PROJECT SUMMARY ABSTRACT Alzheimer's disease is a common neurodegenerative disease that is increasing in prevalence with the aging population, characterized by the accumulation of Amyloid-beta (Aβ) peptide associated plaques and hyperphosphorylated tau protein associated neurofibrillary tangles (NFTs). This proposal seeks to link a known feature of aging, namely impaired thermoregulation and lower body and brain temperature, with this age-related increase in NFT pathology. Older age is associated with a long (10–20 year) preclinical phase before symptom onset, in which Aβ and NFT pathology increases and can be measured with tau PET and plasma markers. Extensive and compelling preclinical (rodent and in vitro) findings show that tau phosphorylation is strongly potentiated by small decreases in temperature (decreases in molecular kinetic energy), owing to the differing dependence of regulatory kinases and phosphatases upon this property. Other molecular processes that cause NFT formation may be similarly temperature dependent. We will build upon the results of our preliminary study in older adults that was motivated by these preclinical findings, providing, to our knowledge, their first human translation. Our preliminary results showed that lower telemetrically measured body temperature (Tb) during the hours the subject was awake – but not during sleep – strongly predicted (R2 = 0.47, p < 0.005) the amount of tau NFT tangles measured with [18-F]-MK-6240 tau PET-MR in early Braak stage areas in cognitively normal (NL) older adults. The purpose of the current project is to verify this strong relationship between lower waking Tb and NFTs, using the same methods, in a larger sample of older adults (n = 100, 50 female, 60–80 years) who are NL or have mild cognitive impairment. Briefly, subjects will undergo medical screening (Visit 1), followed by 7 days of home actigraphy for sleep-wake cycle characterization and further screening, and neuropsychological evaluation in Visit 2. In Visit 3, to take place over 48 hours, subjects will undergo Tb measurement with ingestible telemetric thermometry over 48 hours, simultaneous with two nights of nocturnal polysomnography to integrate Tb with the sleep wake state and measure slow wave sleep, followed by plasma tau and p-tau sampling the following morning. Subjects will be free to return home during the day in between sleep studies. At Visit 4, 18- F]-MK-6240 tau and amyloid PiB PET-MR scanning will be completed. We aim to 1)Verify lower waking Tb prediction of NFT in this sample, 2)Incorporate and account for the effects of Aβ plaque load (known to increase NFTs) and older age into the model, and 3)Test the extent to which the known relationship between Tb and sleep plays a role in Tb–NFT associations. This cross-sectional study will lay the ground work for future prospective studies to determine whether Tb based interventions can prevent the progression of NFT pathology toward reducing Alzheimer’s Disease burd...