# Linking Sleep Dysfunction to Tau-related Degeneration across AD Progression

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2020 · $784,751

## Abstract

PROJECT SUMMARY / ABSTRACT
Wake, sleep and circadian disturbances are common occurrences in Alzheimer' disease (AD), often times
preceding amnestic symptoms. Such disturbances affect the quality of life of patients and caregivers alike and
boost institutionalization. A bidirectional correlation between amyloid-beta (Aβ) deposition and disturbed sleep
contributes to slow wave sleep (SWS) deficits and sleep fragmentation. We discovered converging evidence in
human sleep and neuropathological studies suggesting that individuals with progressive supranuclear palsy
(PSP), a primary tauopathy, show an extreme sleep phenotype featuring a much shorter sleep duration. This
point for a role of tau-related degeneration as an underlying cause of sleep disfunction, independent of Aβ
deposition. Interestingly, brainstem, hypothalamic and basal forebrain nuclei involved in circandian-sleep-wake
regulation develop AD- tau-based neurofibrillary tangles preceding tangles in cortical areas and often, before
Aβ plaques appear. Our working hypothesis is that tau-induced degeneration of key brainstem, hypothalamic
and basal forebrain nuclei controlling 1) SWS; 2) waking-arousal; and 3) circadian timing underlie sleep-wake
behavior in AD, preceding both cognitive decline and later emergence of the feedforward cycle of sleep
disturbance and accelerated Aβ deposition. We will test our hypothesis contrasting sleep-wake behavior in
progressive AD stages versus healthy controls by analyzing differences in objective sleep measurements,
clinical and molecular imaging profiles and quantitative pathoanatomical measures in nuclei involved in wake,
NREM sleep regulation and circadian rhythm. Moreover, we will add a PSP as a positive control group.
We are uniquely poised to succeed due to our group expertise, track record of working together and our
access to uniquely well characterized clinicopathological cohort. This combination of factors creates a unique
opportunity to exploit novel human findings that will inform and complement mechanistic hypotheses and
testing in model systems. This is critical because animals' sleep-wake patterns and AD-like models diverge
from those of humans and experimental models rather mimic non-AD tauopathies than tau-related AD
patterns. We anticipate our findings will inform critical information on the temporal sequence of disrupted sleep
and/or circadian rhythms and the accumulation and spreading of protein aggregates such as phospho-tau and
Aβ in AD. Beyond this, results from this study will inform rational therapies for treating disturbed sleep in AD.

## Key facts

- **NIH application ID:** 9989752
- **Project number:** 5R01AG064314-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Lea Tenenholz Grinberg
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $784,751
- **Award type:** 5
- **Project period:** 2019-08-15 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9989752

## Citation

> US National Institutes of Health, RePORTER application 9989752, Linking Sleep Dysfunction to Tau-related Degeneration across AD Progression (5R01AG064314-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9989752. Licensed CC0.

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