PROJECT SUMMARY / ABSTRACT Sleep-wake (S/W) disturbances are a common problem in neurodegenerative diseases, and often the main reason for institutionalization. However, there are few effective treatments for S/W disruption specific to such diseases and grounded on their underlying causes. Evidence suggests a bidirectional link between S/W disrup-tion and brain accumulation of amyloid-β (Aβ), but we and others have found evidence that specific phosphory-lated tau (p-tau) neuropathology is also involved in S/W problems. In our current funding cycle, we discovered that both Alzheimer's Disease (AD) and Progressive Supranuclear Palsy (PSP) involve tau accumulation, but the patterns of their neuronal losses in S/W-regulating brainstem and hypothalamic nuclei, and also their sleep dysregulation, diverge markedly, pointing to distinct, selective, differential vulnerability to tauopathies. Based on multiple breakthrough findings of divergent S/W behavior profiles of AD & PSP, and novel neuropathological methods we developed, in the proposed renewal we aim to ascertain molecular and neurotransmitter activity changes in vulnerable S/W disruption-driving neuromodulatory subcortical systems (NSS) regions in AD and PSP, toward guiding selection of medications that modulate NSS function. In AD, we found that tau-related neurodegeneration of wake-promoting (W) neurons of NSS contributes strongly to sleep problems and correlates with AD's typical pattern of sleep fragmentation and excessive day- time sleepiness. In contrast, we found that PSP features insomnia, short sleep duration, and deficient daytime sleep recovery, with largely intact W neurons despite presence of tau, thus implicating selective vulnerability of NSS sleep-promoting (S) neurons. In AD, we unexpectedly found tau-related loss of lateral hypothalamic (LH) orexin (ORX) neurons, prior to any losses in the wake-promoting locus ceruleus. We also found an early pattern of neuroinflammatory-related gene upregulation in both locus ceruleus and lateral hypothalamic area in AD that differs from that seen in PSP. Such disease-specific compensatory responses in S/W-regulating nuclei have been entirely unknown and are highly relevant to potential development of targeted drugs. There is thus urgent need to map disease-specific NSS neurobiology beyond neuronal loss or tau/Aβ presence, to enable rational, disease-specific therapies. We hypothesize that our innovative clinicopathogical paradigm can reveal disease-specific pathogenic mechanisms of S/W disturbances, measured by deep antemortem phenotyping of S/W macrostructure (e.g. sleep stages) and microstructure. We will analyze and compare clinical, neurohistopathological and molecular correlates in our ongoing cohorts of antemortem & postmortem PSP, AD, and healthy controls (HC). Our key hypothesis is that tau deposition and later neuronal loss and pan- network compensatory effects on NSS neuroinflammation, neurotransmitter/peptide (NT) release, and NT rec...