until the target duration is reached. Aerobic 
fitness training logs will be maintained for duration of exercise,.. Adherence to the weekly duration goals will be 
followed and recorded by assessing the participant’s attendance and ability to meet weekly exercise duration 
goals.  
Exercise Supervision: We will build on the strengths of current protocols from both the TEAM and ADEPT 
studies. Direct supervision by exercise instructors will occur for all exercise sessions until the weekly duration 
target of 150 minutes a week is reached (not before 6 weeks). We introduce more flexibility in scheduling 
exercise after this if the participant is consistently and safely meeting their target duration goals by allowing 
unsupervised exercise sessions at the approved facility at times when exercise trainers may not be available 
(i.e. early morning, nights, and weekends). Participants are still required to have at least one directly 
supervised exercise session per week to maintain contact with program staff and encourage adherence to the 
program. Unsupervised exercise sessions are conducted similarly to supervised exercise and session data will 
be reviewed by the exercise instructor at the weekly supervised session.  
Adherence and Retention: We use community based exercise facilities given our experience that distance 
to the training site makes recruitment for exercise programs difficult; thus, utilizing community-based  facilities  
increases our base of recruitable subjects by providing easier access and shorter commutes. Additionally, the 
national network is potentially an ideal platform for a future multi-site trial. Each participant receives a one-year 
membership to an approved facility. Exercise protocol adherence is directly monitored as the percentage of the 
weekly exercise duration attained. If participation falls below the target, we work to encourage participants and 
identify problems that may be barriers to exercise compliance. Our history suggests high adherence to 
exercise goals (89%) and low dropout rates over 6-months (5%).  We recognize and anticipate that participants 
may need to miss several exercise sessions due to travel plans, family obligations, etc. Heart rate monitors are 
issued to participants to record exercise data if traveling or for exercise on their own. Participants are strongly 
discouraged from making these accommodations more than 4 weeks total over the course of the study. We 
also encourage retention and adherence through other activities and incentives (small gifts).  
Training Plan for Exercise Instructors: Members of our exercise intervention team have extensive 
experience performing exercise interventions Prior to beginning the trial and periodically thereafter, the 
exercise intervention team holds informational training meetings with exercise trainers to provide an overview 
to the study and discuss the training protocols. During these training sessions, the exercise intervention team 
meets with the exercise instructors to ensure adequate training, compliance with the training plan, and quality 
data collection. Additionally, the exercise intervention team is available by phone to answer questions or 

APEX Protocol 22 April 2016 
12 
 
address unforeseen problems. Turnover of exercise instructors is historically very low although new trainers 
complete the training protocol prior to involvement in the intervention.  
Quality Assurance for Training and Data Collection: While a site is active, a member of the exercise 
intervention team makes site visits regularly to collect data forms, review quality of data collection (e.g., 
completeness and accuracy of data entry) and ensure competency in the standard application of the exercise 
protocol through observations of the exercise instructors. If procedural discrepancies are identified, these are 
then addressed with the instructors.  
Safety: One trainer supervises a maximum of four participants 
at one time. If the participant is deemed a fall risk, the trainers are 
prepared to provide 1:1 supervisor to participant supervision. All of 
the treadmills are equipped with handrails and emergency stop 
switches. All of the trainers are Adult CPR certified and trained in 
the use of portable defibrillators which are available at all of the 
facilities.  
 
Control Group 
Standard-of-care education (SOC) – All study participants 
randomized to the control group will receive education from study 
staff about the importance of maintaining a healthy and active 
lifestyle. Each enrollee will receive our SOC education based on a 
standardized script along with standardized literature, “Exercise 
and Physical Activity: Your Everyday Guide from the National 
Institutes on Aging” and the "KUADC Promoting Healthy Brain 
Aging.” These booklets provide vetted and reliable information for 
older adults on how to exercise.  Participants may ask questions of study staff at that time. Participants 
randomized to the control group will receive no further counseling on physical activity. 
 
 
 

APEX Protocol 22 April 2016 
13 
 
Aim 1: Determine the effect of aerobic exercise on amyloid burden in individuals with preclinical AD 
(cognitively normal with elevated cerebral amyloid) and those without elevated amyloid.  
Rationale:   Amyloid imaging has promise as a potential biomarker for identifying the preclinical stages of 
AD and is being used as an outcome measure to assess biological effects of therapies in clinical trials.  This 
study uses amyloid imaging to 1) identify individuals with early AD pathophysiologic changes (preclinical AD) 
who are likely at higher risk of developing AD, and 2) to assess potential disease-modifying effects of exercise 
on early AD pathophysiology.  Amyloid imaging techniques have demonstrated sensitivity to change in 
response to therapeutic agents (Bapineuzumab, see power analyses below).119  Additionally, amyloid burden 
increases longitudinally in nondemented older adults, with the greatest increase observed in individuals who 
are amyloid elevated at baseline (i.e., similar to our preclinical AD cohort).120  As animal studies15-17 and 
indirect human data97, 98 suggests exercise modifies the AD pathophysiologic cascade, we hypothesize that 
aerobic exercise will be associated with reduced cortical amyloid burden over 52 weeks compared to controls.   
Preliminary Experience:  We have performed 21 Florbetapir PET scans through several clinical trials 
(ADNI, IGIV, Bapineuzumab). Our nondemented sample (n=10, mean age 82) had 4 of 10 individuals with an 
amyloid burden similar to that seen in our AD sample (n=11, mean age 76), 10 of 11 whom demonstrated 
elevated amyloid burden (Figure 2).  
Data Acquisition: Florbetapir PET imaging will be obtained at screening and after 52 weeks of exercise (+/- 
1 week). Subjects will have a catheter placed for IV administration of Florbetapir F 18 Injection. Vital signs will 
be taken in a supine position immediately prior to administration of Florbetapir (within 5 minutes). Subjects will 
receive a single IV bolus of Florbetapir (370 MBq) followed by brain PET imaging of 10 minutes duration, 
approximately 50 minutes post-dose injection. Adverse events will be continuously monitored during the 
imaging session and a participant will have follow-up phone call within 2 business days after the imaging 
session to confirm patient well-being and to collect information about any new adverse events.  
Outcomes: Images will be evaluated qualitatively and quantitatively. Data will be submitted to Avid for 
qualitative analysis. Images will be visually examined by a trained radiologist or nuclear medicine physician 
who is blinded to the subject diagnosis and will be reported as either Aβ elevated (AD-like) or Aβ non-
elevated (not AD-like). Qualitative interpretation will be performed in the following manner: the images will 
be reviewed using a black-white scale with maximum intensity of the scale set to the maximum intensity of 
all brain pixels. A elevated scan will have at least one area where the grey matter is more intense than 
adjacent white matter or at least 2 brain areas where the grey white contrast is reduced or absent. For 
quantitative evaluation, standard uptake values (SUV) will be calculated using SPM software in 6 cortical areas 
(frontal cortex, temporal cortex, parietal cortex, precuneus, anterior and posterior cingulate) and the 
cerebellum. SUV ratios (SUVR) for cortical target areas relative to the cerebellum will also be calculated and a 
global mean SUVR will be calculated from the average across all cortical target areas. 
Statistical Analyses for Aim 1:  This is a two-arm, 2:1 randomized, controlled clinical trial comparing 52 
weeks of aerobic exercise to control intervention. Based on drop out rates from those who have completed our 
exercise trials (2 of 53 [4%] dropped out of the TEAM study and 1 of 11 [9%] dropped out of ADEPT), we 
conservatively estimate that 15% of the subjects will drop out of the study, leaving approximately 85 subjects 
for analysis. We will perform analyses based on intent-to-treat to maintain the benefits of the randomization. 
Per protocol analyses will also be conducted among the subjects that complete a minimum of 80% of their 
sessions. To further assess the response to aerobic exercise, we will conduct analyses that replace the 
primary explanatory factor (treatment group) with continuous measures of increase (change from baseline) in 
aerobic fitness (V02peak). This will allow us to assess the aerobic fitness hypothesis which states that aerobic 
fitness gains mediate neural benefits of exercise.  
We hypothesize that 52 weeks of aerobic exercise will lower amyloid burden as measured by Florbetapir 
PET imaging. Amyloid burden will be measured at baseline and at 52 weeks as a ratio of standard uptake 
values in six regions of interest to the cerebellum.  Our primary amyloid burden outcome measure will be the 
52-week change in Florbetapir cortical-to-cerebellar ratio averaged across these six regions of interest. The 
primary intent-to-treat analysis for amyloid burden will compare the change from baseline to 52 weeks between 
our two treatment groups using the two-sample t-test. Similar analyses will be conducted for each of the ratios 
for the six regions of interest individually (secondary measures), and for per-protocol analyses described 
above. Given the single primary measure for this aim, no multiplicity adjustment will be made and secondary 
endpoints will be clearly indicated as such in resulting manuscripts. To evaluate the appropriateness of our 

APEX Protocol 22 April 2016 
14 
 
approach (two-sample t-test), residual analysis will be conducted. This will include visual inspection of the 
residuals and comparison of the estimated standard deviation across groups to assess homogeneity of 
variances. If these diagnostics indicate concerns with our parametric approach, appropriate alternative 
strategies, such as nonparametric methods like the Wilcoxon rank-sum test or data transformation, will be 
utilized. Ordinary least squares (OLS) regression models will be used for the per protocol analyses that will 
assess increase in aerobic fitness as continuous measures with amyloid burden outcomes. Model assessment 
for these OLS models will also be conducted by assessing model assumptions through residual analyses (e.g., 
predicted versus residual plots, quantile-quantile [q-q] plots, etc.). 
 
Aim 2: Determine if aerobic exercise attenuates structural brain changes in preclinical AD and those 
without elevated amyloid. 
Rationale:  Magnetic resonance (MR) based volumetric studies are increasingly used as surrogate 
outcome measures of disease121 to more efficiently demonstrate an intervention’s disease-modifying effect. 
Our primary focus will be on the effect of exercise in modifying regional atrophy in the hippocampus with 
secondary outcome measures including rates of whole-brain and precuneal atrophy. The hippocampus is an 
important structure in mediating memory processes122 and is among the earliest affected regions in AD.123  
Additionally, atrophy of the hippocampus has been observed in preclinical AD and is associated with 
asymptomatic cerebral amyloid deposition.48, 59 We are also interested in the effect of exercise on regional 
atrophy in the precuneus, an important node in the default mode network that, along with the hippocampus, 
appears to be vulnerable to structural and functional decline associated with asymptomatic cerebral 
amyloidosis.61, 124-128  Importantly, these structures may be responsive to exercise: a randomized controlled trial 
of 52 weeks of exercise attenuated hippocampal atrophy77 while physical activity levels are associated with 
hippocampal and precuneus volumes in nondemented older adults.129  
Preliminary Experience:   Our studies suggest that aerobic fitness (VO2peak) in the earliest stages of AD is 
associated with whole brain atrophy78 and atrophy in the hippocampus79 while decline in aerobic fitness over 2 
years is associated with greater atrophy in the parahippocampus.74  Although our imaging data is limited to 
aerobic fitness measures (rather than an exercise intervention), the data suggest that exercise to maintain or 
enhance aerobic fitness may have disease modifying effects on AD-related structural changes.  Additionally, 
our imaging methods are sensitive to hippocampal and precuneus atrophy as we observed annualized rates of 
atrophy in the hippocampus (1.72% [2.7]) and precuneus (0.56% [0.40]) in nondemented older adults (n=63) 
over two years. We expect to see greater rates of atrophy in our preclinical AD participants which will enhance 
our power to observe exercise-related effects.     
Data Acquisition: We employ the core T1-weighted MPRAGE and FLAIR sequences used by ADNI2 with a 
Siemens 3T Skyra MRI scanner at KUMC’s Hoglund Brain Imaging Center. Our primary imaging measures will 
come from high-resolution structural images (MP-RAGE; 1x1x1.2mm voxels; TR=2300ms, TE=2.98ms, 
TI=1900, FOV=256, Flip angle=9°). We will also acquire additional secondary imaging outcome assessments 
using arterial spin labeling (ASL), diffusion tensor imaging and resting-state functional connectivity data using 
standard ADNI protocols. These secondary measures will allow us to explore exercise effects on regional 
blood flow (ASL), structural white matter changes (DTI), and functional connectivity (BOLD) given our prior 
experience with these measures.74, 130 
Outcomes: Hippocampal and precuneus volumes at baseline and 52 weeks will be assessed by processing 
images via the Freesurfer pipeline131 optimized for longitudinal analysis. Longitudinal processing uses a 
subject-specific template for segmentation132 to initialize the longitudinal image processing to increase 
repeatability and statistical power.  Automated Talairach transformation and segmentation of the cortex, 
subcortical white matter and deep gray matter volumetric structures (including hippocampus) is performed and 
change scores can be calculated to assess atrophy.  
In addition to our primary imaging volumetric outcome measures of precuneus and hippocampal atrophy, 
we will assess measures of whole brain, gray matter, and white matter atrophy from the Freesurfer analysis. 
Additionally, we will use voxel based morphometry (VBM8 for SPM) to explore exercise-related effects on 
regional brain atrophy. VBM examines the whole brain and selected regions of interest in an unbiased way with 
high sensitivity to identify small changes in brain structure over time. We have extensive experience with VBM 
methods.21, 74, 109, 133, 134 This approach has been used effectively in exercise studies of similar duration in 

APEX Protocol 22 April 2016 
15 
 
nondemented older adults118 and will allow us to test our hypotheses while generating important pilot data for 
refining plans for a more definitive study of exercise in AD.  
Statistical Analyses for Aim 2:  We hypothesize that aerobic exercise will attenuate atrophy in the 
precuneus and hippocampus, two regions consistently identified with atrophy in preclinical AD and the earliest 
stages of AD. Volume measures of the hippocampus, precuneus, and of the whole brain (continuous variables) 
will be collected at baseline and 52 weeks. The primary measure of brain atrophy will be hippocampal volume. 
The primary intent-to-treat analysis for atrophy will compare the change from baseline to 52 weeks 
between our two treatment groups. The two-sample t-test of the observed changes will be used for this 
comparison. Similar models will be generated for precuneus volume and whole brain volume, and for the per-
protocol analyses described above. Given a single primary measure for this aim, no multiplicity adjustment will 
be made and secondary endpoints will be clearly indicated as such in resulting manuscripts. Model 
assessment and alternative approaches will follow as described in Aim 1. 
 
Aim 3: Determine the effects of aerobic exercise on cognition in individuals with preclinical AD and 
those without elevated amyloid..  
Rationale:  Substantial evidence, including our own (see background above), exists demonstrating that 
aerobic exercise has a preferential effect on cognition, particularly in executive functioning.69, 70, 135  Thus, our 
primary outcome measure is executive function.  This study, however, extends previous exercise-cognition 
studies as it seeks to provide evidence of a specific effect on AD pathophysiology (i.e., disease modifying 
effect) of aerobic exercise on AD-related pathophysiological change in preclinical AD.  Thus, we will also 
assess key cognitive domains that are associated with asymptomatic cerebral amyloid deposition.   
CSF and imaging studies indicate that declines in global cognitive ability136 and episodic memory (verbal-
based,50 visuospatial-based,137, 138 or both139-141) are associated with the presence of cerebral amyloid. Thus, 
secondary outcomes include verbal and visuospatial-based episodic memory measures where we expect 
decline on these measures will be associated with higher amyloid deposition.  Visuospatial ability is an 
excellent marker of preclinical AD (leading diagnosis by at least 3-years)142-145 and was the strongest cognitive 
indicator for PIB-positive status in a longitudinal study on healthy aging. Visuospatial ability is also strong 
indicator of executive functioning ability.146  Although studies of the cognitive effects of aerobic exercise have 
not resulted in major improvements in episodic memory, no studies have assessed the cognitive effects of 
exercise in a cohort of individuals with preclinical AD who have expected accelerated rates of decline in 
episodic memory.  By selecting amyloid elevated individuals, we are targeting individuals with preclinical AD 
who may benefit most from potential disease-modifying effects of aerobic exercise on AD pathophysiology. 
Thus secondary outcomes include verbal and visuospatial-based episodic memory measures, where we 
expect decline on these measures will be associated with higher amyloid deposition.   
Additionally, three reports indicate cognitive decline in preclinical AD may be mediated by structural 
changes in the hippocampus136, 139, 140 and the concept of preclinical AD posits that hippocampal atrophy is a 
downstream effect of amyloid deposition.  Moreover, this mediation hypothesis may explain a recent finding 
from Kraemer and colleagues147 where better visual memory performance was associated with less 
hippocampal atrophy in exercising nondemented older adults.139 Thus, we will test the mediation effect of 
hippocampal atrophy on the relationship between exercise and cognitive decline over 52-weeks across all 3 
outcomes. We anticipate visual memory to be the strongest of the multiple indicators.   
Data Acquisition: All participants complete a 2- 3 hour neuropsychological test battery at baseline, 26-
weeks, and 52-weeks. This battery includes selected tests with demonstrated responsiveness to aerobic 
exercise and sensitivity to change in preclinical AD.  These tests will be aggregated into several domains: 
Executive Function, Visual Memory, and Verbal Memory, General Health, Emotional Health.  
Outcomes: Cognitive domains of Executive Function, Verbal Memory, and Visual Memory are face valid 
aggregates of related subtests that have generated moderate to large effect sizes across several reviews on 
cognition and aerobic exercise when aggregated. We have expertise using Confirmatory Factor Analysis 
(CFA) to determine the best fitting empirical model of data and create factor score weights that are sensitive 
indicators of cognitive change. 157, 158 CFA is a common method used to aggregate true score (common) 
variance across multiple subtests and attenuate error. Thus, factor scores yield more reliable estimates of 
cognitive ability than individual tests because they are purer indices of ability.159, 160 This is desirable because 
cognitive performance in aging individuals is highly variable. Individual subtests are not as efficient as CFA-

APEX Protocol 22 April 2016 
16 
 
based composite scores. We have shown in previous work142, 161 that longitudinal declines in cognitive ability 
can best be characterized with a model162 of specific mental abilities.  
Statistical Analyses for Aim 3:  This intent-to-treat analysis will use a two-sample t-test to compare change 
from baseline to 52 weeks between our treatment and control groups on the primary (executive function) and 
secondary outcomes (verbal and visual memory). Secondary endpoints will be clearly indicated as such in 
resulting manuscripts; therefore no further multiplicity adjustments will be made. Because cognition is 
measured at three time points (baseline, 26-, and 52-weeks), linear mixed models will also provide additional 
information such as to the functional form of the potential benefits of exercise (e.g., linear increasing benefit 
over time, initial benefit within 26 weeks that is sustained, etc.). Assessments of these linear mixed models will 
be conducted by evaluating model assumptions through residual analyses (similar to that described above).   
A secondary analysis will examine the longitudinal mediation163 effect of hippocampal atrophy on the 
relationship between amyloid binding and cognitive decline (primary and secondary outcomes) over 52-weeks. 
We anticipate the relationship between exercise and improved cognition will be partially mediated by 
hippocampal atrophy. Briefly, to evaluate if hippocampal atrophy is a mediator, we will first assess for a 
positive correlation between cognition with hippocampal volume (i.e., better change in cognition measures 
associated with less hippocampal atrophy as measured by Pearson’s correlation coefficient, or alternatively, 
Spearman’s correlation coefficient if a nonparametric approach is required). We will have already evaluated the 
relationship between exercise and hippocampal changes in Aim 2, anticipating less atrophy in the exercise 
group. If these bivariate relationships demonstrate associations in these hypothesized directions, we will then 
model change in cognition as a function of exercise and hippocampal atrophy (simultaneously) using OLS 
regression. Exercise will be examined both by treatment group assignment and as a continuous measure as 
described above. The attenuation of the effect of exercise on cognition in these models compared to that from 
the models without adjustment for hippocampal atrophy, under these additional conditions, would indicate 
hippocampal atrophy is a mediator of the exercise-cognition relationship. Assessment of the OLS models 
would follow the approach described in Aim 1 (above). 
 
Sample Size Justification 
We have identified primary endpoints for intent-to-treat analyses between treatment groups within each 
study aim: change in amyloid burden (Aim 1); hippocampal atrophy (Aim 2); and change in executive function 
(Aim 3). Other endpoints and analyses will be described in resulting publications as secondary.  For all 
analyses the traditional type I error rate of a=0.05 will be used. We will use two-sided tests to further protect 
against spurious results. Our primary intent-to-treat analyses will be based on the two-sample t-test. Table 2 
presents the power for each aim of our study corresponding 
to our primary measures. Anticipated effect sizes are 
presented using Cohen’s d (expected average group 
difference divided by the assumed, common standard 
deviation). We assumed 15% of our 100 enrolled subjects 
will be lost to attrition, so power calculations assumed 56 
subjects in our exercise intervention arm and 28 subjects in 
our control group. 
Aim 1: A 78 week study assessing Bapineuzumab119 in AD demonstrated a mean change in cortical PIB 
retention (average across six cortical regions) of -0.09 (0.16 SD) for those treated with Bapineuzumab (n=20) 
and 0.20 (0.09) for those on placebo (n=7). Given the differences in our proposed study (preclinical AD 
sample, lower expected amyloid burden, shorter duration) we determined power allowing exercise to have a 
lower effect size. An effect size only 40% as large will produce a Cohen’s d of 0.79. Thus, Aim 1 will have 93% 
power to detect this conservative anticipated effect of exercise on amyloid burden (and 81.9% power to detect 
30% of the Bapineuzumab effect size). 
Aim 2: An 52-week exercise intervention study77 found mean values of hippocampal volume of 4.89 (0.74 
SD) and 4.98 (0.69) at baseline and post-intervention, respectively, in the exercise group (n=60) and 4.90 
(0.80) and 4.83 (0.80), respectively, among controls (n=60). We assumed a high correlation (r = 0.95) for 
within subject baseline and post-intervention measures given our analyses of ADNI data (n=160) suggesting a 
within-subject r >0.99 for hippocampal volumes over 52-weeks. This resulted in an estimated effect size 
(Cohen’s d) of 0.66. Thus, Aim 2 will have 81% power to detect a similar effect size in hippocampal volume. 
Table 2. Anticipated study power 
Study 
aim 
Primary measure* 
Effect size 
(Cohen’s d) 
Power 
Aim 1 
Amyloid burden 
0.79 
92.9% 
Aim 2 
Hippocampal volume 
0.66 
81.4% 
Aim 3 
Executive function 
2.32 
>95% 
*Primary measures are change from baseline to 52-week 
follow-up.  

APEX Protocol 22 April 2016 
17 
 
Aim 3: Preliminary results from our TEAM study indicate that change scores for our composite score of 
executive function produced a Cohen’s d of approximately 2.32 (n=53), providing >95% power to detect this 
effect in executive function.  
Impact of 2:1 Randomization: We have examined the impact of our 2:1 randomization design on the power 
of this study and found its impact minimal. Compared to 1:1 randomization, the decrease in power for our 2:1 
design is <5% for each primary measure. We believe that, in keeping with this funding mechanism (PAR-11-
100) intended for pilot clinical trials, the gain in knowledge and benefits in participant recruitment from utilizing 
a larger experimental exercise arm outweighs this minimal loss in power, particularly given that we have 
sufficient power to assess our primary endpoints presented above (Table 2). 
 
Exploratory Aim: Examine potential underlying mechanisms relating exercise with brain health.  
Although the study’s primary purpose is to assess the impact of aerobic exercise on AD pathophysiology, 
we are collecting additional data to allow us to explore potential underlying mechanisms that may relate 
exercise with brain benefits. These secondary outcome measures include standard measures of physiologic 
adaptations to exercise (VO2peak, body composition, and physical function measures) and plasma based 
measures of BDNF, inflammation, insulin, and anabolic hormones.   
Aerobic Fitness: Peak oxygen consumption (VO2 peak): VO2 peak is the standard, quantitative measure of 
aerobic fitness. VO2 peak will be assessed at baseline and 52-weeks during a graded treadmill exercise test to 
assess physiologic response to exercise and guide the exercise prescription using maximal heart rate 
achieved. We have extensive experience with performing VO2 peak in older adults78, 164 using the modified 
Bruce protocol.165 Subjects are attached to a 12-lead electrocardiograph and wear a non-rebreathing facemask 
to assess heart rates, blood pressure, and expired air (oxygen, carbon dioxide) using a Parvomedics system. 
VO2 peak is considered the highest observed value during the test166, 167 and maximal effort is defined as 
meeting 3 of the 4 following criteria: a plateau in oxygen consumption, a respiratory exchange ratio (RER) 
≥1.0, a maximal heart rate within 90% age-predicted maximum, or volitional fatigue.168 For appropriate exercise 
prescription, adequate maximal exercise testing needs to be performed.  An adequate exercise test will be 
defined as achieving an RER ≥1.0. Subjects not achieving an adequate exercise test will be asked to return to 
on a different day to repeat the test and an alternate modality may be considered.  The test with the greatest 
VO2 will be used to prescribe exercise intensity.  
Body Composition: Participants will be evaluated with dual energy x-ray absorptiometry (DEXA, Lunar 
Prodigy, version 11.2068, Madison, WI) to determine fat-free mass, fat mass, and percent body fat at baseline, 
and 52 weeks. DEXA uses very low X-ray doses (0.02mREM) to detect changes in body composition on the 
order of 1.6-3.8%.169, 170 Body composition is also assessed with standard anthropometric measures including 
body weight using a digital scale accurate to ±0.1 kg (Seca Platform Scale, model 707, Seca Corp.) prior to 
breakfast and after attempting to void. Circumference measurements are taken with a Gullick II circumference 
measurement tape at the smallest girth around the trunk and at the widest protrusion of the buttocks.  
Physical function measures: We will complete an efficient battery of functional assessments indexing 
endurance, strength, balance, and flexibility at baseline and 52 weeks to assess physiologic and functional 
adaptations to exercise. The Physical Performance Test 171 is a short, objective battery of timed physical tasks 
necessary for daily self-care that is commonly used in exercise trials,172 including our own.78, 164 The Senior 
Fitness Test173 is a 7-item battery of measures including flexibility, strength and endurance that is sensitive to 
change with exercise training.174 Grip strength is associated with functional independence175 and will be 
measured in the dominant hand using a grip dynamometer (JAMAR, Sammons Preston, Bolingbrook, IL) as an 
average of 3 maximal grips. Lower extremity strength will be assessed as the average of 3 forceful knee 
extensions with a hand held dynamometer (MicroFET, Hoggan, IN). The Late-Life Functional Disability 
Index176, 177 assesses disability and function across a variety of life tasks and is reliable measure of change in 
function with exercise training.178, 179 
Laboratory assays and blood banking: Phlebotomy will be performed at baseline and after 52 weeks of 
exercise. Serum, plasma, DNA, and platelets will be banked in the Biospecimen Shared Resource (BSR). The 
BSR is the main repository for all KU ADC specimens. The concentrations of insulin, BDNF, IGF-I, TNF-α, C-
reactive protein, and IL-6 will be measured using enzyme-linked immunosorbent assay kits (ELISA).  
 
Exploratory Aim Statistical Analyses: Our exploratory aim will assess potential mechanisms relating 52-
weeks of aerobic exercise to brain health. We will examine if aerobic exercise results in changes in body 
composition and anabolic and inflammatory markers. We will first assess changes over one year in body 

APEX Protocol 22 April 2016 
18 
 
composition (fat and lean mass, BMI) and serum markers (BDNF, insulin sensitivity, IGF-1, TNF-alpha, CRP, 
IL-6) by comparing the aerobic and nonaerobic groups using methods described in aim 1 (two-sample t-test 
with assessment of assumptions). We suspect the aerobic exercise group will have changes in body 
composition (increased lean mass, reductions in fat mass), increased BDNF, reduced inflammatory markers, 
and enhanced insulin sensitivity. Next, we will explore if change in these measures predict 52-week change in 
amyloid burden, brain atrophy, and cognition using OLS models and assessment as described in aim 1.   
 
Data management 
Clinical Data Management System: Study data will be collected and managed using REDCap (Research 
Electronic Data Capture) web-based, electronic data capture tools hosted on a secure, HIPAA compliant 
server at KUMC.180 REDCap provides 1) validated data entry; 2) audit trails; 3) automated export 4) data 
import tools. We have extensive experience developing, maintaining and using REDCap project structures for 
the KU ADC and our TEAM studies. The proposed project will capitalize on this previous work. 
Data Collection Forms:  All data will be collected on standard source documents and entered into standard 
case report forms in REDCap. These forms have been developed and are currently in use to support data 
collection for ongoing exercise interventions and to support the KU ADC clinical and cognitive evaluations. 
Forms include daily exercise data forms used by the exercise instructors and paper and electronic source 
documents for outcome and clinical assessments. The Department of Biostatistics ensures data security by 
managing all data on a secure server that has role-based access that is password protected. All files that are 
modified are backed up daily, with complete backups of the server on a weekly basis. All data are stored in a 
HIPAA compliant manner. 
 
Protection of Human Subjects 
Risks to the Subjects 
Human Subjects Involvement and Characteristics:  We plan to enroll 120 subjects from a screening 
population of 400. Subjects are recruited from the greater metropolitan Kansas City area (population 1.8 
million).   
Inclusion criteria include  
• 
Preclinical AD (CDR 0 [nondemented] with evidence of cerebral amyloidosis)  
• 
Non-elevated Florbetapir PET scan algorithm computerized measuring a mean quantitative standard 
uptake value ratio equal to or greater than 1.0 for 6 regions of interest.  
• 
Age 65 or older 
• 
Sedentary or underactive by the Telephone Assessment of Physical Activity  
• 
Stable doses of medications for 30 days.   
• 
Clinician judgement regarding subject’s health status and likelihood  to successfully complete the 1-
year exercise intervention 
Exclusion criteria include  
• 
Clinically significant major psychiatric disorder (e.g., Major Depressive Disorder) according to DSM-
IV criteria or significant psychiatric symptoms (e.g., hallucinations) that could impair the completion 
of the study 
• 
Clinically-significant systemic illness likely to result in deterioration of the patient’s condition or affect 
the patient’s safety during the study   
• 
History of clinically-evident stroke 
• 
Clinically-significant infection within the last 30 days 
• 
Active cardiac condition (e.g. angina, myocardial infarction, atrial fibrillation) or pulmonary condition 
in the past 2 years that, in the investigator’s opinion, could pose a safety risk to the pariticipant—
unless cleared for exercise by the participant’s primary care physician or cardiologist. 
• 
Uncontrolled hypertension within the last 6 months 
• 
History of cancer within the last 5 years (except non-metastatic basal or squamous cell carcinoma) 
• 
History of drug or alcohol abuse as defined by DSM-IV criteria within the last 2 years   
• 
Insulin-dependent diabetes mellitus  
• 
Significant pain or musculoskeletal disorder that would prohibit participation in an exercise program 
• 
Unwillingness to undergo or contraindication to brain MRI scan. 

APEX Protocol 22 April 2016 
19 
 
• 
History within the last 5 years of primary or recurrent malignant disease with the exception of 
resected localized cutaneous squamous cell carcinoma, basal cell carcinoma, cervical carcinoma, or 
prostate cancer.  
 
Sources of Materials: Research material obtained from participants consists of clinical and behavioral 
data.  This includes information from a subject and collateral source interview, physical / neurological 
examination, and neuropsychological testing.  Blood specimens are obtained for laboratory studies.  Data on 
body composition (fat free mass, fat mass, bone mass) and peak oxygen consumption as well as mood and 
quality of life will be obtained.  These data are used for research purposes only and specific individual results 
are not provided to subjects and their families.  There is no billing of subjects, their families, or third party 
payers for the research assessments. 
Potential risks:  The clinical research procedures consist of history taking, physical / neurological 
examination, and psychometric testing.  Embarrassment could occur should the subjects believe they answer 
questions incorrectly.   
DEXA scanning involves low doses of radiation, equivalent to 0.1 mrem while the typical radiation exposure 
from a normal chest x-ray is 30 mrem.   
Risks involving laboratory testing include minor pain, bruising, and swelling at the needle site, discomfort of 
hunger or thirst due to fasting, and less likely is the possibility of lightheadedness, or even briefly feeling faint 
during the blood drawing procedure. Neuroimaging is associated with risk of anxiety or embedded metal 
displacement. 
Measurement of peak oxygen consumption involves a graded exercise test.  Potential risks of the exercise 
test as well as the exercise intervention include unpredictable changes in blood pressure or heart rhythm, 
myocardial infarction and death as well as the less serious problems of fatigue, muscle soreness, tripping, 
falling, and other injury to tendons, ligaments, joints, and muscles.  There is no statistical information regarding 
serious complications during exercise testing in patients without ischemic coronary heart disease.  A review of 
the experience of 30 cardiac rehabilitation programs reported information on 13,750 participants who 
accumulated 1,629,634 patient hours of supervised exercise.  A total of 50 cardiac arrests were observed, 42 
of which were successfully resuscitated while 8 were fatal.(Haskell 1978)  
 Randomized trials of exercise training in individuals with ischemic heart disease have shown that mortality 
is lower in patients who exercise than those that do not.(Froelicher, Jensen et al. 1985; Belardinelli, Georgiou 
et al. 1999)  It seems reasonable to assume that individuals without recent (> 2 years) clinical evidence of 
ischemic heart disease will have a lower incidence of cardiovascular complications during medically supervised 
exercise testing than individuals with ischemic heart disease.   
Additionally, there are certain risks and discomforts that may be associated with exercise that include 
temporary shortness of breath, muscle fatigue, sweating, and physical discomfort.  Muscles may be sore up to 
three days after performing the exercise.  Also, there exists the possibility of an undiagnosed medical problem 
that may surface during the exercise. During testing, participants will be carefully observed by members of the 
research team to reduce these risks associated with exercise. 
 
Adverse Events: Adverse events will be defined as any untoward medical occurrence in study participants or 
others immediately involved in the performance of the protocol, which does not necessarily have a causal 
relationship with the study treatment, but results in a change in intervention, daily function, hospitalization or 
rated category 3 or above using the  National Cancer Institute Common Terminology Criteria for Adverse 
Events (CTCAE) v3.0.209 Expected events such as slight muscle soreness consistent with exercise, or those 
consistent with a participant’s prior medical history not sufficient to alter the intervention will not be considered 
an AE. Staff involved in performance of the protocol (e.g. trainers, dieticians, coordinators) will continually 
monitor participants for adverse events throughout the intervention, and study staff will assess adverse events 
at every testing visit as well as during regularly scheduled telephone assessments with all randomized 
participants.   
If study staff, tester, participant, caregiver or exercise instructor reports adverse events or complaints, 
relevant information will be collected and documented.   
The participant will be evaluated by the unblinded investigator identified in the protocol.  The investigator 
will have access to training logs, telephone assessment forms, and all study-related testing results. The 

APEX Protocol 22 April 2016 
20 
 
investigator will determine the severity (according to the CTCAE) and relatedness of the AE to the intervention.  
The investigator will identify adverse events of clinical concern, those that may require further workup, or 
suggest that additional participation in the intervention might be a safety risk.  These AEs will first be discussed 
with the participant and then communicated to the study staff or providers with participant’s consent and as 
appropriate.  
 
All maximal exercise testing will be monitored by an appropriate medical monitor.If the subject has 
performed a maximal exercise test in the past, we will, with the participant’s consent, request the records from 
the testing to use as baseline ECG.  Incidental research findings noted by the medical monitor (e.g. ECG 
abnormalities) will be discussed with the participant.  Participants will be referred to a provider as requested.  
Imaging (e.g. MR, DXA) will be formally read only when required by the protocol and as outlined to the 
participant in the consent form. All adverse events will be reported to the investigator, study coordinator, the 
Data Safety Monitoring Board and the Human Subjects Committee per KUMC Human Subject Committee 
reporting policies. 
 
.    
 
Adequacy of Protection Against Risk 
Recruitment and Informed Consent: Recruitment occurs by referrals from organizations serving large 
numbers of older adults, public service announcements through media, physician referral, and word of mouth.   
We are very sensitive to issues related to the subject’s ability to understand the elements of consent and 
their capacity to make decisions.  Individuals with dementia will be excluded from the study.  Informed consent 
will be obtained by study staff (as the designee for Dr. Burns); the purposes of the study, its assessment 
procedures, and risks and benefits are explained.  The original signed consent form is kept with the subject’s 
confidential file and a copy is given to the subject.   
Protection Against Risk:  All research data are maintained confidentially by numerical code in password-
protected databases.  All paper copies are filed by number in accordance with professional standards of 
privileged information.  Confidentiality is strictly safeguarded by HIPAA-compliant standards.   
Empathetic and professional staff mitigates risk of embarrassment.  An experienced nurse clinician 
performs venipuncture.  All women in the study will be post-menopausal and thus not at risk of pregnancy, 
mitigating the risks of low dose radiation from DEXA scanning.  The risk from radiation exposure of this 
magnitude is too small to be measured directly and is considered to be negligible when compared with other 
everyday risk.  Risk from MRI is mitigated by trained technicians who thoroughly screen participants for 
exclusionary conditions prior to each MRI session. 
To protect against and minimize potential risks during the assessment of VO2 peak, subjects will be 
carefully evaluated during the clinical assessment with a physical examination and a resting ECG.  The 
subjects will be screened to exclude those with a history of ischemic heart disease.  During the exercise test, a 
physician will be present and monitor the subject’s heart rhythm by electrocardiography and blood pressure.  
American College of Sports Medicine (ACSM) guidelines will be used to determine whether the exercise test 
should be terminated early.  Criteria for immediate termination include chest discomfort, ST-segment 
depression (>2mm), nervous system symptoms (i.e., ataxia, dizziness), and sustained ventricular tachycardia. 
Risks for the treadmill exercise intervention are similar to those of exercise testing as detailed above. 
Participants will be initially supervised by a fitness specialist to ensure safety.  Kill switches and handrails are 
standard on the treadmills. The program will begin with light exercise and progressively increase in intensity.  
Sessions are supervised by a trained professional who will focus on avoiding injuries and adapting the program 
to participants’ needs.  If subjects develop chest discomfort, other symptoms (for example, dizziness), or injury, 
the session will be discontinued immediately.  
 
Florbetapir PET Results Disclosure:  The KU ADC is disclosing results of the Florbetapir PET scans to 
participants.  This is done under a separate consent to the exercise trial outlined in this proposal although we 
are including information here regarding the rationale for disclosure and how risks will be mitigated.   
 

APEX Protocol 22 April 2016 
21 
 
With the advent of molecular imaging, there is an increasing interest in the use of AD biomarkers in 
diagnosis and risk assessment.  As of February 2011, these techniques are confined to the research arena 
although with the expected approval of agents by the FDA in the near future, their use will likely soon become 
widespread in clinical use.  The KU ADC is at the forefront in this biomarker research and the KU ADC’s 
Florbetapir substudy creates important opportunities that allow us to participate in and shape the national 
conversation on how AD biomarkers are used for risk assessment.  Additionally, identifying a cohort of 
individuals with and without asymptomatic cerebral amyloidosis is designed to provide the essential foundation 
for performing necessary rigorous studies assessing AD prevention strategies. 
In our review of the literature, we believe our choice to reveal amyloid status has several advantages and 
relatively low risks to the participants. Hallmark studies in this area (Roberts et al., 2005; Carpenter et al., 
2008) indicate that most people want to know if they have a specific diagnosis (risk for AD or the diagnosis; 
Bamford et al. 2004; Carpenter & Dave, 2004). In these studies, reports of anxiety and depression were 
actually higher before diagnosis than after, and low reporting of depressive symptoms persisted throughout the 
6-week, 6-month and 1-year follow up periods. Thus, the overwhelming majority of people who received news 
of their elevated risk profile or a diagnosis of AD did not experience grief, depression, or anxiety as a result of 
that disclosure.  Thus “bad news” does not necessarily lead to a catastrophic emotional reaction (Aminzadeh et 
al., 2007; Carpenter et al., 2008)  
Although we do not anticipate many participants to experience reactive depression or anxiety in response 
to amyloid status disclosure, we are putting in place safety monitoring procedures to detect those individuals 
who do experience distress and provide mental health referrals when appropriate. Based on the literature 
(Roberts et al., 2005; Carpenter, 2009; Green et al., 2009), we anticipate 5 categories of possible reaction that 
need to be monitored: relief, depressive reaction, anger, anxiety, or a blend of these four categories.  Negative 
reactions were more likely to occur when the participant is male, lower educated, and young (below age 60). 
Knowing these are demographic characteristics will help the clinical research team to expedite the 
identification of individuals experiencing distress. In the current study we include the identical measures used 
in the hallmark studies to insure that we are using best-practices to monitor for adverse reaction to disclosure 
of asymptomatic cerebral amyloidosis. 
 
Non-elevated Amyloid Group:  We will recruit individuals with non-elevated amyloid PET scans who have 
a mean SUVR (in 6 regions of interest) of 1.0 and greater to be enrolled into the trial as part of the non-
elevated amyloid group.  Based on our first 84 non-elevated participants screened for the study, this 
represents about 1/3rd of those with non-elevated amyloid PET scans.  Participants will be recruited by letter or 
phone calls to those who have been previously screened and meet the criteria or during in-person screening 
visits until a total of 50 nonelevated participants are enrolled.   
SUVR (Standard Uptake Value Ratio) represents a ratio of the retention of radiotracer in the brain 
compared to the patient’s control region of the cerebellum.  A higher is believed to reflect higher levels of 
amyloid in the brain although in this group of individuals who do not evidence of amyloid deposition given their 
non-elevated status, the relevance of the SUVR value remains uncertain.  Nevertheless, this group is of 
scientific interest given some early data suggesting the group may be enriched with individuals who 
accumulate amyloid over time.   
Rationale for not disclosing SUVR values:  Participants will be informed that they are in a group 
representing 1/3rd of those with non-elevated scans that have been selected as eligible to participate based on 
computer algorithm.  Our current practice is not to communicate information on patient’s SUVR values and we 
believe this continues to be important until more data is available to suggest that SUVR values are shown to be 
clinically relevant. There is currently no consensus or evidence that within non-elevated participants SUVR 
values have clinical relevance.  It remains unclear that an SUVR value, especially in the non-elevated range, 
provides any predictive information on risk.  Additionally, it remains unclear whether the sensitivity and 
precision of the measure influences how these values can be interpreted.  Not disclosing SUVR values to 
participants is the current practice for the national Alzheimer’s Disease Neuroimaging Initiative.  We have a 
scientific interest in the group of individuals in the top third of SUVR measures as there is early evidence that 
those with higher amyloid burdens may accumulate amyloid at a more rapid rate than others.  Whether 
individuals who accumulate amyloid are at higher risk of cognitive change is not yet known although given that 
our primary aim is to assess the impact of aerobic exercise on amyloid accumulation.   

APEX Protocol 22 April 2016 
22 
 
Given the burden and expense of amyloid scanning, MRI scanning, and a one-year exercise program, it is 
not feasible to enroll a sample of all non-elevated participants.   
 
Potential Benefits of the Proposed Research to the Subjects and Others  
Subjects potentially benefit from participation in a supervised exercise program.   
 
Importance of the Knowledge to be Gained  
Society benefits from research advances in aging and the maintenance of cognitive and brain health.  
Improved fitness through supervised rehabilitation programs may represent an important therapeutic or 
preventive strategy for dementia. This study will enhance our understanding of the role of exercise in 
promoting healthy brain aging.  Potential benefits outweigh the minimal risks of this research. 
 
Data Safety and Monitoring Plan  
An internal safety committee will meet quarterly to review adverse events and the overall safety of the 
ongoing trial.  The committee will be composed of three clinicians: Mamatha Pasnoor, MD, Richard Dubinsky, 
MD, and James Vacek, MD.  The primary responsibilities of the DSMB are to 1) periodically review and 
evaluate the accumulated study data for participant safety, study conduct and progress, and efficacy when 
planned in the protocol , and 2) make recommendations to the PI concerning the continuation, modification, or 
termination of the trial.  
 Should a study participant experience an AE, relevant information will be collected and documented, and 
the AE will be reviewed by the appropriate investigator within 24 hours.  If the investigator determines the AE is 
directly related to the study, raises concern about increased risk to the participant or overall safety of the study 
design, the safety committee will be notified within 24 hours.  The DSMB will evaluate the AE and will make 
recommendations based on the protocol (e.g. stopping rules).   
 
Women and Minority Inclusion in Clinical Research  
Inclusion of women:  Women are included in all studies described.  We expect that approximately 50% of 
the subjects will be women. 
Inclusion of minorities:  All minority groups are encouraged to participate in this and all our research 
projects.  We place an extra emphasis on the recruitment of minorities through the KU ADC and the Landon 
Center on Aging.  The ADC Education Core recently hired a minority outreach coordinator to increase 
enrollment of African Americans into ADC studies.  The Landon Center on Aging community outreach effort 
specifically targets the Hispanic and African American populations through activity in service agencies for 
these populations and with targeted advertising in minority publications.  In 2003, the University of Kansas 
Medical Center’s outpatient population was composed of 18% African-American, 10% Hispanic, 1% Asian, and 
3% other.  We expect this proportion of minorities will be reflected in our enrollment.  All minority groups are 
encouraged to participate in the research projects. 
 
 
 
 
 
 
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