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

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2021 · $13,828

## Abstract

PROJECT SUMMARY / ABSTRACT (from parent award)
Sleep and circadian disturbances occur often and even precede the onset of cognitive decline, in Alzheimer'
disease (AD) and other neurodegenerative diseases – and constitute a common reason for institutionalization.
Sleep loss, particulary slow wave sleep (SWS), and sleep fragmentation, may contribute causally to AD by
increasing amyloid-beta (Aβ) deposition, as described in PAR-18-497, but Aβ alone appears insufficient to
explain all mechanisms and causation of AD clinical manifestations and disordered sleep. We discovered
converging evidence in human sleep and neuropathological studies suggestive of a primary, novel role of
tauopathy in AD-disordered sleep. In this connection, in postmortem brains of AD subjects, subcortical nuclei
involved in circandian-sleep- -wake regulation are among the first to develop AD-type tau-based neurofibrillary
tangles, before Aβ plaques appear. Our working hypothesis is that tau-induced degeneration of subcortical
nuclei controlling 1) SWS; 2) waking-arousal; and 3) circadian timing is an early contributor to disrupted sleep-
wake behavior in AD, preceding both cognitive decline and later emergence of the feedforward cycle of sleep
disturbance and accelerated Aβ deposition. We propose to test if differences in sleep-wake behavior in
progressive AD stages versus healthy controls vs. PSP ( a pure tauopathy more pronounced in subcortical
areas) are accounted by differences in quantitative pathoanatomical measures (including numbers of total and
specific neuronal population, and hp-tau burden) in nuclei involved in wake and NREM sleep regulation.
We are uniquely poised to suceed due to our access to large longitudinal cohorts of AD and PSP patients and
similarly-aged controls and successful autopsy program, expertise in p-tau and Aβ PET imaging, deep
experience in clinical sleep studies in neurodegenerative disorders, tissue collections of aged controls, cases
encompassing all-AD spectrum and other tauopathies, enabling stereology of whole brain regions, experience
in human subcortical pathoanatomy, and cutting-edge neuropathological methods and brain network approach.
This combination of factors create 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 p-t 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:** 10328419
- **Project number:** 3R01AG064314-02S1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Lea Tenenholz Grinberg
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $13,828
- **Award type:** 3
- **Project period:** 2019-08-15 → 2021-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10328419

## Citation

> US National Institutes of Health, RePORTER application 10328419, Linking Sleep Dysfunction to Tau-related Degeneration across AD Progression (3R01AG064314-02S1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10328419. Licensed CC0.

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