# Clinical Features and Neuropathological Basis of Sleep Wake Behavior in Alzheimer's and PSP

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2024 · $1,477,591

## Abstract

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...

## Key facts

- **NIH application ID:** 10803883
- **Project number:** 2R01AG060477-06
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Lea Tenenholz Grinberg
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $1,477,591
- **Award type:** 2
- **Project period:** 2019-06-01 → 2029-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10803883

## Citation

> US National Institutes of Health, RePORTER application 10803883, Clinical Features and Neuropathological Basis of Sleep Wake Behavior in Alzheimer's and PSP (2R01AG060477-06). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/10803883. Licensed CC0.

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