Role of Sleep Apnea in Cognition and Alzheimer's Disease Biomarkers in WTC Responders

Project Summary
Cognitive decline is the hallmark of Alzheimer’s disease (AD) and biomarkers to measure amyloid beta (Aβ) or
tau burden are increasingly being used to identify early (pre-clinical) AD risk prior to emergence of cognitive
impairment. Disturbances of sleep are common in AD, mild cognitive impairment and also in normal elderly with
Aβ positive biomarkers. This suggests that: i) disturbed sleep contributes to AD-neurodegeneration (i.e. sleep
disturbances such as from obstructive sleep apnea (OSA) are modifiable risk factors for AD); or, ii) sleep is
particularly sensitive to Aβ and neurofibrillary tangle pathology (i.e. sleep disturbance is an early biomarker of
AD), impacting quality of life. Our published data show that increased OSA severity in cognitively normal older
subjects is associated with increased Aβ burden. Our preliminary data also show that OSA is associated with
elevated cerebrospinal fluid (CSF) tau, a finding that may have a stronger link to cognitive decline. We have
recently confirmed an increased prevalence (75%) of new-onset OSA in World Trade Center (WTC) dust-
exposed subjects (i.e. responders) compared to the general population. The WTC responder cohort is aging and
there is evidence of early cognitive impairment and high incidence of cognitive decline compared to age matched
norms. This cohort is unique for its high prevalence of OSA, the availability of longitudinal data on presence and
duration of OSA as well as information on other relevant risk factors for AD such as depression and post-
traumatic stress disorder (PTSD), and provides a unique opportunity to evaluate the relationship between sleep
disruption, biomarkers for AD risk and cognition. The purpose of the present proposal is to examine the impact
of OSA severity and sleep related changes on AD plasma biomarkers, tau burden and cognition in WTC subjects
using novel methodology and adjusting for potential confounders. Aim 1 will examine longitudinal changes in
plasma tau and tau burden in 64 subjects with and without OSA to test the hypothesis that OSA severity is
correlated with (i) changes in plasma tau and (ii) with greater longitudinal tau burden using PET-MR imaging
using 18F-PI2620. Aim 2 will examine the relationship between OSA and cognition using a visual-spatial memory
test (3D-maze) and the subtle cognitive impairment test (SCIT); both tests are sensitive to sleep disruption in
subjects who are cognitively normal or minimally impaired by standard neuropsychological testing. We will test
the hypothesis that OSA severity at baseline predicts longitudinal decline in spatial navigational memory and
SCIT. Demonstration of a relationship between OSA, AD biomarkers and cognitive impairment suggests specific
risk factors for AD might be assessed non-invasively (e.g. by maze/SCIT or by finding OSA or sleep specific
biomarkers). These data will guide future interventional studies targeting sleep disruption (e.g. treatment of
OSA, increase sleep duration) and outcomes (e.g. improvement in cognition) with the long-term goal of improving
the quality of life and health outcomes in the WTC responder cohort.

Grant Number: 5U01OH011852-05
NIH Institute/Center: ALLCDC
Principal Investigator: INDU AYAPPA