# Mechanisms of Obstructive Sleep Apnea in Tau Pathophysiology, Risk and Progression of Alzheimer's Disease

> **NIH NIH R01** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2020 · $544,709

## Abstract

PROJECT SUMMARY: Accumulating evidence suggests that obstructive sleep apnea (OSA), the most
common form of sleep-disordered breathing (SDB), is an important risk factor in the development and
progression of Alzheimer's disease (AD). OSA has a higher prevalence in the elderly population, and it is
thought to cause its deleterious effects through sleep fragmentation and chronic intermittent hypoxia (CIH).
Recent epidemiological evidence suggests CIH as the best predictor of cognitive decline in the elderly with
OSA. Elderly subjects with higher oxygen desaturation index (ODI) and percent time in apnea or hypopnea
have increased risk of developing mild cognitive impairment (MCI) and AD dementia. However, the
mechanism(s) by which CIH impacts cognition, and risk and progression of AD remain(s) largely unknown.
There is a critical need for investigations in animal models in which causal relationships can be established to
understand the exact role(s) CIH play in AD pathophysiology. Neurofibrillary tangles (NFTs), a major
neuropathological hallmark of AD, formed of abnormally hyperphosphorylated tau, are well-known to be better
correlated with cognitive decline than amyloid β plaques in AD. We have strong preliminary data showing that
CIH induces cognitive deficits both in wild-type mice and P301S human tau mouse model of AD and related
tauopathies and it promotes tau propagation through connected anatomical neural circuits. The primary goal of
this proposal is to elucidate the causal relationship between CIH and exacerbation and progression of tau
pathology that increases risk of development and progression of AD. Our central hypothesis is that CIH plays a
role in abnormally hyperphosphorylated tau accumulation and spread and cerebral network dysfunction,
contributing to AD's molecular and cognitive dysfunctions. We will utilize a multi-modal and integrative
approach evaluating in the setting of CIH in P301S human tau transgenic mice, first, trans-synaptic spread of
tau pathology as well as tau aggregation and phosphorylation, second, regional neural network dysregulation
that can result in hyperexcitability, facilitating tau pathology accumulation and propagation, and finally, its
underlying molecular mechanisms with an innovative technology, i.e., translation ribosomal affinity purification
(TRAP)-RNA-Sequencing. TRAP provides us with a unique opportunity to unravel the regional vulnerability to
CIH within the hippocampal formation. Furthermore, we will also evaluate the effect of CIH on hippocampal
synaptic plasticity, including short term plasticity (paired-pulse facilitation) and long-term plasticity (long-term
potentiation, LTP, and long-term depression, LTD), which could provide a neurophysiological basis for CIH-
induced memory deficit. Overall, this project will determine the effect of CIH on the progression of major AD
pathophysiologic and phenotypic hallmarks. Thus, it will unravel the cellular, molecular, and physiological
mechanisms unde...

## Key facts

- **NIH application ID:** 9994810
- **Project number:** 5R01AG064020-02
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Ana C. Pereira
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $544,709
- **Award type:** 5
- **Project period:** 2019-08-15 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9994810

## Citation

> US National Institutes of Health, RePORTER application 9994810, Mechanisms of Obstructive Sleep Apnea in Tau Pathophysiology, Risk and Progression of Alzheimer's Disease (5R01AG064020-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9994810. Licensed CC0.

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