Genes, Exercise, Neurocognitive and Neurodegeneration: Community-Based Approach

Although anticholinesterase therapies have greatly improved the symptomatic treatment of
Alzheimer's disease (AD), they have not been demonstrated to significantly slow the disease
progression; and amyloid-directed therapies have produced disappointing results. A promising
evidence-based and relatively side-effect free lifestyle approach is emerging as an
alternative or adjunct to drug therapy. In cross-section and prospective studies, and a few
randomized controlled trials; aerobic exercise-training has been demonstrated to improve
cognition in older subjects. However, the mechanisms of these effects remain poorly
understood. Because it is now recognized that cardiovascular disease (CVD) risks can
catalyze AD development, it is vital to test whether lifestyle adaptation shown to reduce
CVD risks can favorably modify cognitive trajectories and markers of neurodegeneration. Such
interventions may benefit those at an early and clinically discernible prodromal stage of AD
such as mild cognitive impairment (MCI). Notably, such data are currently lacking in African
Americans (AA)s who harbor higher rate of CVD risks and AD.

While a laboratory approach to exercise intervention study is required to prove causation,
such a design may not lend itself to real-life application, and is demanding for many
economically and educationally disadvantaged older AAs experiencing early symptoms of
cognitive deterioration. To address this concern, the Investigators seek to initiate an
18-month study, testing real-life applicability of the effects of exercise adaptation on
memory in a more ideal community setting. However, those who chose to exercise at an
academic center will not be excluded. Collection of outcome measures at baseline, 3-month,
6-month, 9-month, 12-month and 18-month will provide pilot data to inform dose and duration
effects of exercise on outcome measures. In addition to augmenting enrollments, the proposed
approach will bolster retention.

The objectives of this pilot study, therefore, are to examine the feasibility of a
community-based 18-month study (6-month active intervention and 12-month passive follow-up)
aerobic exercise-training on neurodegeneration in AAs MCI subjects. The Investigators will
test the hypotheses by randomizing subjects into one of 2 groups: 1.) aerobic-exercise; and
2.) stretch-exercise (control). The Investigators proposed that the aerobic-exercise group
will perform better than control group on cognitive measures. Secondarily, the Investigators
will determine whether training-induced changes in cognition relate to increases in brain
volume. Exploratory, the Investigators will also investigate intervention effects on
cerebrospinal fluid (CSF) biomarkers, selected CVD risk factors and biomarkers, cerebral
oxygenation and Hypoxia-Inducible Factors (HIF-1α) gene expression, and Apolipoprotein E
gene (APOE), to assess their mediation of training-induced changes in cognition.

A team of experienced Investigators in neuroimaging, neurology, cognitive neuroscience, and
exercise physiology has been assembled to conduct this study. Working collaboratively with
the District of Columbia Office on Aging (DCOA), the Directors of the Ward 6 Senior Wellness
Center operated by DCOA, and the lead agencies on aging (community grassroots organizations
supported by DCOA), the Investigators will recruit, enroll, randomize, and train
participants at the wellness center. After obtaining informed consent and completing an
initial assessment, participants will undergo initial exercise screening to determine their
ability to exercise safely. Following randomization of 80 volunteers into aerobic-exercise
(40) and control (40); baseline neuropsychological, neuroimaging and biomarker measurements
will be obtained. Both groups will undergo 3 times/week supervised group-specific
intervention at the wellness center for 6 months. After the initial 6 months of active
intervention, the aerobic-exercise group will follow a prescribed but free living 40
minutes, 3 time/week exercise regimen, while the control group returns to usual care.
Baseline tests will be repeated at 3 month, after 6 months (active intervention period); and
at 9, 12 and 18 months (passive follow-up period). Treadmill, lumber puncture (LP) and brain
magnetic resonance imaging (MRI) tests will occur only at baseline and 6 months. Between
groups changes in cognitive performance, biomarkers, and neuroimaging measurements will be
compared using appropriate multivariate methods.

While the Investigators remain cognizant of other planned or ongoing fitness and memory
trial, the proposed study is unique in the sense that: it is a logical extension of the
Investigators' ongoing work; tests the proposed hypotheses in predominantly AA sample in
whom paucity of data remains, and therefore, will advance reduction in health disparity;
will obtain data at multiple time-points (baseline, 3, 6, 9, 12 and 18 months) and therefore
allow for the assessments of the effects of duration and dose of intervention on outcome
measures; test the real-life applicability of the proposed intervention in a community
setting; and generate pilot data on the mechanisms by which these interventions affects
memory. Importantly, outcomes from this study may lead to practical and effective strategy
to delay cognitive decline in populations at most risk, and can prevent or attenuate the
physical, psychological and the economic burden associated with dementia in AAs.

Main inclusion criteria:

- Age > 55 years

- Ability to exercise vigorously without causing harm to self

- Have Mild Cognitive Impairment (MCI) as defined under diagnosis above

- Have a study partner

- Be in good general health

- Willing to exercise for 12 months

- Willingness to undergo neuropsychological evaluation, PET scan of the brain, and have
blood drawn

Exclusion Criteria:

- Age younger than 55 years

- Scored below 24 on the MMSE (have dementia)

- Have a Body Mass Index (BMI) ≥35,

- If a woman and peri-menopausal and unwilling to maintain current hormone replacement
therapy status and allowed medication usage during the study.

- To avoid inaccurate HDL and HDL2-C determinations or avoid bias from familial
hypercholesterolemia, respectively, participants with TG >400 mg/dl and those whose
LDL-C levels >95% or HDL levels <10% of age and sex-adjusted norms will be excluded.

- Excluded medications: Medications with significant effect on memory such as
anticholinergic (diphenhydramine, tricyclic antidepressants, benztropine); sedative
hypnotics such as benzodiazepines; narcotics; and antiparkinsonian medications will
all be excluded.

- Unstable medical conditions indicated by starting new medications within 6 weeks of
enrollment will be disallowed.

- Concomitant Medication: Medications used in the therapy of AD (Reminyl, Aricept,
Exelon, Namenda, Gingko Biloba) will be allowed if stable on these medications for 6
weeks prior to enrollment.

- Excluded Medical Diagnosis: To avoid misclassification bias, the Investigator will
exclude persons with neurological, psychiatry or other clinical conditions likely to
cause dementia. Participants having functional limitation preventing vigorous
exercise, chronic disabling diseases, and alcoholism and drug abuse will be excluded.

- Clinically significant cerebrovascular disease including cortical infarct,
strategically located subcortical gray matter or extensive white matter
abnormalities.

- Treadmill screening exclusion criteria: include >2 mm ST depression, extra systole,
chest pain, arrhythmias, hypotension and or dizziness or significant ST segment
elevation during the treadmill test.