Feasibility of Improving Glycemia With Heat Therapy to Prevent AD (FIGHT-AD)

We will determine if heat therapy can improve blood (Aim 1) and brain (Aim 2) glucose metabolism in cognitively healthy older adults (65+) who are at risk for AD. We will also examine the degree to which changes in blood and brain glucose metabolism track together and explore several additional potential mechanisms that are critical to understanding the brain benefits of heat therapy (Aim 3). These aims will provide a comprehensive understanding of the impact of heat therapy on whole body metabolic function and brain health.

Aim 1. Examine the effects of heat therapy on blood glucose regulation in older adults at risk for AD. We will determine the ability of 10 weeks of heat therapy (3 days/week) to improve blood glucose regulation in older adults at risk for AD. Our primary outcome measures will be change in glycated hemoglobin (HbA1c), and change in insulin sensitivity index (ISI) assessed pre- vs post-intervention. We will also perform continuous glucose monitoring for 7 days prior to and following the intervention, as well as monitor dietary patterns during the intervention. We hypothesize that 10 weeks of heat therapy will lower HbA1c values and improve ISI outcomes. Aim 2. Test the effect of heat therapy on brain glucose metabolism. To date, no studies have examined the impact of heat therapy on brain glucose metabolism. Here we will determine the effect of 10 weeks of heat therapy on brain glucose metabolism in older adults at risk for AD. Our primary outcome measure will be change in [18F] fluorodeoxyglucose (FDG) global standardized uptake value ratio (SUVR) pre- vs post- heat therapy. We hypothesize that individuals will improve (increase) global cerebral glucose metabolism following 10 weeks of heat therapy. We further hypothesize that the degree of change in blood glucose metabolism will track with change in brain glucose metabolism. Aim 3. Explore the effect of heat therapy on fluid biomarkers (proteostasis, inflammation, neuropathology) and neuroimaging markers of brain health. We will explore the effect of heat therapy on plasma markers of proteostasis (HSP's), inflammation (CRP, TNF, IL-6, JNK and IKK) and AD-related neuropathology (Amyloid/Tau/Neurodegeneration; A/T/N measures) markers in plasma at baseline and following 10 weeks of heat treatment. We will also obtain MRI measures of resting state metabolism, brain blood flow, and oxygen uptake for preliminary characterization of intervention-related changes. We hypothesize that proteostasis, inflammation, and AD neuropathology will be beneficially affected by heat treatment. We further hypothesize that we will observe benefits in MRI-related brain outcomes.

Primary Investigators will be blinded to participants group. Due to the type of intervention we are unable to blind participant or certain members of the study team

hemoglobin A1C (HbA1C) test is a blood test that shows what your average blood sugar (glucose) level was over the past two to three months

FDG PET measures reflecting cerebral metabolism standardized to the uptake value of the cerebellum and standardized uptake value ratios (SUVR) will be calculated from native-space region of interest (ROI).

Inclusion Criteria: Age 65 and older Stable medication doses (>1 month) Post-menopausal Clinical Dementia Rating (CDR) of 0 History of or current metabolic impairment (i.e. metabolic syndrome, pre-diabetes, Type 2 Diabetes, etc) Exclusion Criteria: Excluded from or unable to complete an MRI scan. MRI compatible pacemakers will require cardiologist clearance prior to enrolling. ACSM Risk score stratification of "High" unless cleared by a physician prior to participation. Myocardial infarction or symptoms of coronary artery disease in the last 2 years. History of or current diagnosis of disorders with the potential to impair cognition (i.e. AD, Parkinson's disease, stroke (defined as clinical episode w/ neuroimaging evidence in appropriate area to explain symptoms)). Insulin-dependent (Type 1) Diabetes Mellitus. Clinically significant chronic disease such as cancer, HIV, or acquired immunodeficiency syndrome. Clinically significant depressive symptoms that may impair cognition, use of psychoactive and investigational medications, and significant visual or auditory impairment. Orthopedic complications that would preclude individuals from safely entering a hot tub. Untreated hypothyroidism or diseases associated with heat intolerance (i.e. Graves disease, etc). Contraindication for temperature pill ingestion (i.e. inflammatory bowel disease, diverticulitis or related).