Diet and Exercise Trial to Improve Insulin Resistance, Increase Cerebral Blood Flow, Alter Metabolomic Biomarkers, and Decrease Alzheimer's Disease Risk

Research Strategy Design. The study investigators propose recruiting 40 middle-aged (45-65 years) participants from the Wisconsin Alzheimer's Disease Research Center's (ADRC) "IMPACT" cohort to participate in a 12 week diet and exercise intervention with a 6-month follow-up. The Wisconsin ADRC has a special emphasis in preclinical AD, and participants are recruited with the expectation of being approached for intervention studies. Since the treatment will be applied to groups of 10 participants each, consisting of a total of 4 groups, the study investigators will not be able simultaneously to roll out the treatment program in all groups. Subsequently, an incomplete stepped wedge cluster randomized trial (SWCRT)48,49 will be considered. The design allows each block (intervention group) to be randomized to the intervention in a stepped fashion, initially providing a baseline measure, as indicate by '0' in the design matrix below, then followed by the 12 week intervention 'X' with '.' indicating no measurement, and '1a' indicating measurement post-12 week diet and exercise intervention and '1b' 6 months after the intervention.

Time 1 Time 2 Time 3 Time 4 Time 5 Time 6 Time 7 Group 1 0 X 1a 1b . . . Group 2 . 0 X 1a 1b . . Group 3 . . 0 X 1a 1b . Group 4 . . . 0 X 1a 1b

Timeline. It is anticipated that after recruitment and random assignment to one of the 4 groups, baseline data collection and the 12 week intervention will begin for the first group in month 3 of the 24 month study. Baseline data collection will be completed for all groups by month 12, and post 12-week diet and exercise intervention data collection will be completed by month 15. Post 6 month follow-up data collection will be completed by month 20. The study investigators will share the results of baseline and follow-up findings in manuscripts and at national meetings, in addition to using the generated data to design a larger intervention trial.

Participants. The study investigators will recruit 40 sedentary (exercise <1 hour/week) participants who are 45-65 years of age, have impaired fasting glucose and are cognitively normal (based on the comprehensive ADRC battery). The cohort has received detailed annual medical and cognitive evaluation since enrolling in the Wisconsin ADRC. The cohort is well-characterized for health status and medication use, has undergone genotyping AD-related risk genes, and has banked fluid samples and DNA. Importantly, participants are characterized on metabolic risk, with slightly more than half meeting criteria for central obesity and/or elevated fasting glucose. Exclusion criteria are: active lifestyle (exercise >1 hour/wk); body mass index > 40; MRI contraindications; history of neurological disease, prior neurosurgery; diagnosed and/or treated type 1 or 2 diabetes; pregnancy; acute or subacute active cardiac disease (ongoing chest pain or myocardial infarction < 3 months); significant orthopedic or musculoskeletal condition that limits weight bearing.

Eligibility, Screening and Testing. Following IRB approval, a study coordinator will send an invitation letter describing the study to eligible participants previously identified via fasting glucose levels as pre-diabetic. Interested participants will be contacted by the study coordinator for further eligibility screening. Exercise testing will take place at the School of Nursing Exercise Physiology Laboratory. After an overnight fast, participants will arrive in the morning at the Clinical Research Unit to have blood samples collected for Metabolomics, A1C, glucose and insulin, receive cognitive testing, and magnetic resonance imaging (MRI). Participants will undergo MRI at the Wisconsin Institutes for Medical Research (WIMR).