Investigating Gains in Neurocognition in an Intervention Trial of Exercise

The investigators are conducting a 12-month, multi-site, randomized dose-response exercise
trial (i.e., brisk walking) in 639 cognitively normal adults between 65-80 years of age.
Participants will be randomized to a (a) moderate intensity aerobic exercise condition at the
public health recommended dose of 150 minutes/week (N=213), (b) a moderate intensity exercise
condition at 225 minutes/week (N=213), or (c) a light intensity stretching-and-toning control
condition for 150 minutes per week (N=213). Participants will meet 3 days/week for site-based
exercise and do home-based activity on two more days of the week for 12 months. A
comprehensive state-of-the-science battery of cognitive, MRI, amyloid imaging, physiological
biomarkers, cardiorespiratory fitness, physical function, and quality of life measures will
be assessed at baseline and after completion of the intervention.

Specific Aims include:

1. Cognitive Enhancement: Using a comprehensive neuropsychological battery and the NIH
Toolbox, the investigators will test (a) whether a 12-month moderate intensity exercise
intervention improves cognitive performance in older adults and (b) whether the
improvements occur in a dose-dependent manner. Hypothesis: PA will enhance cognitive
performance non-uniformly with the greatest effects occurring for executive and
declarative memory functions. The investigators also predict that these improvements
will follow a dose-dependent trajectory with 225 minutes/week of PA demonstrating
greater improvements than 150 minutes/week of PA.

2. Brain Augmentation: The investigators will test (a) whether a 12-month PA intervention
augments MRI markers of brain health and (b) whether changes happen in a dose-dependent
manner. Hypothesis: PA will most profoundly influence the volume, microstructural white
matter integrity, cerebral blood flow, and connectivity of regions supporting
declarative memory (e.g., hippocampus) and executive function (e.g., prefrontal cortex;
PFC). Further, the investigators predict that 225 minutes/week will result in greater
effects than 150 minutes/week. The investigators predict that these changes in brain
outcomes will mediate the cognitive improvements in Aim 1.

3. Biomediators: The investigators will test the hypothesis that cardiometabolic,
inflammatory, and neurotrophic changes mediate improvements in brain and cognition.
Hypothesis: (1) decreases in pro-inflammatory cytokines, (2) decreases in central
adiposity, arterial stiffness, and insulin resistance, and (3) increases in
brain-derived neurotrophic factor (BDNF) levels will statistically mediate changes in
cognitive performance (Aim 1) and brain health (Aim 2), and that the strength of this
mediating relationship might vary as a function of certain apriori moderating variables
of interest

4. Moderators: To examine subgroups (i.e., individual differences) that attenuate or
magnify the effect of the intervention on cognitive, brain, and physiological systems to
better understand the factors that predict 'responders' versus 'non-responders' to the
intervention. The investigators will examine three categories of variables: (1)
demographic (e.g., age) (2) genetic (e.g., APOE), and (3) baseline Aβ burden.
Hypothesis: The favorable effects of PA on brain and cognition will be greatest for
older individuals with greater Aβ burden, and in those with a genetic susceptibility for
accelerated cognitive decline.

5. Exploratory Aims: The investigators will explore (a) whether baseline brain health
metrics predict adherence and compliance to 12-months of PA, and (b) the utility of
multi-modal brain imaging analytical approaches to more comprehensively understand the
effects of PA on the aging brain.

Inclusion Criteria:

- Men and women 65 - 80 yrs

- Ambulatory without pain or the assistance of walking devices

- Able to speak and read English

- Exercise level of <20 minutes per week

- Medical clearance by PCP

- Living in community for duration of the study

- Reliable means of transportation

- No diagnosis of a neurological disease

- Eligible to undergo MRI

Exclusion Criteria:

- Current diagnosis of a DSM-V Axis I or II disorder including Major Depression

- History of major psychiatric illness including schizophrenia (not including general
anxiety disorder or depression)

- Current treatment for cancer - except non-melanoma skin

- Neurological condition (MS, Parkinson's, Dementia, MCI) or brain injury (traumatic or
Stroke)

- Type I Diabetes or insulin-dependent diabetes

- Current alcohol or substance abuse

- Current treatment for congestive heart failure, angina, uncontrolled arrhythmia, DVT
or other cardiovascular event

- Myocardial infarction, coronary artery bypass grafting, angioplasty or other cardiac
condition in the past year

- Regular use of an assisted walking device

- Presence of metal implants (pacemaker, stents) that would be MR ineligible

- Claustrophobia

- Color Blindness

- Not fluent in English

- Not medically cleared by PCP

- Engaging in >20 minutes of moderate intensity physical activity

- Traveling consecutively for 3 weeks or greater during the study