Friday, May 16, 2025
5/16/2025
Establishing Sleep Apnea as a non-cognitive phenotype of brainstem ADRD pathologies in older adults - 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 older adults at risk of AD dementia and facilitate its prevention. Cell-specific data will drive drug discovery of targeted sleep apnea treatments for older adults with ADRD and sleep apnea unresponsive to current treatments.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).