Investigating Gains in Neurocognition in an Intervention Trial of Exercise

This randomized control trial will examine whether a 12 month monitored exercise intervention improves brain health in cognitively normal older adults. This trial will also address several important unanswered questions: (1) Are the recommended public health guidelines of 150 minutes/week of exercise sufficient for improving cognitive performance? (2) Does exercise influence brain structure and/or function? (3) Is there a dose-response effect of exercise on the above variables such that greater amounts of exercise brings about greater benefits in cognitive and brain health? (4) What are the mechanisms by which exercise influences brain health? and (5) What factors attenuate or magnify the effects of exercise on brain and cognitive health and contribute to the individual variability in intervention outcomes?

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.

Due to Covid-19 pandemic, the exercise intervention was moved to fully home based during the months of March 2020 through August 2020. During this time, study participants were mailed wrist based heart rate monitors to track intensity. Exercise videos were developed and released to study participants to enhance adherence to the prescribed volume of exercise. Study participants were contacted weekly to obtain weekly exercise volume, mode and intensity. From August 2020 to end of the trial, participants will have flexibility to complete randomized goal of exercise. The study recommends three supervised sessions per week but will work with study participants who feel unsafe exercising in one of the study locations.

The outcome measures to be collected during March 2020 and July 2020 were delayed in those subjects had original intervention end date during this time. For these study participants, many signed a study consent extension and continued the intervention until study sites were allowed to re-open after careful planning and approved mitigation plans at each respective university. Once approved to re-open, participants were scheduled for their post assessment outcome collection.

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. Amyloid Diminution: We will test (a) assess Amyloid deposition changes in response to physical activity and (b) whether changes occur in a dose-dependent manner and (c) examine baseline Amyloid as a moderator of intervention effects and (d) examine changes in Amyloid as a mediator of changes in brain and cognition. Hypothesis: We predict that Aβ burden will be attenuated over the course of the intervention for the aerobic exercise groups compared to control group. Further, we predict that 225 minutes/week of aerobic exercise will result in a greater effect on Aβ than 150 minutes/week
6. 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.

Eligibility Criteria:
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 \<60 minutes per week (less than 20 minutes / 3 days 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 \>60 minutes of moderate intensity physical activity (more than 20 minutes day / 3 days per week)
* Traveling consecutively for 3 weeks or greater during the study