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

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2022 · $804,861

## Abstract

PROJECT SUMMARY / ABSTRACT
Sleep disturbances occur frequently in neurodegenerative disease and constitute the most common reason for
institutionalization. Sleep disruption has also been proposed to contribute causally to increasing amyloid beta
(Aβ) deposition, which has fueled interest in bidirectional relationships of sleep and Alzheimer's Disease (AD),
but its relationship to the other major AD neuropathology – accumulation of pathogenic tau-related
neurofibrillary tangles – is unknown. In AD, sleep dysfunction includes sleep fragmentation, sundowning, and
daytime sleepiness, measured by short sleep latencies on the multiple sleep latency test (MSLT). In contrast,
we found that Progressive Supranuclear Palsy (PSP), a different tauopathy not associated with Aβ deposition,
features marked reductions in duration of both Rapid Eye Movement (REM) sleep and Non-REM (NREM)
sleep, and prolonged sleep latencies seen by MSLT. The tau neuropathologies of AD and PSP both begin
subcortically, in brainstem and hypothalamus. Their divergent sleep-wake behavior profiles – in PSP,
dramatically decreased total sleep time, absent daytime sleep, vs. in AD, sleep redistributed across night & day
periods, with little reduction of total sleep time – along with contrasting tau burden in sleep- and wake-related
brainstem nuclei (Prelim. Res.), provides a novel opportunity to discover the neurobiological basis of their
disturbed sleep-wake rhythms. We will test the novel hypothesis that differential vulnerabilities of nuclei in
wake-promoting (loss in AD > PSP) and sleep-promoting (loss in PSP > AD) neurons determines the different
pattern of sleep-wake disturbances in these 2 contrasting tauopathies.
The premise of this proposal is that: 1) sleep-wake disturbances are common to both of these tauopathies; 2)
leveraging the subcortical anatomically distinct neurodegeneration foci seen early in PSP & AD, that segregate
functionally as wake-predominant in AD and sleep-predominant nuclei in PSP, as natural lesions, will uncover
mechanisms of their differential profiles of disturbed sleep and wakefulness; and 3) future design of efficient,
specific treatments for sleep in PSP and AD will require understanding of their respective mechanisms.
We will test our idea by determining if differences in sleep-wake behavior in PSP and AD subjects vs. healthy
controls (HC) are quantitatively attributable to corresponding altered pathoanatomical measures (including total
numbers of neurons and of specific neuronal subpopulations, and hp-tau burden) in nuclei involved in wake
and NREM sleep regulation. We will assess quantitative clinical neurohistopathological correlates in respective
subsamples of PSP, AD, and control subjects who completed sleep measures prior to death and autopsy. The
project represents a unique collaborative/interdisciplinary opportunity with highly specialized brain collections
and sleep analysis, whose results may yield an unprecedented disease-specific mechanis...

## Key facts

- **NIH application ID:** 10374178
- **Project number:** 5R01AG060477-04
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Lea Tenenholz Grinberg
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $804,861
- **Award type:** 5
- **Project period:** 2019-06-01 → 2024-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10374178

## Citation

> US National Institutes of Health, RePORTER application 10374178, Clinical Features and Neuropathological Basis of Sleep Wake Behavior in Alzheimer's and PSP (5R01AG060477-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10374178. Licensed CC0.

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