aeRobic Exercise and Cognitive Health

The prevalence and costs associated with Alzheimer's disease (AD) are projected to increase
exponentially owing to the unprecedented expansion in the elderly segment of the United
States' population. Given this looming specter, delaying the onset of AD symptoms and
curbing the progression of the underlying disease process has become a national public
health imperative (U.S. DHHS 2014). Delaying symptom onset by as little as 5 years could
reduce the prevalence of AD by half (U.S. DHHS 2014, Khachaturian 2009). Unfortunately,
currently available drug treatments for AD are not curative. Similarly, clinical trials
testing novel disease-modifying therapeutics have been disappointing (Sperling 2011). The
urgency of alternative approaches for halting the global crisis posed by AD cannot be
overstated.

Animal studies have demonstrated that aerobic exercise (EXER) is a low-cost, low-risk
intervention capable of altering the AD pathological process (Adlard 2005, Wu 2008).
Randomized controlled trials (RCTs) of EXER in older adults have also revealed its
beneficial effects on AD-relevant measures such as brain glucose metabolism and
memory/executive function (Erickson 2011, Baker 2009). Importantly, a recent evidence review
found that of 7 key modifiable risk factors for AD, physical activity had the highest impact
on reducing the national prevalence of AD (Barnes 2011). However, there are presently no
RCTs examining the effects of EXER in middle-aged, asymptomatic individuals at increased
risk of AD. This is an important knowledge gap for several reasons. Interventions to halt
the AD pathological cascade are more likely to be effective if implemented prior to
pervasive neuronal damage (Sperling 2011). Secondly, persons with specific risk factors for
developing AD (such as parental family history (FH)) represent a choice target population
for any credible attempts at reducing the growing burden of AD (Jarvik 2008). Lastly, a key
limitation of prior EXER RCTs is the failure to adequately account for participants'
physical activity levels outside of the intervention.

Accordingly, the main objective of this study is to pilot a 26-week trial of EXER among
asymptomatic, middle-aged adults with and without family history (FH) of AD enrolled in the
Wisconsin Registry for Alzheimer's Prevention (WRAP) or the Wisconsin Alzheimer's Disease
Research Center (WADRC). The investigators' near-term goal is to assess the feasibility and
acceptability of this structured intervention and preliminarily evaluate (i) its effect on
AD-relevant outcomes such as glucose metabolism and (ii) the mechanism for such effects. The
investigators' longer-term goal is to use the data gathered via this pilot to further refine
the intervention, estimate effect sizes for key outcomes, and seek NIH funding for a longer
and more definitive assessment of whether EXER can effectively curtail AD progression in
midlife. The specific aims are:

AIM 1: Determine the feasibility and acceptability of a 26-week, 3-4 days per week,
structured EXER regimen among middle-aged adults with FH of AD. Hypothesis: The
investigators will successfully enroll the 30 participants (15 each in EXER and usual
physical activity groups) targeted for this study. At least 90% of the participants within
the EXER group, called the enhanced physical activity group, will complete ≥80% of scheduled
training sessions.

AIM 2: Preliminarily characterize the effect of the EXER intervention on AD-related brain
alteration. Hypothesis: Compared to participants randomized to the usual physical activity
group, those randomized to the enhanced physical activity group will demonstrate preserved
brain glucose metabolism. Similar effects will be seen in secondary outcomes including
cerebral blood flow, hippocampal volume, vascular health, memory/executive function, and
mood.

AIM 3: Preliminarily evaluate (i) the biological mechanisms by which EXER affects brain
health and cognition, and (ii) the individual difference factors that potentially moderate
EXER's effects. Hypotheses: (i) Persons in the enhanced physical activity group will exhibit
significant increases in circulating neurotrophins and improved cardiorespiratory fitness,
and (ii) the beneficial effects of EXER will be more pronounced for participants with
decreased sedentary behaviors outside of the intervention (measured via accelerometry).

AIM 4: Preliminarily determine whether EXER improves vascular health. Hypothesis:
Individuals in the enhanced physical activity group will exhibit comparatively increased
cerebral blood flow, and improved endothelial function.

Inclusion Criteria:

- Age between 45 and 80 at baseline visit.

- Must be currently physically inactive (i.e. not meeting national guidelines of 150+
minutes per week of moderate exercise).

- Participant is not pregnant at the time of the PET and MR imaging exams.

- Willing and able to complete all assessments and exercise intervention faithfully.

- Fluent and proficient in English language and capable of completing
neuropsychological testing in English.

- Participant must have physician clearance to participate in this study.

Exclusion Criteria:

- Any significant neurologic disease, such as Parkinson's disease, multi-infarct
dementia, Huntington's disease, normal pressure hydrocephalus, brain tumor,
progressive supranuclear palsy, seizure disorder, subdural hematoma, multiple
sclerosis, or history of significant head trauma (10 min or more of loss of
consciousness) followed by persistent neurologic deficits or known structural brain
abnormalities.

- Presence of pacemakers, aneurysm clips, artificial heart valves, ear implants, metal
fragments, or foreign objects in the eyes, skin, body. X-ray may be used to establish
suitability for MRI.

- Inability to complete exercise test due to medical restrictions such as hip surgery,
knee surgery, arthritis, or other orthopedic concerns that prevent being able to walk
on a treadmill, type I or II diabetes mellitus, and documented vascular disease such
as coronary artery disease.

- Clinically significant findings from the exercise test that prohibit participation in
moderate intensity exercise (i.e. 3rd degree heart block).

- Current Axis I DSM-IV disorder including but not limited to major depression within
the past two years, history of bipolar I disorder, history of schizophrenia spectrum
disorders (DSM IV criteria).

- History of alcohol or substance abuse or dependence (DSM IV criteria).

- Any significant systemic illness or unstable medical condition that could affect
cognition, CBF or BOLD, or cause difficulty complying with the exam. History of
chemotherapy, thyroid disease, or renal insufficiency are excluded.

- Severe untreated hypertension (>200/100mmHG).

- Participants who do not have the cognitive competence and legal capacity to make
informed medical decisions are excluded at entry. If a participant experiences
significant cognitive decline during the study such that they no longer have medical
decision making capacity the investigators will enact procedures that have been
approved locally by the IRB and legal counsel at the University of Wisconsin-Madison:
A) use their initial expressed and written consent as an indicator of willingness to
continue to participate in the study; AND B) require that they provide assent at the
time of follow-up visits witnessed and counter signed by their caregiver; AND C)
signed consent from the patient's legally authorized representative.

- Current use of antipsychotic medications such as non-SSRI antidepressants,
neuroleptics, chronic anxiolytics, or sedative hypnotics, as well as some cardiac
glycosides such as Digoxin.

- Investigational agents are prohibited.

- Exceptions to these criteria will be rare but may be considered on a case-by-case
basis at the discretion of the investigators in consultation with study physicians.