The overall goal of the CYCLE-AD trial is to determine the role of long-term, high intensity exercise in slowing or delaying the onset of cognitive and AD-related brain changes in e4 carriers. Successful translation and demonstration of the effectiveness of a scalable home-based exercise intervention capable of slowing or delaying disease onset will transform AD treatment, improve patient outcomes and quality of life, and reduce health care costs.

The apolipoprotein E epsilon 4 (APOE e4) allele is the most important genetic risk factor for late onset Alzheimer's disease (AD). A recent review by the World Health Organization highlighted the potential protective role of physical activity and exercise against cognitive decline, all-cause dementia, AD, and vascular dementia in healthy individuals. In an 18-month longitudinal observational study, investigators showed that sedentary e4 carriers experience significant declines in episodic memory and hippocampal volume compared to 4 carriers who engaged in moderate PA. Importantly, among 4 non-carriers, no significant longitudinal changes in cognition and brain imaging were observed whether the non-carriers were sedentary or engaged in moderate PA, suggesting that PA has a specific neuroprotective role in delaying the progression of AD in e4 carriers. Based on the results, a pragmatic, randomized controlled trial with blinded clinical and imaging outcomes is proposed to determine the impact of a home based, high intensity exercise intervention in healthy, cognitively intact e4 carriers between the ages of 65 and 80 years. The CYCLE-AD (CYcling to Cease or Limit the Effects of Alzheimer's Disease) trial will recruit otherwise healthy sedentary carriers randomized to one of two groups (n=75 each): 1) an Indoor Cycling (IC) group that participates in high-intensity interval training (HIIT; 60-90% of heart rate reserve) in their home via the commercially available Peloton® cycling system or 2) a Usual and Customary Care (UCC) group, in which participants engage in their habitual level of PA. Investigators hypothesize that an 18-month high-intensity aerobic exercise regimen will slow AD-related disease progression in sedentary elders at genetic risk for AD. Participants in the intervention group will engage in exercise 3x/week (minimum 90 minutes/week) for 18 months. Primary outcome measures, obtained at study entry and at 18 months, will include comprehensive cognitive testing and brain MR imaging to assess disease progression and a comprehensive PA/fitness assessment to measure the degree of change in physical fitness due to high intensity aerobic exercise.

Inclusion Criteria:

1. Healthy elders, ages 65-80 years, inclusive
2. No cognitive impairment based on screening examination
3. APOE ε4 genotype
4. Inactive; defined as exercising less than 3x per week at moderate-vigorous intensity
5. Fluent in English (a requirement for neurocognitive testing)
6. Does not plan to travel for more than 2 consecutive weeks over the course of the study
7. Demonstrate ability to safely mount and dismount Peloton stationary cycle
8. In-home Wi-Fi (Peloton system requires Wi-Fi to transmit exercise data)
9. Medical clearance by the study doctor to participate in exercise program
10. Participant must meet Peloton height and weight safety requirements

Exclusion Criteria:

1. Any significant neurologic disease, including dementia, mild cognitive impairment, Parkinson's disease, Huntington's disease, normal pressure hydrocephalus, brain tumor, progressive supranuclear palsy, seizure disorder, subdural hematoma, stroke, multiple sclerosis, or history of significant head trauma with a reported loss of consciousness for greater than 30 minutes.
2. Significant medical illnesses/conditions that is unstable and/or uncontrolled (lung or kidney disease, cancer).
3. History of schizophrenia or bipolar disorder.
4. Major Depression within the past year.
5. History of alcohol or substance abuse or dependence within the past 2 years.
6. Current use of Alzheimer's disease medications, including cholinesterase inhibitors and memantine.
7. Any unstable or severe cardiovascular disease or asthmatic condition.
8. History of imaging confirmed transient ischemic attack or a score of >4 on the modified Hachinski ischemic scale.
9. Significant abnormalities in laboratory blood tests that is considered to be a contraindication to exercise.
10. Exclusion criteria specific to MR scanning (weight inappropriate for height, ferrous objects within the body, pregnancy, and a history of claustrophobia).
11. A musculoskeletal issue (arthritis, osteoporosis, back problem) that would limit one's ability to engage in exercise