# Establishing Sleep Apnea as a non-cognitive phenotype of brainstem ADRD pathologies in older adults

> **NIH NIH R01** · BETH ISRAEL DEACONESS MEDICAL CENTER · 2021 · $1,293,402

## Abstract

PROJECT SUMMARY
Alzheimer’s disease and related dementias (ADRD) and sleep apnea are common aging phenotypes. Sleep
apnea may also be an AD phenotype, as ADRD pathologies may disrupt neural circuits subserving breathing in
sleep. Yet, no study has examined if ADRD pathologies in “sleep apnea” circuits are related to sleep apnea.
Like other ADRD phenotypes such as cognition or mobility, sleep apnea is multi-dimensional. Defects in 3 key
dimensions can lead to sleep apnea: a) failure to maintain airway patency, b) inefficient respiratory drive, and
c) aberrant apnea termination by arousal. In model organisms, interconnected, neurochemically and spatially
distinct brainstem circuits control these key dimensions. However, the role of ADRD pathologies in human
sleep apnea is unknown, as multi-dimensional sleep apnea studies with collection of CNS tissues are rare, and
ADRD staging does not assess sites of underlying circuits. In pilot studies, 3 key dimensions were measured to
obtain sleep apnea phenotypes from older adults in the community using novel sensors. Few older adults with
sleep apnea in the Rush Memory and Aging Project (MAP, R01AG17917) were obese, suggesting a minor
structural and an important neurogenic contribution. We documented mixed ADRD pathologies in postmortem
brainstem tissues of 3 “sleep-apnea” circuits that serve each of the 3 key dimensions in MAP adults with sleep
apnea. Thus, testing if ADRD degenerative changes may lead to sleep apnea in old age is feasible.
This innovative clinical-postmortem proposal will leverage unique clinical, pathological and biospecimen
resources from older adults from MAP, a community-based cohort study with brain donation. This study will I)
obtain comprehensive sleep apnea phenotyping of 3 key sleep apnea dimensions using a novel sensor and
MRI to quantify upper airway structure in older adults with and without ADRD, and II) quantify degenerative
changes in brainstem “sleep apnea” circuit nodes by staining for both pathology markers and cell type specific
markers and integrate these novel data. Aim 1 will test the hypothesis that demographic and clinical predictors
are differentially associated with three key physiological dimensions of sleep apnea. Aims 2&3 will test the
hypotheses that degenerative changes i.e. ADRD pathologies (Aim 2) and subtype specific neuronal loss (Aim
3) within the 3 “sleep apnea” circuits are related to these key sleep apnea dimensions. Aim 4 will test the
hypotheses that AD pathology is present in “sleep apnea” circuits of older adults without clinical AD dementia,
and that circuit ADRD pathologies in these individuals is associated with sleep apnea and its key dimensions.
Showing that sleep apnea is a common and early non-cognitive phenotype of AD, much as REM sleep
behavior disorder is an early marker of PD, will drive a paradigm shift in our concept of the relation between
ADRD and sleep apnea. Showing that sleep apnea is a consequence of AD may be used to identify ...

## Key facts

- **NIH application ID:** 10178701
- **Project number:** 1R01AG071638-01
- **Recipient organization:** BETH ISRAEL DEACONESS MEDICAL CENTER
- **Principal Investigator:** ARON S BUCHMAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $1,293,402
- **Award type:** 1
- **Project period:** 2021-04-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10178701

## Citation

> US National Institutes of Health, RePORTER application 10178701, Establishing Sleep Apnea as a non-cognitive phenotype of brainstem ADRD pathologies in older adults (1R01AG071638-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10178701. Licensed CC0.

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