7. PROJECT SUMMARY Cerebral deposition of amyloid-beta peptides is a key mechanism in the development of Alzheimer's disease (AD). Experimental models show that the sleep-wake cycle may regulate amyloid-beta levels, suggesting that poor sleep quality may affect the pathophysiological mechanisms of amyloid-beta deposition. Sleep changes dramatically throughout the lifespan. With age, it becomes more fragmented, declines in the quantity and quality of deep stages and there is an increase in the prevalence of obstructive sleep apnea (OSA). The goals of our funded R01 are to test how sleep quality and severity of OSA lead to amyloid deposition. In the first 4 years of our current funding we have made excellent progress in addressing these goals. So far, we have enrolled 192 healthy elderly in a 2-year longitudinal study that includes home sleep-monitoring, brain MRIs and a lumbar puncture (LP) done at baseline and follow-up. In addition, we obtained home sleep measurements in a group of subjects with available PiB-PET scans as well as in-lab NPSG recordings in a subset with available CSF. We found: a) lower slow wave sleep (SWS) duration and lower slow wave activity (SWA) associated with high cerebrospinal fluid (CSF) Aβ42 levels at cross-section; b) a high prevalence of OSA in the absence of excessive daytime sleepiness, history of cardiovascular events or cognitive impairment; and, c) severity of OSA associated with longitudinal decreases in CSF Aβ42 and increases in PiB-PET SUVR uptake. Such changes are potentially consistent with longitudinal increases in brain amyloid burden, suggesting that disrupted sleep, very common in our cohort, contributes to amyloid deposition in healthy elderly. In this competitive renewal, we will extend our prior work by adding new follow-ups (baseline and 24 months) to a group of normal sleep breathing controls and mild-to-moderate OSA subjects retained in the cohort (planned n=112 including attrition rates). All subjects will receive a structural 3T MRI, 2 nights of NPSGs and an amyloid 18F-florbetaben (FBB) PET-MR scan in both visits. The goals of this study are: 1) to examine the direct contribution of age-related SWS loss on longitudinal changes in amyloid deposition; and, 2) to examine the longitudinal effects of mild-to-moderate OSA on amyloid deposition. This novel proposal may identify: i) a relationship between sleep disturbances and longitudinal increase in amyloid burden; ii) enhancement of SWS and treatment of OSA as novel therapeutic targets for AD prevention.