Treating Sleep Apnea to Improve Cognitive Function, Alzheimer's Disease Pathology, and Astrocyte Activation in Older Adults With Cognitive Impairment: A Multi-Centre Randomized Controlled Trial
Phase: NA
Conditions: Obstructive Sleep Apnea (OSA), Mild Cognitive Impairment (MCI), Cognitive Decline Prevention in Pre-frail Older Adults
Sponsor: Sunnybrook Health Sciences Centre

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CONFIDENTIAL 
 
i 
 
 
CPAP Randomized Controlled Trial 
 
Treating Sleep Apnea to Improve Cognitive Function, 
Alzheimer’s Disease Pathology, and Astrocyte Activation in 
Older Adults with Cognitive Impairment: A Multi-Centre 
Randomized Controlled Trial 
 
 
Protocol Number: CTO 5040 
Version Number: 1.2 dated November 10, 2024 
 
  
Principal Investigator: Dr. Andrew Lim 
Regulatory Sponsor: Sunnybrook Research Institute 
Funding Agency: Weston Family Foundation 
 
 
 
 
 
 
 
 

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PROTOCOL SIGNATURE PAGE 
 
I have read this protocol in its entirety and its appendices. I agree to comply with the 
requirements of the study protocol and procedures for data recording/reporting and 
acknowledge my responsibility for the well-being of each research participant, and to ensure 
that all persons involved in study activities are adequately informed about the protocol, the 
investigational product, and their trial-related duties. The signature below constitutes the 
agreement to conduct this study in accordance with the REB approved protocol, GCP and 
applicable regulatory requirements, including confidentiality, ethical guidelines and regulations 
regarding the conduct of research in humans. 
 
Qualified Investigator: 
Name: 
(Print) 
 
Title & Institution:  
(Print) 
 
Signature: 
 
Date of signature: 
(yyyy-mmm-dd) 
 
 

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TABLE OF CONTENTS 
PAGE 
PROTOCOL SIGNATURE PAGE ............................................................................................... II 
TABLE OF CONTENTS ............................................................................................................. III 
LIST OF ABBREVIATIONS ....................................................................................................... VI 
PROTOCOL SUMMARY ......................................................................................................... VIII 
1 
KEY ROLES AND CONTACT INFORMATION ................................................................... 1 
2 
INTRODUCTION ................................................................................................................ 3 
2.1 
Background ............................................................................................................ 3 
2.2 
Pre-Clinical and Clinical Data to Date ..................................................................... 4 
2.3 
Anticipated Benefits and Rationale ......................................................................... 8 
3 
STUDY OBJECTIVES ........................................................................................................ 9 
3.1 
Primary Objective ................................................................................................... 9 
3.2 
Secondary Objective(s) ........................................................................................... 9 
4 
STUDY DESIGN .............................................................................................................. 10 
4.1 
General Design ..................................................................................................... 10 
4.2 
Primary Outcomes ................................................................................................ 10 
4.3 
Secondary Outcomes ........................................................................................... 10 
5 
PARTICIPANT SELECTION AND WITHDRAWAL ........................................................... 12 
5.1 
Inclusion Criteria ................................................................................................... 12 
5.2 
Exclusion Criteria .................................................................................................. 12 
5.3 
Participant Recruitment ......................................................................................... 13 
5.4 
Participant Screening ............................................................................................ 15 
5.5 
Screen Failures ..................................................................................................... 15 
5.6 
Randomization and Blinding ................................................................................. 16 
5.7 
Participant Withdrawal and Discontinuation of Study Procedures ......................... 16 
6 
INTERVENTIONS ............................................................................................................ 17 
6.1 
Continuous positive airway pressure (CPAP) ........................................................ 17 
6.1.1 
Acquisition ................................................................................................. 17 
6.1.2 
Receipt of Device ...................................................................................... 17 
6.1.3 
Administration of CPAP Intervention ......................................................... 17 
6.2 
Brain Health PRO platform (BHP) ......................................................................... 18 
6.2.1 
Administration of BHP Intervention ............................................................ 18 
7 
STUDY SCHEDULE AND PROCEDURES ...................................................................... 20 
7.1 
Overview of Study Schedule ................................................................................. 20 
7.2 
Study Instruments ................................................................................................. 20 
7.2.1 
Eligibility Screening and Basic Information ................................................ 20 
7.2.2 
Sleep Disorders and Patient Reported Sleep Outcomes ........................... 20 
7.2.3 
Cognitive Evaluation .................................................................................. 20 
7.2.4 
Functional Status ...................................................................................... 21 
7.2.5 
Sleep Physiology ....................................................................................... 22 
7.2.6 
CPAP Adherence ...................................................................................... 23 
7.2.7 
MRI Brain .................................................................................................. 23 

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7.2.8 
Plasma Samples ....................................................................................... 23 
7.3 
Premature Withdrawal .......................................................................................... 24 
7.4 
Study Close-Out ................................................................................................... 24 
7.5 
Protocol Deviations ............................................................................................... 24 
8 
ASSESSMENT OF SAFETY ............................................................................................ 25 
8.1 
Definitions ............................................................................................................. 25 
8.1.1 
Adverse Events ......................................................................................... 25 
8.1.2 
Serious Adverse Events ............................................................................ 25 
8.1.3 
Unexpected Adverse Event ....................................................................... 25 
8.2 
Assessment of an Adverse Event ......................................................................... 26 
8.2.1 
Relationship (Causality/Relatedness) ........................................................ 26 
8.2.2 
Expectedness ............................................................................................ 26 
8.2.3 
Seriousness .............................................................................................. 26 
8.2.4 
Severity ..................................................................................................... 26 
8.3 
Adverse Event Recording ..................................................................................... 26 
8.4 
Reporting of SAEs and Unanticipated Events ....................................................... 27 
8.4.1 
Investigator reporting: Notifying the REB ................................................... 27 
8.4.2 
Investigator reporting: Notifying the Sponsor ............................................. 27 
8.4.3 
Sponsor Reporting of SAEs and Unanticipated Events: Notifying Health 
Canada ..................................................................................................... 27 
8.5 
Reporting and Entry Timelines .............................................................................. 28 
9 
STATISTICAL CONSIDERATIONS .................................................................................. 29 
9.1 
Study Hypotheses ................................................................................................. 29 
9.2 
Sample Size Considerations ................................................................................. 29 
9.3 
Stopping Rules ..................................................................................................... 29 
9.4 
Final Analysis Plan ............................................................................................... 29 
10 
DATA HANDLING AND RECORD KEEPING ................................................................... 31 
10.1 
Confidentiality ....................................................................................................... 31 
10.2 
Source Documents ............................................................................................... 31 
10.3 
Data Management Responsibilities ....................................................................... 32 
10.4 
Data Capture ........................................................................................................ 32 
10.4.1 Case Report Forms ................................................................................... 32 
10.5 
Records Retention ................................................................................................ 32 
10.6 
Clinical Trial Registration ...................................................................................... 33 
11 
QUALITY CONTROL AND QUALITY ASSURANCE ........................................................ 34 
12 
ETHICS CONSIDERATIONS ........................................................................................... 35 
12.1 
Ethical Standard ................................................................................................... 35 
12.2 
Research Ethics Board (REB) ............................................................................... 35 
12.3 
Ethical Concerns Surrounding Randomization ...................................................... 35 
12.4 
Consent ................................................................................................................ 36 
12.5 
Participant Compensation ..................................................................................... 36 
13 
LITERATURE REFERENCES .......................................................................................... 38 
SUPPLEMENTAL MATERIALS ................................................................................................ 41 
APPENDICES ........................................................................................................................... 42 

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APPENDIX A: SCHEDULE OF EVENTS .................................................................................. 43 
APPENDIX B: OVERVIEW OF STUDY SCHEDULE ................................................................ 44 
APPENDIX C-1: INCLUSION/EXCLUSION LIST ...................................................................... 45 
APPENDIX C-2: DEMOGRAPHICS & MEDICAL INFORMATION ............................................ 47 
APPENDIX C-3: STOP-BANG .................................................................................................. 49 
APPENDIX C-4: ISI ................................................................................................................... 51 
APPENDIX C-5: CAMRBRIDGE-HOPKINS .............................................................................. 53 
APPENDIX C-6: MAYO SLEEP QUESTIONNAIRE (Q1 ONLY) ............................................... 54 
APPENDIX C-7: PROMIS ......................................................................................................... 55 
APPENDIX C-8: SLEEP DIARY ................................................................................................ 56 
APPENDIX C-9: MOCA ONLINE V8.1 ...................................................................................... 60 
APPENDIX C-10: LOGICAL MEMORY ..................................................................................... 61 
APPENDIX C-11: GERIATRIC DEPRESSION SCALE (SHORT FORM) .................................. 64 
APPENDIX C-12: SDMT ........................................................................................................... 65 
APPENDIX C-13: TRAILS A+B ................................................................................................. 68 
APPENDIX C-14: DIGIT SPAN ................................................................................................. 72 
APPENDIX C-15: HOPKINS VERBAL ...................................................................................... 74 
APPENDIX C-16: ADAS-COG-13 ............................................................................................. 78 
APPENDIX C-17: LAWTON BRODY IADL ................................................................................ 79 
 

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LIST OF ABBREVIATIONS 
The following abbreviations describe terms, documents and study personnel used in the 
conduct of this study protocol. 
AE 
Adverse Event/Adverse Experience 
AD 
Alzheimer’s disease 
AHI 
Apnea hypopnea index 
BHP 
Brain Health Pro 
CC 
Coordinating Centre 
CCNA 
Canadian Consortium on Neurodegeneration in Aging 
CPAP 
Continuous Positive Airway Pressure 
CRF 
Case Report Form 
EC 
Ethics Committee 
EEG 
Electroencephalography 
IB 
Investigator’s Brochure 
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
eCRF 
Electronic Case Report Form 
pCRF 
Paper Case Report Form 
GCP 
Good Clinical Practice 
GFAP 
Glial Fibrillary Acidic Protein 
HSAT 
Home sleep apnea test 
ICF 
Informed Consent Form 
MCI 
Mild Cognitive Impairment 
MOCA 
Montreal Cognitive Assessment 
MRI 
Magnetic Resonance Imaging 
ODI 
Oxygen Desaturation Index 
OSA 
Obstructive Sleep Apnea 
PET 
Positron Emission Tomography 
PHI 
Personal Health Information 
PI 
Principal Investigator 
PSG 
Polysomnography 
PVS 
Perivascular Space 
QI 
Qualified Investigator 
REB 
Research Ethics Board 
RCT 
Randomized Controlled Trial 

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REM 
Rapid Eye Movement 
SAE 
Serious Adverse Event/Serious Adverse Experience 
SDMT 
Symbol Digit Modalities Test 
SOP 
Standard Operating Procedure 
SRI 
Sunnybrook Research Institute 
SUADR 
Serious and Unexpected Adverse Drug Reaction 
TMF 
Trial Master File 
 
 
 
 
 

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PROTOCOL SUMMARY 
Protocol Title (Short 
Title) 
Treating Sleep Apnea to Improve Cognitive Function, Alzheimer’s 
Disease Pathology, and Astrocyte Activation in Older Adults with 
Cognitive Impairment: A Multi-Centre Randomized Controlled Trial 
(CPAP Randomized Controlled Trial) 
Protocol Number 
CTO 5040 
Phase 
II 
Study Design 
Single-blinded randomized controlled trial 
Study Duration 
3 years 
Setting 
Community-dwelling older adults who respond to recruitment 
initiatives and advertisements, or patients attending dementia 
prevention clinics, memory clinics, or sleep clinics throughout the 
Greater Toronto Area 
Sample Size 
206 participants randomized to either: 
Early CPAP group: Brain Health Support PRO sleep modules 
(BHP-sleep; a web-based sleep education intervention) and 
Continuous Positive Airway Pressure (CPAP) for 8 months; or 
Later CPAP group: BHP-sleep for first 4 months, then BHP-sleep 
and CPAP for remaining 4 months of participation. 
Target sample size for each group is 103.  
Main Inclusion 
Criteria 
Older adults with mild cognitive impairment (MCI) and previously 
untreated obstructive sleep apnea (OSA) 
Primary Outcome(s): 
This trial tests the hypothesis that in older adults with MCI and 
previously untreated OSA, 4 months of web-based sleep education 
and CPAP will improve cognitive function more than web-based 
sleep education alone. This trial also tests the hypothesis that 8 
months of CPAP will improve cognitive function more than 4 months 
of CPAP. 
The primary outcome of this study will be change in the Symbol Digit 
Modalities Test (SDMT). The SDMT is a test of speeded executive 
function that is predictive of clinically significant improvement in 
patients with MCI. 
Additional cognitive measures that supplement the primary outcome 
of this study will be: attention and executive function (Trail Making 
Test A & B), working memory (Digit Span and Letter-Number 
Sequencing), verbal learning and memory (Hopkins Verbal Learning 
Test), and severity of cognitive impairment (Alzheimer’s Disease 
Assessment Scale – Cognitive Subscale; ADAS-Cog-13). 

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Secondary 
Outcome(s): 
This trial will also assess change in 1) Magnetic Resonance Image 
(MRI) quantified brain perivascular spaces (PVS) 2) plasma glial 
fibrillary acidic protein (GFAP) and 3) plasma pTau-181. 
This trial will also aim to identify features of sleep physiology that 
mediate the impact of CPAP on cognitive function. 
An exploratory subset of 28 participants (14 per group) will be invited 
to participate in a sub-study with its own protocol and informed 
consent process where changes in microglial activation will be 
assessed by [18F]FEPPA Positron Emission Tomography (PET). 
Planned Treatment 
Early CPAP group: Participants randomized to this group will start 
BHP-sleep and CPAP simultaneously and continue both for 8 
months. BHP-sleep consists of the sleep modules of the Canadian 
Consortium on Neurodegeneration in Aging’s (CCNA) online Brain 
Health PRO platform covering sleep physiology, healthy sleep 
habits, and information about sleep disorders like sleep apnea.  
Participants will receive a study-provided auto-titrating CPAP device, 
with settings set by one of the study sleep medicine physicians 
according to current clinical practice parameters. Participants will 
undergo an in-person mask fitting, and then will be supported by a 
sleep technologist with extensive clinical experience with CPAP.   
Later CPAP group: Participants randomized to this group will start 
BHP-sleep without CPAP for first 4 months, followed by BHP-sleep 
and CPAP simultaneously for remaining 4 months of participation. 
Statistical Analysis: 
For our primary analysis, this trial will model performance on the 
SDMT as a function of time (baseline vs. 4 months) and study group 
(Early CPAP vs. Later CPAP). In secondary analyses, we will 
consider a series of models replacing the SDMT with our secondary 
cognitive endpoints. 
We will repeat the analyses above, considering the change between 
baseline and 8 months. We will also conduct a mixed-effect analysis 
including both the 4-month and 8-month time points. 
We will again repeat the analyses above, replacing our cognitive 
outcomes with a) plasma GFAP b) plasma pTau-181 and c) MRI 
PVS burden. 
Finally, we will use mediation analysis to examine the extent to 
which the effect of CPAP on change in SDMT is mediated by 
specific changes in sleep physiology. 
 
 
 

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1 KEY ROLES AND CONTACT INFORMATION 
Regulatory Sponsor: 
Sunnybrook Research Institute (SRI) 
2075 Bayview Avenue 
Toronto, ON Canada M4N 3M5 
Principal Investigator: 
Dr. Andrew Lim 
Associate Professor, Division of Neurology 
Sunnybrook Health Sciences Centre 
University of Toronto 
2075 Bayview Avenue – Room M1-600 
Toronto, ON, M4N 3M5 
p: 416-480-6100 x2461 
f: 416-480-6092 
andrew.lim@sunnybrook.ca 
Co-Investigators: 
Dr. Mark Boulos 
Sunnybrook Health Sciences Centre 
Dr. Douglas Bradley 
University Health Network 
Dr. Kevin Thorpe 
University of Toronto 
Dr. Howard Chertkow 
Rotman Research Institute 
Dr. Jennifer Rabin 
Sunnybrook Health Sciences Centre 
Dr. Brian Murray 
Sunnybrook Health Sciences Centre 
Dr. Carmela Tartaglia 
University Health Network 
Dr. Sandra Black 
Sunnybrook Health Sciences Centre 
Dr. Joel Ramirez 
Sunnybrook Health Sciences Centre 
Dr. Sara Mitchell 

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Sunnybrook Health Sciences Centre 
Dr. Sylvie Belleville 
Universite de Montreal 
 

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2 INTRODUCTION  
This study document is the protocol for research involving human participants. This study is to 
be conducted according to Canadian and international standards, and in compliance with the 
protocol, the International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use (ICH) Good Clinical Practice E6 (GCP), World Medical 
Association Declaration of Helsinki: Ethical Principles for Medical Research Involving Human 
Participants, as well as applicable regulatory and institutional requirements and research 
policies.  
2.1 
Background  
Sleep disruption and cognitive impairment frequently coexist. Several forms of sleep disruption, 
including sleep apnea (1), are associated with more rapid cognitive decline and Alzheimer’s 
disease (AD) related brain changes. However, observational studies, particularly those in older 
adults, cannot determine whether sleep disruption contributes to or is a consequence of AD-
related brain changes. Indeed, there has been a lack of randomized controlled trials (RCT) 
demonstrating an impact of any sleep intervention on cognitive decline or key AD-related brain 
changes.  
Of particular interest is obstructive sleep apnea (OSA), a disorder characterized by repetitive 
obstruction of the upper airway in sleep leading to hypoxia, sleep fragmentation, and disrupted 
slow wave sleep. OSA is seen in up to 50% of patients with mild cognitive impairment (MCI) 
(Figure 1) and associated with more rapid cognitive decline (1). It is effectively treated by 
continuous positive airway pressure (CPAP); the application of positive airway pressure to splint 
open the upper airway preventing collapse. Observational studies suggest CPAP use is 
associated with improved cognitive function (Figure 2) and reduced perivascular space (PVS) 
burden (Figure 3). 
This study will address residual knowledge gaps left by other observational studies of CPAP in 
MCI patients. The randomized design of this study will allow greater causal certainty than 
observational studies and may support a change in practice. This study may support screening 
for and treatment of OSA in individuals with MCI to improve cognition. There will be much 
deeper mechanistic dissection, particularly of microglial activation and perivascular biology 
(assessed using a neural network MRI segmentation tool we developed called SynthSegCSVD) 
(Figure 4). This will provide therapeutic targets for addressing the adverse effects of OSA on 
MCI-related outcomes in the individuals who cannot tolerate CPAP. This study will also use 
wearable sensors to assess the role of changes in sleep physiology in mediating the link 
between CPAP and MCI-related outcomes. 
This study may provide evidence that for the ~50% of patients with MCI who have OSA, 
treatment with CPAP can improve cognition, and reduce key pathophysiological contributors to 
dementia including neurofibrillary tangle pathology (Figure 5), astrocyte (Figure 6) and microglial 
activation (Figure 7), and enlargement of perivascular spaces. This will support widespread 
treatment of OSA in patients with cognitive impairment to slow cognitive decline and reduce 
dementia-related brain changes. Moreover, it will identify the key sleep changes mediating 
these effects, which can then be specifically targeted by other interventions. 

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Our four key end users are 1) patients with MCI, sleep apnea, or both 2) sleep and dementia 
physicians who care for them 3) allied health practitioners supporting these patients and who 
would support CPAP adherence and 4) public health officials who would fund screening and 
treatment of sleep apnea. 
2.2 
Pre-Clinical and Clinical Data to Date 
 
 
Figure 1: Sleep apnea is common in adults with MCI. We measured sleep apnea in 121 
adults with MCI in the Memory and Aging Project using the WatchPAT wearable sensor. 61 
participants (52%) had at least moderate sleep apnea. 
 

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Figure 2: CPAP improves hypoxia, sleep fragmentation and cognitive function in patients with 
sleep apnea. We treated 66 patients with newly diagnosed moderate sleep apnea (AHI>15; 
Apnea hypopnea index) with 4 months of CPAP. We measured oxygen saturation with pulse 
oximetry. We measured sleep fragmentation with 10 days of wrist actigraphy. Cognition was 
measured with the Toronto Cognitive Assessment. 4 months of CPAP was associated with 
dramatically reduced hypoxia (time with SpO2<90%, panel A) and sleep fragmentation (kRA, 
panel B), and improved delayed memory performance (panel C). 
 
 

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Figure 3: CPAP use stabilizes MRI-visible perivascular space volumes. We treated 66 
patients with newly diagnosed moderate (AHI>15) sleep apnea with 4 months of CPAP. We 
measured MRI-visible perivascular space volumes, which are thought to be a key contributor 
to cognitive impairment. ~50% of participants used CPAP >4 hours a day. In those not 
adherent with CPAP, PVS volumes increased over 4 months. However, CPAP adherence 
was associated with stabilisation of PVS volumes. 
 
 
Figure 4: SynthSegCSVD, a new Convolutional Neural Network-Based Tool for Segmentation 
of Perivascular Spaces. We have developed and validated SynthSegCSVD for rapid 
automated segmentation of PVS from heterogeneous MRI datasets. This panel shows 
example SynthSegCSVD output showing PVS segmentation. 
 

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Figure 5: Better sleep consolidation is associated with lower neurofibrillary tangle density in 
genetically at risk adults. (interaction estimate, −0.42; SE, −0.17; P= .02) (2). 
 
 
Figure 6: More consolidated (less fragmented) sleep is associated with lower expression of 
plasma glial fibrillary acidic protein (GFAP), a marker of astrocyte activation. In 415 older 
adults, we assessed gene expression in the dorsolateral prefrontal cortex by RNAseq and 
related this to sleep consolidation assessed by wrist accelerometry. Better sleep 
consolidation (lower sleep fragmentation) was associated with lower expression of GFAP. 

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Figure 7: More fragmented sleep is associated with higher expression of TSPO, a marker of 
microglial activation. In 152 older adults, we assessed gene expression in the dorsolateral 
prefrontal cortex by RNAseq and related this to sleep fragmentation assessed by wrist 
accelerometry. Higher sleep fragmentation was associated with greater expression of TSPO. 
 
2.3 
Anticipated Benefits and Rationale 
 
This study will provide class I evidence that CPAP, in combination with an online sleep 
optimization program, will improve memory and concentration, reduce Alzheimer’s associated 
proteins, prevent brain blood vessel damage, and reduce brain inflammation, in adults with OSA 
and MCI. This will suggest that large scale screening for and treatment of OSA may be an 
effective means of preventing and potentially improve dementia-related outcomes. Moreover, it 
would be the first proof that improving sleep can in principle prevent dementia and open the 
door to trials of other interventions to improve sleep to prevent dementia. 
 
  
 

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3 STUDY OBJECTIVES 
The overall goal of this randomized controlled trial is to test the hypothesis that in older adults 
with MCI and previously untreated OSA, 4 months of web-based sleep education and CPAP will 
improve cognitive function more than web-based sleep education alone. Secondarily, this trial 
will test the hypothesis that 8 months of CPAP will improve cognitive function more than 4 
months of CPAP. Moreover this trial will test several mechanistic hypotheses, namely that 4 
months of CPAP will 1) stabilize the growth of MRI-quantified brain perivascular spaces, a key 
correlate of cognitive impairment, 2) reduce plasma glial fibrillary acidic protein, a marker of 
astrocyte activation, 3) reduce plasma pTau-181, a marker of neurofibrillary tangle pathology – 
one of the pathological hallmarks of Alzheimer’s disease, and 4) identify features of sleep 
physiology that mediate the impact of CPAP on cognitive function. 
An exploratory subset of 28 participants (14 per group) will be invited to participate in a sub-
study with its own protocol and informed consent process aimed to assess change in microglial 
activation assessed by [18F]FEPPA Positron Emission Tomography (PET). 
3.1 
Primary Objective 
 
The specific primary objectives are: 
 
(1) Cognitive Function: Test the hypothesis that in adults with MCI and previously untreated 
moderate-severe OSA, 4 months of web-based sleep education and CPAP will improve 
cognitive function (or slow cognitive decline) as measured by the Symbol Digit Modalities Test 
(SDMT) more than web-based sleep education alone. 
 
(2) Treatment Duration: Test the hypothesis that 8 months of CPAP will improve cognitive 
function (or slow cognitive decline) as measured by SDMT more than 4 months.  
3.2 
Secondary Objective(s) 
 
The specific secondary objectives are: 
 
(3) Neurobiological Mechanisms: Test the hypothesis that 4 months of web-based sleep 
education and CPAP will reduce a) astrocyte activation (plasma GFAP) b) neurofibrillary tangle 
burden (plasma pTau181) and c) MRI-visible perivascular space burden more than web-based 
sleep education alone. 
(4) Sleep Physiology: Identify features of sleep physiology (i.e. decreased hypoxic burden and 
fragmentation, increased slow-wave power and REM sleep) that mediate the impact of CPAP 
on cognitive function. 
 

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4 STUDY DESIGN 
4.1 
General Design 
The general design of this study is a single-blinded randomized controlled trial of 206 adults 
randomized into two groups:  
Early CPAP group: Participants randomized to this group will start BHP-sleep and CPAP 
simultaneously and continue both for 8 months. BHP-sleep consists of the sleep modules of the 
Canadian Consortium on Neurodegeneration in Aging’s (CCNA) online Brain Health PRO 
platform covering sleep physiology, healthy sleep habits, and information about sleep disorders 
like sleep apnea.  Participants will receive a study-provided auto-titrating CPAP device, with 
settings set by one of the study sleep medicine physicians according to current clinical practice 
parameters. Participants will undergo an in-person mask fitting, and then will be supported by a 
sleep technologist with extensive clinical experience with CPAP.   
Later CPAP group: Participants randomized to this group will start BHP-sleep without CPAP for 
first 4 months, followed by BHP-sleep and CPAP simultaneously for remaining 4 months of 
participation. 
4.2 
Primary Outcomes 
The primary outcome of this study will be change in the Symbol Digit Modalities Test (SDMT). 
The SDMT is a test of speeded executive function that is predictive of clinically significant 
improvement in patients with MCI with a well-defined minimal clinically significant change (2) 
and that is responsive to CPAP in observational studies (3). 
Additional cognitive measures that supplement the primary outcome of this study will be: 
attention and executive function (Trail Making Test A & B), working memory (Digit Span and 
Letter-Number Sequencing), verbal learning and memory (Hopkins Verbal Learning Test), and 
severity of cognitive impairment (Alzheimer’s Disease Assessment Scale – Cognitive Subscale; 
ADAS-Cog-13). 
4.3 
Secondary Outcomes 
Vascular risk factors and AD-biomarkers: Plasma pTau181 (for AD pathology) and GFAP (for 
astrocyte activation) will be assessed. pTau181 has been shown to be strongly predictive of 
both amyloid and tau pathology as measured by PET (4,5) while plasma GFAP correlates 
strongly with 18F-SMBT-1 PET, a marker of brain reactive astrocytes (6). This protocol does not 
include plasma amyloid beta 42 as recent studies suggest that pTau181 alone has similar 
performance to a larger panel of biomarkers in discriminating between levels of a PET proxy of 
AD pathology (4) and our previous work showed a stronger association between sleep 
fragmentation and burden of tau pathology than burden of amyloid pathology (7). 
Aliquots will be sent to and analysed in the Toronto laboratory of Co-I Dr. Tartaglia on the 
Quanterix SIMOA platform, a semi-automated digital ELISA platform. Analysis will include 
quantification of plasma p-tau-181 using the ptau-181 V2.1 Advantage assay, and GFAP using 
the GFAP discovery assay. 
Remaining aliquots will be retained for future studies. 

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Blood levels of various fats, sugars, and proteins (like cholesterol or glucose) will be 
assessed. 
Participants will undergo MRI using the Canadian Dementia Imaging protocol consisting of a 3D 
T1, interleaved 3mm PD/T2, 3D FLAIR, T2*, DTI, and resting state BOLD. Perivascular spaces 
and white matter hyperintensities will be quantified with the SynthSegCSVD algorithm 
developed and validated in our laboratory, a robust neural network based tool (Figure 4). 
Sleep physiology will be assessed using wearable sensors: at-home sleep apnea testing 
apparatus (for oximetry metrics including AHI, ODI, mean SpO2, hypoxia burden, and time with 
O2<92%), EEG headband (sleep staging, including % slow wave sleep, % REM sleep, total 
EEG sleep time, and NREM slow wave power), and wrist-worn accelerometry (for total sleep 
time and sleep fragmentation). 

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5 PARTICIPANT SELECTION AND WITHDRAWAL  
Community-dwelling older adults who respond to recruitment initiatives and advertisements, or 
patients attending dementia prevention clinics, memory clinics, or sleep clinics throughout the 
Greater Toronto Area. Target sample size is 206 adults over the age of 55 with MCI and 
previously untreated OSA. 
5.1 
Inclusion Criteria 
Each participant must meet all of the following inclusion criteria to participate in this study: 
1) Informed consent obtained and signed. 
2) Age >55 
3) MCI: Participants will undergo a video-based screening, including a clinical interview, 
Logical Memory II, MoCA, and Lawton-Brody Instrumental Activities of Daily Living Scale 
Score. A participant will be considered to have MCI if they have: 
a. MoCA score of 13-24, and 
b. Logical Memory II Score ≤ 8 (>=16 years of education), ≤ 4 (8-15 years of 
education) or ≤ 2 (0-7 years of education), and 
c. Lawton-Brody IADL Score >14/23, and 
d. do not meet DSM IV criteria for dementia, and 
e. have a change in self-perceived cognition from previous 
4) Moderate-severe OSA: Participants who screen positive for MCI will be mailed an at-
home sleep apnea testing device (Apnealink, ResMed, San Diego, California, USA), an 
FDA-approved self-administered 3-channel portable device that assesses for sleep 
apnea based on airflow as assessed using an intra-nasal pressure transducer, pulse 
oximetry assessed using a finger probe, and respiratory effort using a band around the 
chest.. Participants with ODI>5 will undergo in-lab polysomnography (PSG) for 
confirmation and characterization of sleep apnea. A participant will be considered to 
have moderate-severe OSA if they have on PSG: 
a. AHI>15, and 
b. ODI>10, and 
c. central apneas<10% of all apneas, and 
d. periodic limb movement index <15.  
5.2 
Exclusion Criteria 
All potential participants meeting any of the following exclusion criteria will be excluded from 
participation in this study:  
1) drowsiness-related driving accidents or near misses in the past 12 months 
2) drives as their primary occupation  
3) unable to complete cognitive evaluation in English 
4) unable to participate in video-based cognitive assessment 
5) not a resident of Ontario 
6) contraindications to MRI 

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7) contraindications to CPAP or unwilling to start CPAP 
8) no available study partner to support CPAP 
9) previously treated for sleep apnea 
10) clinically significant insomnia (ISI > 15), restless legs syndrome, or shift work 
11) taking disease modifying agents for MCI 
5.3 
Participant Recruitment  
 
We estimate that we will need to enroll 206 participants with MCI and sleep apnea in order to 
have 80% power to detect a minimal clinically significant change in the SDMT of 3.8 points 
assuming CPAP adherence of 62% and loss-to-follow-up of 10%. In our data, the prevalence of 
moderate or greater OSA among patients with MCI is ~50% (Figure 1). Assuming that of these 
~25% will already be on CPAP, this would require identifying ~550 adults with MCI who would 
be willing to participate in the study. In or to reach ~550 of these individuals, we will use a 
combination of the following recruitment strategies: 
 
1) Geotargeted mailings. We will send geotargeted mailings to adults In the GTA over the 
age of 55, inviting those with cognitive concerns and symptoms compatible with sleep 
apnea to go to our study website. A similar approach was used in the Canadian 
Consortium on Neurodegeneration in Aging Can Thumbs Up Brain Health Support 
Program (CTU-BHSP) study. In CTU-BHSP, one participant enrolled for every 130 
postcards mailed, of which 1/3 had MCI. We plan to send out up to 40,000 postcards, 
which should yield ~100 interested potential participants with MCI. We will retain the 
option to scale up as needed to increase enrolment. 
2) Online advertisements. We will produce geotargeted ads to run through Instagram and 
Facebook. A similar approach was used in the CTU-BHSP study, where $500 spent on 
geotargeted Facebook and Instagram advertising to reach 39,000 adults resulted in 18 
enrolled participants with MCI. We plan to run an advertising campaign with double the 
reach of CTU-BHSP, which should yield ~40 interested potential participants with MCI. 
We will retain the option to scale up as needed to increase enrolment. 
3) Clinic-based recruitment. We will recruit from Toronto Dementia Research Alliance 
affiliated clinics at the Toronto Western Hospital, Baycrest Hospital, and Sunnybrook 
hospital. Collectively, these clinics see ~80 patients with MCI per month. Between these 
three clinics, we anticipate recruiting up to 10 adults with MCI per month over 24 
months. This should yield ~240 interested potential participants with MCI. Flyers will be 
placed in clinic rooms and/or bulletin boards and will also be available for potential 
participants to take home.  Potential participants may also be approached by a member 
of their care team who can provide them with a study flyer which will contain contact 
information for the study.  Potential participants will be given the opportunity to verbally 
agree with their clinic care team to share contact information (name, phone, email) with 
study staff so that they may be contacted to discuss interest in participating in this study. 
If applicable, potential participants may also consent for clinical information relevant to 
this protocol (i.e. MCI diagnosis, cognitive test results) to be shared with the study team. 
4) Baycrest Centre. The Baycrest Centre offers a number of recruitment sources, 
including but not limited to: 

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a. Rotman Database: The Rotman Research Institute manages a database of 
research volunteers, with >16,000 active participants. Some of these individuals 
have received a diagnosis of MCI. 
b. Cogniciti. The Cogniciti Brain Health Registry (www.cogniciti.com), based at 
Baycrest, includes >10,000 individuals in the GTA who have undergone online 
cognitive testing and who have also indicated their desire to be contacted about 
clinical trials. We anticipate based on pilot work that we will find 1,200 adults with 
MCI. An already established pipeline is in pl ace in Dr. Chertkow’s lab (co-PI of 
this protocol) to screen these individuals by videoconferencing for MCI. This 
should yield ~300 interested potential participants with MCI, with option to scale 
up as needed to increase enrolment.  Potential participants may also be provided 
a study flyer which will contain contact information for the study.  Potential 
participants will be given the opportunity to verbally agree to share contact 
information (name, phone, email) with study staff so that they may be contacted 
to discuss interest in participating in this study. If applicable, potential participants 
may also consent for clinical information relevant to this protocol (i.e. MCI 
diagnosis, cognitive test results) to be shared with the study team. 
c. Kimel Family Centre for Brain Health. The Kimel Centre 
(https://kimelcentre.baycrest.org/) is enrolling 2,000 individuals aged 50 or over 
interested in dementia prevention, all of whom are screened cognitively prior to 
entry in programs. These individuals are entered into the Rotman database at 
Baycrest and given the opportunity to indicate their desire to be contacted about 
clinical trials. We anticipate of these 2,000 participants, 600 will have MCI based 
on their cognitive evaluations. Through Dr. Chertkow (co-PI of this protocol and 
Scientific Director of the Kimel Centre, and also Dr. Nicole Anderson, Associate 
Scientific Director of the Kimel Centre), this should yield ~400 interested potential 
participants with MCI, with an option to scale up as needed to increase 
enrolment. Kimel Centre participants will be reached through 5 mechanisms: 1) 
through the Rotman database 2) through physical flyers placed in Kimel Centre 
spaces 3) through regular email newsletters sent out by the Kimel Centre 4) in 
person by Kimel centre staff during Kimel clinic visits, and 5) the study PI will 
conduct a series of in-person education sessions at the Kimel centre addressing 
sleep more broadly and also this study more specifically..  For 1) Kimel Centre 
staff will identify Kimel Centre participants who are already part of the Rotman 
database who have already consented to recontact and will provide their contact 
information (name, phone, email) to our study staff.  For 2) the physical flyers will 
direct participants to the study website / study email address / study phone.  For 
3) the newsletters will direct potential participants to the study website / study 
email address / study phone.  For 4) Kimel Centre staff will a) provide 
participants with a study flyer and b) obtain consent from potential participants to 
share contact information with our study staff.  For 5) at the conclusion of in-
person education sessions hosted by the study PI, attendees will be provided the 
physical flyer for the study, directing them to the study website / study email 
address / study phone. If applicable, potential participants may also consent for 

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clinical information relevant to this protocol (i.e. MCI diagnosis, cognitive test 
results) to be shared with the study team. Finally,  
d. Baycrest cognitive neurology clinics: Flyers will be placed in clinic rooms 
and/or bulletin boards and will also be available for potential participants to take 
home.  Potential participants may also be approached by a member of their care 
team who can provide them with a study flyer which will contain contact 
information for the study.  Potential participants will be given the opportunity to 
verbally agree with their clinic care team to share contact information (name, 
phone, email) with study staff so that they may be contacted to discuss interest in 
participating in this study. If applicable, potential participants may also consent 
for clinical information relevant to this protocol (i.e. MCI diagnosis, cognitive test 
results) to be shared with the study team. 
5.4 
Participant Screening  
Potential participants, irrespective of the recruitment source, will be required to proceed to the 
study website where they will fill out a short REDCap-hosted online questionnaire. The 
questionnaire will include collection of basic demographics and subjective sleep and cognitive 
information, limited to information necessary for determining eligibility. This includes email 
address, phone number, and implied consent to be contacted by study staff for additional 
screening. 
Potential participants who fill out the REDCap-hosted online questionnaire will be contacted by 
study staff to assess eligibility. This includes: 
1) An in-depth video-conference to establish a diagnosis of MCI and to confirm all 
inclusion/exclusion criteria.  This will consist of a clinical interview, Logical Memory II, MoCA, 
and Lawton-Brody Instrumental Activities of Daily Living Scale Score, as well as screening for 
clinically significant insomnia (Insomnia severity index>15) or restless legs syndrome 
(Cambridge Hopkins questionnaire). 2) If MCI confirmed, participants will be mailed a home-
based sleep apnea test (HSAT), namely the Apnealink which will be self-administered. With our 
community-based recruitment model, using a HSAT is necessary to minimize the number of 
participants without sleep apnea who need to undergo polysomnography. The Apnealink is 
considered a Type 4 sleep monitor by the American Academy of Sleep Medicine and has been 
validated against polysomnography. 3) Individuals who screen positive for OSA on the HSAT 
will meet with a study physician by video call or in person prior to in-lab PSG.  The study 
physician will confirm inclusion and exclusion criteria, including positive results for both MCI and 
OSA, and will perform a standard clinical assessment to ensure clinical appropriateness of and 
eligibility for CPAP. The participant will then be scheduled for an in-lab PSG. 4) Participants that 
meet the criteria for MCI and OSA, and satisfy all other inclusion/exclusion criteria, will have a 
video-conference with study staff to discuss the final determination of eligibility, obtain informed 
consent, and to unlock their randomization assignment. 
5.5 
Screen Failures 
 
Participants that do not meet the criteria for MCI or OSA, or do not meet all of the inclusion 
criteria or have at least one of the exclusion criteria at any stage of the screening process are 
deemed as screen failures and will have a video-conference with study staff to discuss their 

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reason for not being eligible. These participants who have failed the screening criteria are 
ineligible for participation and will be informed that they do not meet the study’s inclusion criteria 
and they will be thanked for their time. They will be encouraged to try to participate in future 
studies for which they may be eligible, and they will have an opportunity to ask questions 
pertaining to their screening for this study. Screen information will be retained as part of the trial 
for further analyses. 
5.6 
Randomization and Blinding 
Participants will be randomized 1:1 to one of the following groups:  
Early CPAP group: Brain Health Support PRO sleep modules (BHP-sleep; a web-based sleep 
education platform) and Continuous Positive Airway Pressure (CPAP) for 8 months; or 
Later CPAP group: BHP-sleep for first 4 months, then BHP-sleep and CPAP for remaining 4 
months of participation. 
From the beginning of month 5 until the end of month 8, both groups will be receiving CPAP. 
Randomization will be performed using an instance of the OxMAR software package hosted on 
a Sunnybrook Research Institute computer.  Randomization will be carried out in blocks of 2 
and stratified such that equal numbers from each recruitment type (i.e. clinic, community) will be 
in each group.  
Research personnel not involved in assessments or interventions will access the randomization 
list to allocate participants in each group. Personnel performing outcome assessments and 
methodologists performing analyses will be blinded to group allocation. Randomization will be 
completed by a dedicated analyst, who will distribute randomization codes (using a random 
number generator) to determine the treatment arm to which each participant is allocated. 
Assessors and Research Assistants administering the interventions will be blinded and as such, 
only the analyst overseeing randomization will have access to the password-protected 
randomization list. 
5.7 
Participant Withdrawal and Discontinuation of Study Procedures 
At their own discretion, participants may withdraw from the study at any time and for any 
reason. Study participants may also be withdrawn from the study at the discretion of an 
investigator for reasons such as, but not limited to safety, participant compliance or behavioral 
concerns.  
Participants withdrawing from the study should be contacted by the study research team 
requesting a final visit and to follow up with any unresolved adverse events. Once withdrawn 
from the study, no further study procedures or evaluations should be performed, or additional 
study data collected. However, every effort should be made to obtain permission to document 
the reason for withdrawal and to collect participant outcomes, such as survival data up to the 
protocol-described end of participant follow up period, where possible. Any data collected prior 
to the withdrawal of consent may be retained and used by the sponsor. 

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6 INTERVENTIONS  
6.1 
Continuous positive airway pressure (CPAP) 
 
Participants randomized to the Early CPAP group will receive a study-provided auto-titrating 
CPAP device, with settings set by one of the study sleep medicine physicians according to 
current clinical practice parameters (9). Participants will undergo an in-person mask fitting at 
their baseline study visit, and then will be supported by a sleep technologist with extensive 
clinical experience with CPAP who will contact participants by telephone or video call. Masks, 
tubing, chin straps, and other equipment necessary to optimize CPAP adherence will be 
provided by the study as necessary to optimize adherence, which will be tracked through 
participants’ CPAP devices. 
 
At the start of the 5th month, participants in the Later CPAP group will receive a study-provided 
auto-titrating CPAP device following the same protocol. 
6.1.1 
Acquisition 
This study will use only CPAP devices that are clinically approved for the treatment of sleep 
apnea in Canada, and will be purchased by the study directly from the manufacturer.   
6.1.2 
Receipt of Device 
 
Upon receipt of the CPAP equipment, an inventory will be performed and a receipt log filled out 
and signed by the research team member accepting the shipment. Designated study staff will 
count and verify that the shipment contains all the items noted in the shipment inventory. Any 
damaged or unusable product in a given shipment will be documented in the study files. We will 
notify the manufacturer of any damaged or unusable product that was supplied to the site. 
6.1.3 
Administration of CPAP Intervention 
 
The CPAP intervention will be overseen by one of the study physicians (Dr. Boulos, Dr. Lim, Dr. 
Murray, or Dr. Bradley, with Dr. Bradley playing principally a consultative role) assisted by a full-
time sleep technologist.   
 
To initiate CPAP, participants will come in-person to the study centre to meet with the sleep 
technologist, who will oversee initial mask fitting and selection, CPAP teaching, and set-up 
under the direction of the sleep physicians.  The technologist will contact participants by 
telephone or video call according to the study schedule. Calls will address a) anticipation and 
troubleshooting of common CPAP barriers (mask leak, mask fit, bloating, claustrophobia, etc.) 
b) education around the OSA physiology and consequences c) motivational enhancement and 
d) engagement of study partners, following principles shown to be effective at achieving high 
levels of CPAP adherence in adults with MCI (10). Between scheduled calls, the technologist 
will be available during business hours as needed for both remote and in-clinic visits. 
Participants will be provided an auto-titrating CPAP device. CPAP adherence and technical 
efficacy will be assessed by remotely interrogating participants’ CPAP machines.  Should high 

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residual AHI persist, participants may be brought in for an in-lab CPAP titration at the discretion 
of the study physician. 
 
We will compute several measures of adherence including: 1) % of days adherent, defined as 
use over 4 hours, for months 0-4 and 5-8, 2) mean nightly usage in hours for months 0-4 and 5-
8, and 3) cumulative number of days used >4h since entry into the study (a measure of the total 
cumulative duration of CPAP adherence). A participant will be considered adherent if they used 
CPAP for >4h on >80% of nights over the 4-month period. 
 
Risks and side effects related to CPAP are minor and may include: congestion or runny nose, 
dry mouth, nostrils, eyes, facial pain or skin irritation, claustrophobia. CPAP is not an 
experimental device and is being used in this study according to its intended use. In the unlikely 
event of an emergency related to CPAP use, participants will receive the same care as they 
would in usual care pathways. That is, participants are encouraged to contact the sleep 
technologist for the study during business hours. If the emergency is more urgent, participants 
are encouraged to use local emergency services, and then contact the sleep technologist for the 
study during business hours. 
 
6.2 
Brain Health PRO platform (BHP) 
The BHP web-based education platform (11) is a 45-week, multidomain, web-based formal 
educational program designed to increase dementia literacy, foster engagement, and convey 
best available evidence for lifestyle changes that can mitigate dementia risk. The program was 
developed as a collaborative effort by CCNA investigators with recognized expertise in the 
program’s content areas, along with input from older-adult citizen advisors. The program was 
refined and updated based on feedback from focus-groups and a 3-month pilot study to assess 
usability and accessibility. 
This protocol will utilize the sleep modules of the BHP platform covering sleep physiology, 
healthy sleep habits, and information about sleep disorders like sleep apnea.  
6.2.1 
Administration of BHP Intervention 
Participants in both groups will register at baseline on the BHP website and obtain a personal 
password. Participants will need to provide a valid e-mail address and password in order to 
login and participate in BHP. Participants will also be asked to enter a preferred name (this can 
be a first name or nickname), which they will be referred to as throughout their participation in 
the program. Name and e-mail address will not be included in the study data set. All data from 
BHP will be de-identified and linked to participant study ID prior to being included in our dataset. 
Registration will also include viewing a brief video explaining the program. 
The program content consists of 24 chapters discussing the following topics.  Participants will 
be invited to read the content at their own pace and will be given the opportunity to discuss with 
research staff at scheduled check-in calls. Specific chapters are: 
1) What is sleep? 
2) How do we sleep? 

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3) Measuring sleep 
4) Why do we sleep – Emotional health and well-being 
5) Why do we sleep – Physical health 
6) Why do we sleep – To strengthen memory 
7) How much sleep do you need? 
8) Dreams 
9) Sleep changes across adulthood and factors that may disturb sleep 
10) Insomnia 
11) Insomnia 2 
12) Daytime sleepiness 
13) Sleep apnea: Definition, symptoms, causes 
14) Sleep apnea: Treatments 
15) Restless legs syndrome 
16) Movements during sleep 
17) REM sleep behavior disorder (RBD) 
18) Disrupted sleep: when to be concerned 
19) Sleep in Alzheimer’s disease 
20) Sleep in Parkinson’s Disease 
21) Lighting up the aging brain: the effects of light 
22) Sleep and physical activity 
23) Recommendations for better sleep 
24) Sleep and sex differences 
We will track adherence through metadata from the BHP platform that can be exported 
by the study team and includes: participant ID, date an account was created, and date 
specific chapters are read. 

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7 STUDY SCHEDULE AND PROCEDURES 
7.1 
Overview of Study Schedule 
An overview of the study schedule can be found in Appendix B. 
7.2 
Study Instruments 
Copies of each study instrument can found in Appendix D. 
7.2.1 
Eligibility Screening and Basic Information 
Screening Checklist for Eligibility: The screening checklist for eligibility is a simple document 
with inclusion and exclusion criteria. All inclusion criteria and no exclusion criteria must be met 
to be eligible (video conference). See Appendix C-1. 
Demographic and Medical Information: Basic demographic and medical information include age, 
sex, education, and past/present medications and medical comorbidities. (video conference). 
See Appendix C-2. 
7.2.2 
Sleep Disorders and Patient Reported Sleep Outcomes 
Sleep Apnea: As an initial screen for sleep apnea, we will use the STOP-Bang questionnaire 
competed on an online form (12). See Appendix C-3. 
Insomnia Severity Index (ISI): A 7-item questionnaire assessing sleep onset, sleep 
maintenance, sleep satisfaction, and sleep problems. Each item is rated on a scale ranging from 
0-4 with total scores ranging from 0 to 28 and higher scores suggesting more severe insomnia 
(13). The ISI is administered as a questionnaire which can be administered via any interphase 
(face-to-face or video conferencing). We will administer it via video conferencing. See Appendix 
C-4. 
Restless Legs.  RLS will be assessed using the 8-item Cambridge Hopkins Questionnaire (14) 
administered by video conference. See Appendix C-5. 
REM Sleep Behaviour Disorder RBD will be assessed using a single question from the Mayo 
sleep questionnaire: “Have you ever been told, or suspected yourself, that you seem to ‘act out 
your dreams’ while asleep (for example, punching, flailing your arms in the air, making running 
movements, etc.)?” (15). See Appendix C-6. 
Self-Report Sleep Quality: We will use the PROMIS Sleep Disturbance and PROMIS Sleep 
Related Impairment short form questionnaires to assess subjective sleep quality (16). See 
Appendix C-7. 
Sleep Diary: We will use a 10-day sleep diary to complement the accelerometry data. See 
Appendix C-8. 
7.2.3 
Cognitive Evaluation 
Montreal Cognitive Assessment: The Full MoCA via Audio-Visual Conference consists of a 30-
point test assessing the following items: short term memory recall, visuospatial abilities, 

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executive functioning, phonemic fluency, verbal abstraction, attention, concentration, working 
memory, language, and orientation (17). The remote version of the MoCA will be administered 
using the validated online full MoCA (version 8.1) via audio-visual conference (18). See 
Appendix C-9. 
Logical Memory: Logical Memory I & II (Story A) from the Wechsler memory scale assesses 
memory and free recall (19). This test will be completed via video conferencing in which the 
participant will be instructed to listen to a story and repeat it back after it has been read to the 
best of his/her ability. The participant will then be asked to recall the story approximately 30 
minutes later.   Because this test is an auditory test to begin with (i.e., it does not require visual 
stimuli such as paper and pencil questionnaires), it can be administered using any modality 
(face-to-face or via video conference). We will conduct it via video conferencing. See Appendix 
C-10. 
Geriatric Depression Scale: The GDS Short Form is a brief, 15-item questionnaire in which 
participants are asked to respond by answering yes or no in reference to how they felt over the 
past week (20). See Appendix C-11. 
Symbol Digit Modalities Test (SDMT): Our primary outcome measure is the total score on the 
SDMT, a, a test of speeded executive function.  A recent study estimated a minimal clinically 
important difference in the SDMT in a sample of adults with MCI of -3.8 points, corresponding to 
an effect size of -0.42 (2). An observational study of CPAP in adults with MCI found a similar 
effect size of CPAP (6-month effect size 0.46) on a very similar test, the Digit Symbol 
Substitution Test subtest of the Wechsler Adult Intelligence Scale (3).  The test-retest 
correlation for the SDMT in clinically stable individuals with MCI over a mean follow-up of 19 
months is 0.78 (2). See Appendix C-12. 
Trail Making Test A&B: The TMT A & B is a two-part test that assesses attention speed, and mental 
flexibility and has been widely used in clinical settings for assessing deficits in attention and executive 
functioning (21). See Appendix C-13. 
Digit Span: The digit span forward and backward from the WAIS-III will be administered as an 
assessment of working memory (21). See Appendix C-14. 
Letter Number Sequencing: The Letter Number Sequencing Test (23) is a test of working memory. 
The Hopkins Verbal Learning Test-Revised (HVLT-R):  A brief, multicomponent word-list learning task 
that was developed by Brandt and Benedict (24) to assess verbal learning and memory. The HVLT-R 
consists of three free recall learning trials, a delayed recall trial and a recognition task, and yields a 
number of raw and calculated scores including total recall score, delayed recall score, percentage 
retention and a recognition discrimination index (RDI). See Appendix C-15. 
ADAS-Cog:  The ADAS-Cog-13 consists of 13 brief cognitive tests assessing memory, 
language, attention, concentration, and praxis. Scores range from 0 to 85 with higher scores 
indicating increased severity of cognitive impairment. See Appendix C-16. 
7.2.4 
Functional Status 
IADL: The Lawton-Brody Instrumental Activities of Daily Living (IADL) scale measures 
participant’s ability to engage in instrumental activities of daily living via questionnaire assessing 
activities such as preparing meals and managing personal finances (25). Responses range from 

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0 (normal ability) to 3 (dependent for functioning) with total scores ranging from 0 to 23. This 
assessment of functional independence is collected via questionnaire, which can be 
administered via any interface (face-to-face or video conferencing). We will administer it via 
video conferencing. See Appendix C-17. 
7.2.5 
Sleep Physiology 
Sleep Apnea: At screening baseline, 16 weeks, and 32 weeks, participants will undergo 1 night 
of Apnealink from which we will extract oximetry metrics including ODI, AHI, mean SpO2, 
hypoxia burden, and time with SpO2<92%.  An entry requirement will be ODI>5 OR time with 
SpO2<92% of >10 minutes.  The ApneaLink is an FDA-approved self-administered 3-channel 
portable device that assesses for sleep apnea based on airflow as assessed using an intra-
nasal pressure transducer, pulse oximetry assessed using a finger probe, and respiratory effort 
using a band around the chest.  It is considered a Type 4 sleep monitor by the American 
Academy of Sleep Medicine and has been validated against polysomnography (26). 
EEG: At baseline, 16 weeks and 32 weeks, participants will undergo 3 nights of home EEG 
using a wearable headband (MUSE-S, Interaxon, Toronto) which will undergo automated sleep 
staging using a random forest based model developed by our lab based on 308 MUSE-S 
recordings with simultaneous in-lab PSG.  To develop our own model, we divided our set of 
n=308 recordings with simultaneous PSG-MUSE EEG recordings randomly into n=215 training 
and n=93 test recordings.  The MUSE-S provides four-channel EEG, triaxial accelerometer 
(ACC), and PPG data.  After segmentation into 30-second epochs and normalization of each 
channel within each epoch, we extract statistical and morphological features are extracted from 
each epoch. EEG signals undergo bandpass filtering to isolate frequency components, enabling 
the extraction of power spectral density (PSD) across different frequency bands (Delta, Theta, 
Alpha, Beta, Gamma). Similarly, PPG data is filtered and denoised before features such as 
PSD, dominant frequency, heart rate variability, and respiratory rate are extracted. For sleep 
stage classification, a 1-D Convolutional Neural Network (CNN) architecture is employed. 
Ground truth labels were obtained from visual analysis of simultaneously recorded full PSG.  
Extracted features from MUSE EEG, accelerometer, and PPG data are fed into the model, 
which consists of Conv1D layers with ReLU activation, followed by MaxPooling1D layers. The 
hierarchical features extracted by the CNN are then flattened and passed through densely 
connected layers with ReLU activation. The output layer employs softmax activation to output 
class probabilities. The model is trained using categorical cross-entropy loss and the Adam 
optimizer, with a learning rate of 0.001, over 10 epochs with a batch size of 32. For sleep vs 
wake classification, a Decision Tree classifier is used. This classifier is configured with specific 
parameters controlling its complexity and generalization ability, such as with a Gini impurity 
criterion for splitting, limiting the maximum depth of the tree to 50, and setting minimum samples 
per leaf to 5 and minimum samples for splitting to 5. Post-processing involves applying majority 
voting on predicted sleep stages to smooth transitions and enhance the coherence of the sleep 
architecture. Finally, the performance of the trained models, whether binary or multiclass, is 
evaluated using appropriate metrics such as accuracy, sensitivity, specificity, and F1-score. 
Sleep metrics such as total recording time, total sleep time, sleep latency, and time spent in 
different sleep stages (N1, N2, N3, and REM) are calculated over all test subjects to assess the 
efficacy of the classification pipeline.  .  In the n=93 test set, we saw improved performance 
compared to the manufacturer provided model, correctly classifying a much larger proportion of 
epochs of slow wave sleep (72% vs. 56%), REM sleep (89% vs. 71%), and wake (94% vs. 
71%).   

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Accelerometry The AX3 is an accelerometer used to detect detecting movement, vibrations, and 
orientation changes. The AX3 will be mailed to participants and a sponsor site study steam 
member will instruct the participant on the proper application and use of the device through 
videoconference.  The participant will be given a copy of the instruction script, in addition to an 
instruction card containing contact information of research staff should they have any questions. 
The participant will be shown how to place the device on their non-dominant wrist by research 
staff, and participants will be instructed to wear the devices continuously for 10 days, even when 
bathing or swimming. During the 10 days, participants will be asked to track their work and 
sleep hours in a diary.  At the end of 10 days, participants will return the device to the sponsor 
site using a pre-paid parcel system. This procedure will be repeated at 4 months and 8 months  
7.2.6 
CPAP Adherence 
CPAP adherence will be automatically logged by the CPAP devices for the duration of the 
study period, and accessible remotely from the study centre.  We will compute several 
measures of adherence including: 1) % of days adherent, defined as use over 4 hours, for 
months 0-4 and 5-8. 2) mean nightly usage in hours for months 0-4 and 5-8 3) cumulative 
number of days used >4h since entry into the study (a measure of the total cumulative duration 
of CPAP adherence).   
7.2.7 
MRI Brain 
Participants will be imaged using the Canadian Dementia Imaging protocol consisting of a 3D 
T1, interleaved 3mm PD/T2, 3D FLAIR, T2*, DTI, and resting state BOLD. Perivascular spaces 
and white matter hyperintensities will be quantified with the SynthSegCSVD algorithm 
developed and validated in our laboratory, a robust neural network based (i.e. applies an AI 
deep learning method) tool.  The SegCSVDPVS segmentation model employs a convolutional 
neural net (CNN) based on the UNet architecture and incorporates several advanced machine 
learning techniques to ensure accurate and robust PVS segmentation. Central to the 
development of SegCSVDPVS was the curation of a diverse dataset consisting of T1-weighted 
images sourced from several multi-site studies spanning a wide range of patient populations. 
Ground truth PVS labels for this dataset were generated using a semi-automated procedure 
consisting of: “RORPO” filtering to identify small tubular structures on the T1; false positive 
minimization using the FreeSurfer segmentation output; and manual refinement by a trained 
image analyst to correct any remaining errors.  
7.2.8 
Plasma Samples 
Collection: Blood samples (10 ml) will be collected in plasma vacutainer tubes and centrifuged 
at 1000×g for 10 minutes. Plasma will be separated and preserved in a freezer at -80oC in a 
secure freezer.  All samples will be de-identified and preserved at -80oC and assayed together 
in a batch after the collection of the last sample  
Vascular Risk Factors: Classical vascular risk factors will also be assessed (lipid profile 
including LDL, HDL, and triglycerides; fasting glucose; haemoglobin A1C) 
Plasma AD Biomarkers: We will assess plasma pTau181 (for AD pathology) and GFAP (for 
astrocyte activation).  pTau181 has been shown to be strongly predictive of both amyloid and 
tau pathology as measured by PET (4,5) while plasma GFAP correlates strongly with 18F-
SMBT-1 PET, a marker of brain reactive astrocytes (6). 

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7.3 
Premature Withdrawal 
Participants may be withdrawn or be discontinued from the study for any of the following reasons: 
1. 
At the participant’s request (withdrawal of consent) 
2. 
At the discretion of the investigator, if deemed appropriate, for any reason 
3. 
If an intolerable or life-threatening adverse event occurs  
Participant data collected to the date of discontinuation or withdrawal will be included in the 
analysis. 
7.4 
Study Close-Out 
At the close of the study, participants will be able to keep their CPAP equipment.  Clinical care 
will initially continue with the study physician, but arrangements will be made to transfer clinical 
care to another physician if desired by the study participant.  Ongoing CPAP support would be 
transitioned to local CPAP suppliers.   
7.5 
Protocol Deviations 
It is the responsibility of the investigator to ensure that only investigative procedures, as outlined 
in this protocol are performed on study participants; the occurrence of deviations from the 
protocol or SOPs are limited; and compliance with the regulations is maintained. Planned 
deviations from the protocol must not be implemented without prior agreement from the sponsor 
and approval from the local REB, as required, unless to eliminate an immediate hazard to a 
participant. 
Planned or unplanned deviations may occur on the part of the participant, the investigator, or 
study research team. In resolution to a deviation, corrective/preventative actions are to be 
developed and implemented in a timely manner. Protocol deviations will be documented and 
reported as required and assessed where necessary during analysis. 
 
 
 

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8 ASSESSMENT OF SAFETY 
The safety of research participants is foremost and should always be considered throughout the 
conduct of research.  
8.1 
Definitions 
8.1.1 
Adverse Events 
An adverse event (AE) is any untoward medical occurrence in a participant that occurs from the 
time of enrollment and up to 30 days after study participation has ended. For the purposes of 
reporting, an AE is defined as any unfavourable or unintended sign (e.g., including an abnormal 
laboratory finding), symptom, or disease associated with study procedures that are both non-
serious and either temporally or causally related to study procedures. Pre-existing conditions, 
which increase in frequency or severity or worsen in nature during, or as a consequence of, a 
study procedure, may also be considered an AE if it meets the definition of being both non-
serious and related to a study procedure. 
An AE does not include: 
 
Medical or surgical procedures (e.g., surgery, endoscopy, tooth extraction, transfusion). 
 
The condition that leads to the procedure is the AE. 
 
Situations where an untoward medical occurrence has not occurred (e.g., hospitalization 
for elective surgery, social and/or convenience admissions). 
 
Worsening of symptoms associated with expected decline in memory or an associated 
co-morbid condition and not related to a study procedure. 
 
Those medical or surgical adverse events that are not related to the study procedures 
8.1.2 
Serious Adverse Events 
A serious adverse event (SAE) or reaction is any untoward occurrence related to study 
procedures that: 
 
Results in death, 
 
Is life-threatening, 
 
Requires inpatient hospitalization or prolongation of existing hospitalization, 
 
Results in persistent or in significant disability/incapacity, 
 
Is a congenital abnormality or a birth defect. 
The term "life-threatening" in the definition of "serious" refers to an event in which the participant 
was at risk of death at the time of the event; it does not refer to an event which hypothetically 
might have caused death if it were more severe. 
8.1.3 
Unexpected Adverse Event 
An unexpected adverse event is any AE that is not identified in nature, severity or frequency in 
the relevant safety document(s) or is not identified as a possible risk in the study protocol or the 

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informed consent form. 
8.2 Assessment of an Adverse Event 
8.2.1 
Relationship (Causality/Relatedness) 
The causality assessment is the determination, according to the investigator’s clinical judgment, 
of the existence of a reasonable possibility that study procedures caused or contributed to an 
adverse event.  
If the investigator or delegated sub-investigator is unsure about whether or not study procedures 
caused or are related to the event, then the event will be handled as “related” to study 
procedures for reporting purposes of the trial. If the causality assessment is "unknown but not 
related”, this should be clearly documented in the source documents.  
8.2.2 
Expectedness  
Events are classified as unforeseen or unexpected if the nature, severity or frequency is not 
consistent with the risk information set out in the relevant safety document(s). 
8.2.3 
Seriousness 
Events are classified as serious if associated with effects threatening the life or physiological 
functions of a participant. Refer to the definition for “Serious Adverse Events” in section 8.1.2. 
8.2.4 
Severity  
The term "severe" is often used to describe the intensity (severity) of a specific event (e.g. mild, 
moderate, or severe myocardial infarction); the event itself, however, may be of relatively minor 
medical significance (such as severe headache). This is not the same as "serious," which is 
based on participant/event outcome or action criteria usually associated with events that pose a 
threat to a participant's life or functioning. The terms “serious” and “severe” are not 
synonymous. Seriousness (not severity) serves as a guide for defining regulatory reporting 
obligations. 
To assess the severity of an adverse event the investigators will use the following: 
Severity 
Definition 
Mild 
Awareness of event but easily tolerated 
Moderate 
Discomfort enough to cause interference with usual activity 
Severe 
Inability to carry out usual activity, incapacitating, requires medical intervention 
8.3 
Adverse Event Recording 
 

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All AEs both non-serious and either temporally or causally related to study procedures (i.e., a 
new event or an exacerbation of a pre-existing condition) that occur from the time of enrollment 
and up to 30 days after study participation has ended will be recorded as an AE. The 
Investigator must follow all AEs until the AE resolves, or until the Investigator determines the 
event is chronic or clinically stable. If an AE remains unresolved at the conclusion of the AE 
reporting period, the Investigator will make a clinical assessment to determine whether 
continued follow-up of the AE is warranted. The Investigator should attempt to establish a 
diagnosis of the event based on signs, symptoms and/or other clinical information. In such 
cases, the diagnosis should be documented as the AE and not the individual signs/symptoms.  
The following are not considered AEs and therefore do not require recording:  
 
Pre-existing diseases or conditions identified and recorded at screening/baseline unless, 
at the discretion of the investigator, the disease or condition worsens in severity or 
frequency  
 
At the discretion of the investigator, events considered likely manifestations of the 
underlying disease or that commonly occur in the study population independent of study 
procedures 
 
Elective medical or surgical procedures.  
8.4 
Reporting of SAEs and Unanticipated Events 
8.4.1 
Investigator reporting: Notifying the REB 
 
Serious adverse events and unanticipated events should be recorded and reported to the REB 
in accordance with local reporting requirements and timelines.   
8.4.2 
Investigator reporting: Notifying the Sponsor 
 
The investigator is responsible for reporting serious adverse events and unanticipated events to 
the sponsor in accordance with applicable regulations and reporting requirements and timelines.   
 
Events that are assessed to be serious and unexpected and related or cannot be ruled out 
as related to the study procedures are reportable. Reporting should include a description of the 
event in sufficient detail to allow for a complete medical assessment of the case and 
independent determination of possible causality. The minimum information required includes at 
least one identifiable participant, one identifiable reporter, one serious reaction, and one suspect 
procedure.  
8.4.3 
Sponsor Reporting of SAEs and Unanticipated Events: Notifying Health 
Canada 
 
In the event of an incident related to a failure of the device used in this protocol or deterioration 
in its effectiveness, or any inadequacy in its labelling or in its directions for use that leads to the 
death or a serious deterioration in the state of health of a patient, user or other person, or could 
do so were it to recur, the sponsor of this study will report the incident to Health Canada. The 

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sponsor will report the incident and the circumstances surrounding it to the Minister and to the 
manufacturer or importer of the device within 72 hours after it comes to the attention of the 
qualified investigator. 
8.5 
Reporting and Entry Timelines 
 Study investigators will report SAEs to the sponsor within the following timelines:  
 
All deaths and immediately life-threatening events, whether related or unrelated, will 
be recorded and reported to the sponsor within 24 hours of site awareness.  
 
Serious adverse events other than death and immediately life-threatening events, 
regardless of relationship, will be reported to the sponsor within 72 hours of site 
awareness.  
Adverse event information will be entered into the CRF in a timely manner and no later than 15 
days from the time the investigator becomes aware of the event. 
 
Serious adverse event information will be entered into the CRF in a timely manner and within 
72 hours from the time the investigator becomes aware of the event. 

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9 STATISTICAL CONSIDERATIONS 
9.1 
Study Hypotheses 
 
This RCT will test the hypothesis that treatment of OSA with CPAP in patients with MCI will slow 
cognitive decline and prevent accumulation of astrocyte activation, PVS burden, and biomarkers 
of brain AD pathology. 
9.2 
Sample Size Considerations 
 
Our primary outcome measure is the total score on the Symbol Digit Modalities Test (SDMT), a, 
a test of speeded executive function, at 4 months. A recent study estimated a minimal clinically 
important difference in the SDMT in a sample of adults with MCI of -3.8 points, corresponding to 
an effect size of -0.42 (2). An observational study of CPAP in adults with MCI found a similar 
effect size of CPAP (6-month effect size 0.46) on a very similar test, the Digit Symbol 
Substitution Test subtest of the Wechsler Adult Intelligence Scale (3). The test-retest correlation 
for the SDMT in clinically stable individuals with MCI over a mean follow-up of 19 months is 0.78 
(2). In a recent study of adults with MCI, overall CPAP adherence was ~70% (10). In order to 
account for this, we will design our study to detect a smaller effect size of 0.26. Assuming a test-
retest correlation of 0.78, and a 2-tailed type I error rate of 0.05 in a 2-group ANCOVA model, 
we estimate that a total sample size of 184 will provide 80% power to detect an effect estimate 
of 0.26. To account for an estimated 10% drop out, we will aim to recruit a total sample size of 
206 participants (103 per group). 
9.3 
Stopping Rules 
 
This study will be stopped prior to its completion if: 1) the intervention is associated with adverse 
events that call into question the safety of the intervention; 2) difficulty in study recruitment or 
retention will significantly impact the ability to evaluate the study endpoints; 3) any new 
information becomes available during the trial that necessitates stopping the trial; or 4) other 
situations occur that might warrant stopping the trial. 
9.4 
Final Analysis Plan 
 
Our primary analysis will be an intent-to-treat (ITT) analysis comparing difference on the SDMT 
at 4 months as a function of assigned treatment group (CPAP vs. web education alone), 
adjusted for baseline SDMT. The analysis will use linear regression, adjusted for baseline 
SDMT, age, sex, years of education and recruitment source (direct from community vs. 
hospital/clinic). Participants will be analyzed in the treatment group to which they were assigned 
irrespective of their actual treatment adherence. Intention to treat analyses preserve the benefits 
afforded by randomization (most importantly, the elimination of selection bias in treatment 
assignment), and are conservative in their estimates of treatment effect. As a secondary 
analysis, we will carry out a “per protocol” analysis where participants will be classified based on 
actual CPAP usage with participants considered CPAP users if they used CPAP >4h per night 
>80% of days over the preceding four months, and non-users if less than that.  

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Further analysis will be an intent-to-treat analysis comparing difference on the SDMT at 8 
months, adjusted for baseline SDMT, as a function of assigned treatment group (CPAP 4 
months vs. CPAP 8 months). The analysis will use linear regression, adjusted for baseline 
SDMT, age, sex, years of education and recruitment source (direct from community vs. memory 
clinic). As a secondary analysis, we will carry out a “per protocol” analysis where participants 
will be classified based on actual CPAP usage with participants considered CPAP users if they 
used CPAP >4h per night >80% of days in the four months leading up to cognitive evaluation.  
We plan to repeat our initial analyses replacing our cognitive outcomes with a) plasma GFAP b) 
plasma pTau-181 and c) MRI PVS burden. 
 
In exploratory analyses we will use a linear mixed effect models to model the effect of CPAP 
dose on the SDMT at 4 and 8 months in a time-dependent manner. CPAP dose will be defined 
in two ways; (a) cumulative dose, defined as total number of days since randomization where 
CPAP was used for more than 4 hours, (b) average dose, defined as the average number of 
hours CPAP was used per day over the previous four months. In each of the models, an 
interaction between dose and time will be fit to estimate the time-specific dose effects. 
Additionally, the models will adjust for baseline SDMT, age, sex, education, and recruitment 
source, with individual-specific random intercepts. Since only two time-points are being used, 
they will be considered discrete variables and so random slopes do not apply. 
 
In further exploratory analyses, we will use mediation analysis to examine the extent to which 
the effect of CPAP on SDMT is mediated by sleep physiology (e.g. slow wave sleep). Slow 
wave sleep percentage will be our primary mediator but we will consider in secondary analyses 
the other sleep parameters estimated from our wearable sensors. We plan to repeat these 
analyses replacing our cognitive outcomes with a) plasma GFAP b) plasma pTau-181 and c) 
MRI PVS burden. An additional sub-group analysis will be done for recruitment source. 
 
In lieu of propensity score matching, we will include as covariates in our non ITT models factors 
reported to predict CPAP adherence in a recent observation study of patients with MCI 
(baseline OSA severity, race (10)), and health behaviours and risk factors that may plausibly 
correlate with CPAP adherence and affect cognitive function (objectively measured physical 
activity from actigraphy, smoking, alcohol consumption, body habitus measured by BMI, 
depressive symptoms measured by the Geriatric Depression Scale, conscientiousness and 
neuroticism measured by the Big Five Inventory, vascular risk factors including measured blood 
pressure, and years of education). 

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10 DATA HANDLING AND RECORD KEEPING 
10.1 Confidentiality 
 
Information about study participants will be kept confidential and managed according to the 
requirements of the Personal Health Information Protection Act of 2004 (PHIPA) and the 
Research Ethics Board. PHIPA outlines the rules for the collection, use and disclosure of 
personal health information. The Act requires each participant to consent to the collection, use 
and access of personal health information (PHI), unless consent is waived by the REB. Where 
consent is required, each participant must be informed of the following:  
 
 What PHI will be collected during this study 
 Who will have access to that information and why 
 Who will use or disclose that information 
 The rights of a research participant to revoke their authorization for use of their PHI.  
 
In the event that a participant revokes authorization to collect or use PHI, the investigator may 
use all information collected prior to the revocation of participant authorization. For participants 
that have revoked authorization to collect or use PHI, attempts should be made to obtain 
permission to collect at least vital status (i.e. that the participant is alive) at the end of their 
scheduled study period. 
10.2 Source Documents 
 
Source data/documents are original documents, data and records in a clinical study that are 
necessary for the reconstruction and evaluation of the study. Examples of these original 
documents and data records include, but are not limited to: 
 
Worksheets 
 
hospital records  
 
medical records 
 
memorandum  
 
participants’ diaries or evaluation checklists  
 
pharmacy dispensing records  
 
recorded data from automated instruments (i.e. ECGs) 
 
copies or transcriptions certified after verification as being accurate and complete  
 
participant files and records kept at the pharmacy  
 
entries entered directly into the printed CRF 
 
Each participating site will maintain appropriate medical and research records for this study, in 
addition to regulatory and institutional requirements for the protection of confidentiality of 
participants. If electronic source data documents is printed it should be signed and dated by the 
investigator to confirm content and filed with other source documents.  

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The investigator(s) and research team members listed on the Task Delegation Log (TDL) will 
have access to participant medical records and will collect only the information needed for the 
study. Sponsor delegated monitors, representatives of institutional committees and regulatory 
authority representatives of the country in which the study is being conducted will also have 
access to examine records for the purposes of quality assurance reviews, audits and evaluation 
of study safety and progress. 
 
10.3 Data Management Responsibilities 
Data collection and accurate documentation are the responsibility of the study personnel under 
the supervision of the investigator. All source documents and applicable laboratory reports 
should be reviewed as needed and used to ensure that data collected for the purposes of the 
study are accurate and complete. Contemporaneous review of laboratory results and the 
assessment of clinical significance for those results considered out of range should be 
documented by means of dated signature by the reviewing investigator. Study personnel, 
including data entry team members, should use source documents to complete case report 
forms (CRFs).  
As part of the safety plan for this study, the investigator will review individual study participant 
records to ensure that appropriate mechanisms to protect the safety of study participants are 
being followed, that protocol requirements are being adhered to, and that data is accurate, 
complete, and secure. Participant records include, but are not limited to: consent forms, case 
report forms, data forms, laboratory specimen records, inclusion/exclusion forms, and medical 
charts. All study data will be collected by a member of the study research team and recorded in 
accordance with applicable procedures. 
 
10.4 Data Capture 
10.4.1 Case Report Forms 
 
The study case report form (CRF) is the primary data collection instrument for the study. 
Electronic/Paper case report forms (eCRFs/pCRFs) will be used to collect data for this study. 
CRFs are to be completed by data capture personnel and signed off by the investigator in a 
timely manner. Good documentation practices should be implemented according to standard 
operating procedures. All data requested on the CRF must be recorded and verifiable by source 
document.  
 
10.5 Records Retention 
 
Primary source data will be stored using on networked servers in locked rooms at Sunnybrook 
Health Sciences Centre to which only study staff will have access, as well as on Sunnybrook 
REDCap servers. Hard copies of any data collection forms will be stored in locked cabinets 
located at the workplaces of study research staff and accessible only by study staff. 

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10.6 Clinical Trial Registration 
 
In accordance with Health Canada’s Notice “Registration and Disclosure of Clinical Trial 
Information, November 30, 2007”, this trial will be registered on clinicaltrials.gov. 

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11 QUALITY CONTROL AND QUALITY ASSURANCE 
Data validation and quality control checks will be defined and implemented. Inconsistent and 
questionable data detected during the data entry or data validation process will be queried. 

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12 ETHICS CONSIDERATIONS 
12.1 
Ethical Standard 
The investigator will ensure that this study is conducted in accordance with the principles set 
forth in The Belmont Report: Ethical Principles and Guidelines for the Protection of Human 
Participants of Research, and codified in the Tri-Council Policy Statement and/or the ICH E6.  
12.2 
Research Ethics Board (REB)  
The protocol, informed consent form(s), recruitment materials, and all participant materials will 
be submitted to the REB for review and approval. Approval of both the protocol and the consent 
form must be obtained before any participant is enrolled. Any amendment to the protocol will 
require review and approval by the REB before the changes are implemented in the study, 
unless to eliminate an immediate hazard.  
12.3 
Ethical Concerns Surrounding Randomization 
CPAP is an established treatment for sleep apnea that is effective at improving sleepiness in 
some patients. However, there is a lack of class I evidence for its efficacy in preventing most 
important clinical outcomes including cardiovascular disease and dementia. Thus, randomized 
controlled trials of CPAP vs. usual care continue to be ethically performed in myriad patient 
populations including survivors of stroke (e.g. Sleep SMART Trial clinicaltrials.gov 
NCT03812653). To address ethical consideration pertaining to potential randomization of 
participants with severe sleep apnea to usual care we will a) exclude participants who have had 
a sleepiness related traffic accident or near-miss within the last 12 months and b) we will limit 
the period of randomized treatment to 4 months, after which all participants will receive CPAP. 
This reflects the fact that in local patterns of care, time from referral for a PSG to final receipt of 
CPAP is generally more than 4 months, and so even participants on the web-based education 
arm will receive CPAP no later than usual patterns of clinical care. These considerations are 
discussed in further depth in a letter of support from the chair of the Sunnybrook Research 
Ethics Board, which we have included in the supplementary material.  
We opted for a duration a) long enough to see effects on cognition and biomarkers while b) 
short enough to maintain high adherence, c) and ethically/practically allow randomization of 
more severe patients. Even a few days of sleep manipulation can alter CSF/plasma tau (3, 4) 
and 1-4 months of CPAP can modify CSF AD biomarkers (5) and PVS burden (Figure 3). 
Meanwhile, others have shown that adherence declines beyond 3 months (6) but that intensive 
support can maintain high adherence in individuals with MCI for at least 3 months (7). Moreover, 
ethical considerations make it difficult to randomize symptomatic individuals to non-CPAP 
beyond 4 months. As discussed above, to mitigate these ethical risks, this protocol includes a 4 
month extension period during which both arms will receive CPAP to evaluate the effects of up 
to 8 months of treatment. 
CPAP RCTs often have low adherence (6). Longer RCTs have excluded participants with 
significant sleepiness, who are the most likely to adhere to CPAP. Our relatively shorter duration 
(4 months) allows us to ethically randomize individuals with relatively severe symptoms, who 
are more likely to adhere. Secondly, longer RCTs have shown better adherence in early stages 
of the trial than later stages. By limiting randomization to 4 months, we maximize adherence. 
Further, recent studies have shown that a high-contact high-support approach can achieve 

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overall adherence levels at 3 months exceeding 70% (7). We will implement a similar high-
contact high-support approach in this protocol.  
12.4 
Consent  
Informed consent is a process that is initiated prior to the individual agreeing to participate in the 
study and continues throughout study participation.  A consent form describing in detail the 
study procedures and risks will be reviewed with and given to each participant. Consent forms 
will be REB-approved, and the participant is required to read and review the document or have 
the document read to him or her. The investigator or designee will explain the research study to 
the participant and answer any questions that may arise. The participant will sign the informed 
consent document prior to any study-related assessments or procedures. Participants will be 
given the opportunity to discuss the study with their surrogates or think about it prior to agreeing 
to participate. They may withdraw consent at any time throughout the course of the study. A 
copy of the signed informed consent document will be given to participants for their records.  
Prior to involvement in any study-related activities, consent must be obtained in writing for each 
participant using the current REB approved informed consent from. It is the responsibility of the 
investigator to ensure that all advertisements and written information, including the informed 
consent form, disseminated to participants has been approved by the local REB prior to use. 
The ethics approved Informed Consent Form (ICF) and any other written information, must be 
provided to each participant, allowing ample time to ask and have answered any questions prior 
to making a decision regarding participation. Neither the investigator nor study staff should 
unduly influence or coerce a participant to participate in the study.  
 
The ICF will be signed and dated by the participant and individual obtaining consent. The 
consent process will be documented in the clinical or research record.  
The original ICF, in its entirety, will be maintained by the site, and a complete copy of the signed 
ICF provided to the participant. The rights and welfare of the participants will be protected by 
emphasizing to them that the quality of their clinical care will not be adversely affected if they 
decline to participate in this study. 
The provision of consent is an ongoing process and should be maintained throughout the 
duration of the study.  Participants may withdraw consent at any time throughout the course of 
the study. 
12.5 
Participant Compensation 
Participants will be compensated $50 for each in-person study visit (screening PSG, initial visit 
with physician, and study visits at 0, 4, and 8 months), which is intended to cover the costs of 
parking and meals.  In addition, participants completing the at home screening process (video 
assessment + sleep wearable sensors) will be compensated $10.  Finally, participants will be 
able to keep the CPAP study apparatus at the end of the study.   
 
 

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13 LITERATURE REFERENCES 
1. 
Yaffe K, Laffan AM, Harrison SL, Redline S, Spira AP, Ensrud KE, et al. Sleep-disordered 
breathing, hypoxia, and risk of mild cognitive impairment and dementia in older women. 
JAMA. 2011 Aug 10;306(6):613-9. PubMed PMID: 21828324. Epub 2011/08/11. Eng. 
2. 
Borland E, Edgar C, Stomrud E, Cullen N, Hansson O, Palmqvist S. Clinically Relevant 
Changes for Cognitive Outcomes in Preclinical and Prodromal Cognitive Stages: 
Implications for Clinical Alzheimer Trials. Neurology. 2022 Sep 13;99(11):e1142-e53. 
PubMed PMID: 35835560. PMCID: PMC9536741. Epub 2022/07/15. 
3. 
Richards KC, Gooneratne N, Dicicco B, Hanlon A, Moelter S, Onen F, et al. CPAP 
Adherence May Slow 1-Year Cognitive Decline in Older Adults with Mild Cognitive 
Impairment and Apnea. J Am Geriatr Soc. 2019 Mar;67(3):558-64. PubMed PMID: 
30724333. PMCID: PMC6402995. Epub 2019/02/07. 
4. 
Jack CR, Wiste HJ, Algeciras-Schimnich A, Figdore DJ, Schwarz CG, Lowe VJ, et al. 
Predicting amyloid PET and tau PET stages with plasma biomarkers. Brain. 2023 May 
2;146(5):2029-44. PubMed PMID: 36789483. PMCID: PMC10151195. Epub 2023/02/16. 
5. 
Mielke MM, Hagen CE, Xu J, Chai X, Vemuri P, Lowe VJ, et al. Plasma phospho-tau181 
increases with Alzheimer's disease clinical severity and is associated with tau- and amyloid-
positron emission tomography. Alzheimer's & dementia : the journal of the Alzheimer's 
Association. 2018 Aug;14(8):989-97. PubMed PMID: 29626426. PMCID: PMC6097897. 
Epub 2018/04/08. 
6. 
Chatterjee P, Dore V, Pedrini S, Krishnadas N, Thota R, Bourgeat P, et al. Plasma Glial 
Fibrillary Acidic Protein Is Associated with 18F-SMBT-1 PET: Two Putative Astrocyte 
Reactivity Biomarkers for Alzheimer's Disease. J Alzheimers Dis. 2023;92(2):615-28. 
PubMed PMID: 36776057. PMCID: PMC10041433. Epub 2023/02/14. 
7. 
Lim AS, Yu L, Kowgier M, Schneider JA, Buchman AS, Bennett DA. Modification of the 
Relationship of the Apolipoprotein E epsilon 4 Allele to the Risk of Alzheimer Disease and 
Neurofibrillary Tangle Density by Sleep. JAMA neurology. 2013;In Press. Epub October 21, 
2013 
8. 
Yalamanchali S, Farajian V, Hamilton C, Pott TR, Samuelson CG, Friedman M. Diagnosis 
of obstructive sleep apnea by peripheral arterial tonometry: meta-analysis. JAMA 
otolaryngology-- head & neck surgery. 2013 Dec;139(12):1343-50. PubMed PMID: 
24158564. 
9. 
Morgenthaler TI, Aurora RN, Brown T, Zak R, Alessi C, Boehlecke B, et al. Practice 
parameters for the use of autotitrating continuous positive airway pressure devices for 
titrating pressures and treating adult patients with obstructive sleep apnea syndrome: an 
update for 2007. An American Academy of Sleep Medicine report. Sleep. 2008 
Jan;31(1):141-7. PubMed PMID: 18220088. PMCID: PMC2225554. Epub 2008/01/29. 
10. Richards KC, Lozano AJ, Morris J, Moelter ST, Ji W, Vallabhaneni V, et al. Predictors of 
Adherence to Continuous Positive Airway Pressure in Older Adults With Apnea and 
Amnestic Mild Cognitive Impairment. J Gerontol A Biol Sci Med Sci. 2023 Oct 
9;78(10):1861-70. PubMed PMID: 37021413. Epub 2023/04/07 
11. Feldman HH, Belleville S, Nygaard HB, Montero-Odasso M, Durant J, Lupo JL, et al. 
Protocol for the Brain Health Support Program Study of the Canadian Therapeutic Platform 

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Trial for Multidomain Interventions to Prevent Dementia (CAN-THUMBS UP): A Prospective 
12-Month Intervention Study. J Prev Alzheimers Dis. 2023;10(4):875-85. PubMed PMID: 
37874110. PMCID: PMC10258470. Epub 2023/10/24 
12. Chung, F., H. R. Abdullah and P. Liao (2016). "STOP-Bang questionnaire: a practical 
approach to screen for obstructive sleep apnea." Chest 149(3): 631-638. 
13. Bastien, C. H., A. Vallieres and C. M. Morin (2001). "Validation of the Insomnia Severity 
Index as an outcome measure for insomnia research." Sleep Med 2(4): 297-307. 
14. Allen, R. P., B. J. Burchell, B. MacDonald, W. A. Hening and C. J. Earley (2009). "Validation 
of the self-completed Cambridge-Hopkins questionnaire (CH-RLSq) for ascertainment of 
restless legs syndrome (RLS) in a population survey." Sleep medicine 10(10): 1097-1100. 
15. Boeve, B. F., J. R. Molano, T. J. Ferman, G. E. Smith, S.-C. Lin, K. Bieniek, W. Haidar, M. 
Tippmann-Peikert, D. S. Knopman and N. R. Graff-Radford (2011). "Validation of the Mayo 
Sleep Questionnaire to screen for REM sleep behavior disorder in an aging and dementia 
cohort." Sleep medicine 12(5): 445-453. 
16. Lan Yu,Daniel J. Buysse,Anne Germain,Douglas E. Moul,Angela Stover,Nathan E. 
Dodds,Kelly L. Johnston &Paul A. Pilkonis (2011). “Development of Short Forms From the 
PROMIS™ Sleep Disturbance and Sleep-Related Impairment Item Banks.” Behavioral 
Sleep Medicine 10(1). 
17. Nasreddine, Z. S., N. A. Phillips, V. Bedirian, S. Charbonneau, V. Whitehead, I. Collin, J. L. 
Cummings and H. Chertkow (2005). "The Montreal Cognitive Assessment, MoCA: a brief 
screening tool for mild cognitive impairment." J Am Geriatr Soc 53(4): 695-699 
18. Chapman, J. E., D. A. Cadilhac, B. Gardner, J. Ponsford, R. Bhalla and R. J. Stolwyk 
(2019). "Comparing face-to-face and videoconference completion of the Montreal Cognitive 
Assessment (MoCA) in community-based survivors of stroke." J Telemed Telecare: 
1357633X19890788 
19. Doppelt, J. E. and W. L. Wallace (1955). "Standardization of the Wechsler adult intelligence 
scale for older persons." J Abnorm Psychol 51(2): 312-330. 
20. J A Yesavage, T L Brink, T L Rose, O Lum, V Huang, M Adey, V O Leirer (1982). 
“Development and validation of a geriatric depression screening scale: a preliminary 
report.” J Psychiatr Res. 17(1):37-49. 
21. Esther Strauss, O. S. (1998). Trail Making Tests. New York, Oxford University Press. 
22. Wechsler D. WAIS-III Administration and Scoring Manual. The Psychological Corporation; 
1997]. 
23. Wechsler D. The Psychological Corporation; 1997. WMS-III Administration and Scoring 
Manual. 
24. Benedict RHB, Schretlen D, Groninger L, & Brandt J (1998). Hopkins Verbal Learning Test 
– Revised: Normative Data and Analysis of Inter-Form and Test-Retest Reliability. The 
Clincal Neuropsychologist, 12(1), 43–55. 
25. Lawton, M. P. and E. M. Brody (1969). "Assessment of older people: self-maintaining and 
instrumental activities of daily living." Gerontologist 9(3): 179-186 
26. Crowley KE, Rajaratnam SM, Shea SA, Epstein LJ, Czeisler CA, Lockley SW. Evaluation of 
a single-channel nasal pressure device to assess obstructive sleep apnea risk in laboratory 
and home environments. J Clin Sleep Med. 2013; 9(2): 109-16 

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27. Onder, N. S., M. E. Akpinar, O. Yigit and A. P. Gor (2012). "Watch peripheral arterial 
tonometry in the diagnosis of obstructive sleep apnea: influence of aging." Laryngoscope 
122(6): 1409-1414. 
28. Hedner, J., D. P. White, A. Malhotra, S. Herscovici, S. D. Pittman, D. Zou, L. Grote and G. 
Pillar (2011). "Sleep staging based on autonomic signals: a multi-center validation study." J 
Clin Sleep Med 7(3): 301-306. 
 

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SUPPLEMENTAL MATERIALS 
 

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APPENDICES 

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APPENDIX A: SCHEDULE OF EVENTS 
 
 
 

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APPENDIX B: OVERVIEW OF STUDY SCHEDULE 
Date 
Venue 
Staff 
Activities 
Compensation 
Pre-
Baseline 
Online Form 
None 
Online Screening Questionnaire 
- STOP-BANG 
- presence of cognitive difficulties 
- collect contact information 
None 
Pre-
Baseline 
Video (1 
hour) 
Coordinator 
/ RA 
- informed consent 
- exclusion criteria: driving, non-resident of 
Ontario, CPAP contraindicated or unwilling to 
start, no study partner, shift work, Insomnia 
Severity Index, Cambridge-Hopkins RLS, MRI 
contraindications 
- inclusion criteria: decline in cognition from 
previous, Lawton-Brody IADL 
- cognitive screening: video MoCA, Logical 
Memory II 
- Sleep wearables: Apnealink 
$10 upon 
completion of 
home sleep 
assessment 
Pre-
Baseline 
Video (1 
hour) 
Sleep 
Physician + 
RA  
- clinical sleep assessment + information 
necessary to prescribe CPAP 
$50 
Pre-
Baseline 
In-Person 
(overnight) 
RA 
- in-lab PSG 
$50 upon 
completion of 
PSG 
Pre-
Baseline 
Video 
(30min) 
Coordinator 
/ RA 
- discuss final determination of eligibility + 
randomization 
None 
Week 0 
In-Person 
(2-3 hours) 
Coordinator 
/ RA 
- phlebotomy 
- cognitive evaluation (SDMT, Trails A&B, Digit 
Span Forward and Backward, Letter-Number, 
Hopkins Verbal Learning, ADAS-Cog) 
- BH-PRO training 
- CPAP mask fitting + teaching (early CPAP 
group) 
- MRI 
Sleep wearables: MUSE-EEG, Actigraphy 
$50 
Weeks 0-
16 
Video/Phone 
Coordinator 
/ RA 
- Week 0 days 1, 2, 5, 7; weeks 1, 2, 3, 4, 6,8, 
10, 12, 16 (early CPAP group): calls with study 
staff to support CPAP 
None 
Week 16 
In-Person 
(2-3 hours) 
Coordinator 
/ RA 
- phlebotomy 
- cognitive evaluation (SDMT, Trails A&B, Digit 
Span Forward and Backward, Letter-Number, 
Hopkins Verbal Learning, ADAS-Cog) 
- CPAP mask fitting + teaching (later CPAP 
group) 
- MRI 
- Sleep wearables on CPAP: Apnealink, MUSE-
EEG, Actigraphy 
$50 
Weeks 16-
32 
Video/Phone 
Coordinator 
/ RA 
- Week 16 days 1, 2, 5, 7; weeks 17, 18, 19, 20, 
22, 24, 28, 32 (later CPAP group):  calls with 
study staff to support CPAP 
None 
Week 32 
In-Person 
(2-3 hours) 
Coordinator 
/ RA 
- phlebotomy 
- cognitive evaluation (SDMT, Trails A&B, Digit 
Span Forward and Backward, Letter-Number, 
Hopkins Verbal Learning, ADAS-Cog) 
- Sleep wearables on CPAP: Apnealink, MUSE-
EEG, Actigraphy 
$50 
 
 

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APPENDIX C-1: INCLUSION/EXCLUSION LIST 
INCLUSION CRITERIA 
CRITERIA 
MET? 
(Should be Yes) 
SUPPORTING SOURCE 
DOCUMENT 
NAME OR 
LOCATION 
DATE 
(mm-dd-yy) 
Informed consent obtained and signed 
 Yes 
 No 
 
 
Age > 55 
 Yes 
 No 
 
 
MoCA score 13-24 
 Yes 
 No 
 
 
Logical Memory II score: 
< 8 (if > 16 years of education) 
< 4 (if 8-15 years of education) 
< 2 (if > 0-7 years of education) 
 Yes 
 No 
 
 
Lawton-Brody IADL score >14 
 Yes 
 No 
 
 
DSM IV criteria for dementia not met 
 Yes 
 No 
 
 
Change in self-perceived cognition from previous 
 Yes 
 No 
 
 
Apnealink ODI > 5 
 Yes 
 No 
 
 
PSG AHI > 15 
 Yes 
 No 
 
 
PSG ODI > 10 
 Yes 
 No 
 
 
PSG central apneas <10% of all apneas 
 Yes 
 No 
 
 
PSG periodic limb movement index <15 
 Yes 
 No 
 
 
 
EXCLUSION CRITERIA 
CRITERIA 
MET? 
SUPPORTING SOURCE 
DOCUMENT 

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(Should be No) 
NAME OR 
LOCATION 
DATE 
(mm-dd-yy) 
Drowsiness-related driving accidents or near 
misses in the past 12 months 
 Yes 
 No 
 
 
Drives as their primary occupation 
 Yes 
 No 
 
 
Unable to complete cognitive evaluation in 
English 
 Yes 
 No 
 
 
Unable to participate in video-based cognitive 
assessment 
 Yes 
 No 
 
 
Not a resident of Ontario 
 Yes 
 No 
 
 
Contraindications to MRI 
 Yes 
 No 
 
 
Contraindications to CPAP or unwilling to start 
CPAP 
 Yes 
 No 
 
 
No available study partner to support CPAP 
 Yes 
 No 
 
 
Previously treated for sleep apnea 
 Yes 
 No 
 
 
Clinically significant insomnia (ISI > 15) 
 Yes 
 No 
 
 
Restless Legs Syndrome 
 Yes 
 No 
 
 
Shift Work 
 Yes 
 No 
 
 
Taking disease modifying agents for MCI 
 Yes 
 No 
 
 
 
 

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APPENDIX C-2: DEMOGRAPHICS & MEDICAL INFORMATION 
Question 
Response 
1. What is your date of birth? 
 
2. What is your current age? 
 
3. What sex was originally listed on your 
birth certificate? 
 
4. What is your gender/do you think of 
yourself as: 
Female 
Male 
Transgender woman/trans woman/male 
to female (MTF) 
Transgender man/trans man/ female to 
male (FTM) 
Genderqueer/gender non-conforming 
neither exclusively male nor female 
Additional gender category (or other) 
Don’t know 
 
5. People living in Canada come from 
many different cultural and racial 
backgrounds. Are you… (Choose all 
that apply): 
White 
Chinese 
South Asian 
Black 
Filipino 
Latin American 
Southeast Asian 
Arab 
West Asian 
Japanese 
Korean 
First Nations 
 

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Inuit 
Metis 
Other 
Don’t Know 
6. What is your handedness? 
 
7. Please indicate your highest level of 
education: 
Fewer than 12 years of formal education 
High school 
Undergraduate degree (bachelor's, 
associate) 
Graduate degree (master's, doctorate, 
professional degrees) 
 
8. What is your household income? 
 
9. List the medications you are currently 
taking. 
 
10. List the medications that you are not 
currently taking but were taking in the 
past 2 years. 
 
11. List any previous diagnosis or major 
health concerns. 
 
 
 

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APPENDIX C-3: STOP-BANG 
 

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APPENDIX C-4: ISI 
Insomnia Severity Index (ISI) 
The Insomnia Severity Index has seven questions. The seven answers are added up to get a total score. When 
you have your total score, look at the 'Guidelines for Scoring/Interpretation' below to see where your sleep 
difficulty fits. 
 
For each question, please CIRCLE the number that best describes your answer. 
 
1-3: Please rate the CURRENT (i.e. LAST 2 WEEKS) SEVERITY of your insomnia problem(s). 
Insomnia Problem 
None 
Mild 
Moderate Severe Very Severe 
1. Difficulty falling asleep 
0 
1 
2 
3 
4 
2. Difficulty staying asleep 
0 
1 
2 
3 
4 
3. Problems waking up too early 
0 
1 
2 
3 
4 
 
4. How SATISFIED/DISSATISFIED are you with your CURRENT sleep pattern? 
Very Satisfied 
Satisfied 
Moderately Satisfied 
Dissatisfied 
Very Dissatisfied 
0 
1 
2 
3 
4 
 
5. How NOTICEABLE to others do you think your sleep problem is in terms of impairing the quality of your life?  
Not at all Noticeable 
A Little 
Somewhat 
Much 
Very Much Noticeable 
0 
1 
2 
3 
4 
 
6. How WORRIED/DISTRESSED are you about your current sleep problem?  
Not at all Worried 
A Little 
Somewhat 
Much 
Very Much Worried 
0 
1 
2 
3 
4 
 
7. To what extent do you consider your sleep problem to INTERFERE with your daily functioning (e.g. daytime 
fatigue, mood, ability to function at work/daily chores, concentration, memory, mood, etc.) CURRENTLY? 
Not at all Interfering 
A Little 
Somewhat 
Much 
Very Much Interfering 
0 
1 
2 
3 
4 
 
Guidelines for Scoring/Interpretation: 
 
Add the scores for all seven items (questions 1 + 2 + 3 + 4 + 5 +6 + 7) =      _       your total score  
Total score categories: 
0–7 = No clinically significant insomnia 
8–14 = Subthreshold insomnia 
15–21 = Clinical insomnia (moderate severity)  
22–28 = Clinical insomnia (severe) 
 

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Used via courtesy of www.myhealth.va.gov with permission from Charles M. Morin, Ph.D., Université Laval 
 
 
 
 
Completed by: _______; _____/______/________ 
                             Initial         DD       MM        YYYYY 
Please indicate if: ☒ Completed   ☐ Test not administered   ☐ Test not completed 
If either not administered or not completed, code reason: 
 

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APPENDIX C-5: CAMRBRIDGE-HOPKINS 
 

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APPENDIX C-6: MAYO SLEEP QUESTIONNAIRE (Q1 ONLY) 
Have you ever been told that you seem to “act out your dreams” while 
sleeping (punched or flailed arms in the air, shouted, or screamed? 
 No 
 Yes 
 
 

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APPENDIX C-7: PROMIS 
 

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APPENDIX C-8: SLEEP DIARY 
General Instructions 
What is a Sleep Diary? A sleep diary is designed to gather information about your daily sleep pattern. 
How often and when do I fill out the sleep diary? It is necessary for you to complete your sleep diary every 
day. If possible, the sleep diary should be completed within one hour of getting out of bed in the morning. 
What should I do if I miss a day? If you forget to fill in the diary or are unable to finish it, leave the diary blank 
for that day. 
What if something unusual affects my sleep or how I feel in the daytime? If your sleep or daytime 
functioning is affected by some unusual event (such as an illness, or an emergency) you may make brief notes 
on your diary. 
What do the words “bed” and “day” mean on the diary? This diary can be used for people who are awake or 
asleep at unusual times. In the sleep diary, the word “day” is the time when you choose or are required to be 
awake. The term “bed” means the place where you usually sleep. 
Will answering these questions about my sleep keep me awake? This is not usually a problem. You should 
not worry about giving exact times, and you should not watch the clock. Just give your best estimate. 
Sleep Diary Item Instructions 
Use the guide below to clarify what is being asked for each item of the Sleep Diary. Date.: Write the date of the 
morning you are filling out the diary. 
1. Yesterday, I took a nap for ______ minutes.   A nap is a time you decided to sleep during the day, 
whether in bed or not in bed. Count all the times you napped at any time from when you first got out of 
bed in the morning until you got into bed again at night. Count how many minutes you napped during 
each nap and add them up to obtain the total time you napped in minutes. 
2. I went to bed at _____. Write the time that you got into bed. This may not be the time you began “trying” 
to fall asleep. 
3. I was able to go to bed at my preferred time (as early or late as desired) Respond YES or NO if you 
were able or not to go to bed at your preferred time. 
4. I turned off the lights at _____. Write the time that you turned the lights off with the intention to sleep. 
5. Once the lights went out, I fell asleep in about _________ minutes. Write the time in minutes that it 
took you to fall asleep, after the lights were turned off.  
6. During the night, I woke up for about _______ minutes. Count all the times you woke up at any time 
from the time you first fell asleep and your final awakening, not counting your final awakening. Count how 
many minutes you were awake during each awake time and add them up to obtain the total time you were 
awake. For example, if you woke 3 times for 30 minutes first time, 20 minutes second time, and 5 minutes 
third time, add them all up (30+20+5= 55 min) 
7. This morning I woke up at _____. Record the last time you woke up in the morning. 
8. I got up at ______.  Record the time you got out of bed for the day with no further attempt at sleeping. 
This may be different from your final awakening time (e.g. you may have woken up at 6:35 a.m. but did 
not get out of bed to start your day until 7:20 a.m.) 
9. I woke up spontaneously (i.e. without an alarm clock or any external noise or light) yes/no. 
Respond YES or NO, if you were woken up by an alarm clock or any other external noise such as traffic, 
sirens, pets or noise created by other members of your household.  

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10. I find that my sleep has been:  Record the number that best describes your sleep quality: 1 = very 
relaxing; 2 = restful; 3 = neutral; 4 = not very relaxing; 5 = not restful at all.

 
 
 
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Sample 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Today’s Date 
04-05-
19 
 
 
 
 
 
1. Yesterday, I took a nap for ______ 
minutes. 
(Indicate the total length of all your naps in 
minutes. Here is an example: 15 minutes the 
first nap + 10 minutes the second nap = 25 
minutes total. ) 
25 min. 
 
 
 
 
 
2. I went to bed at _____. 
22h00 
 
 
 
 
 
3. I was able to go to bed at my preferred 
time (as early or late as desired) 
YES 
 
 
 
 
 
4. I turned off the lights at _____. 
22h30 
 
 
 
 
 
5. Once the lights went out, I fell asleep in 
about ___min. 
30 min. 
 
 
 
 
 
6. During the night, I woke up for about 
_____ min. Here is an example: 30 minutes 
the first time I woke up + 20 minutes the 
second time I woke up + 5 minutes the third 
time I woke up = 55 minutes in total) 
55 min. 
 
 
 
 
 
7. This morning I woke up at _____. 
7h00 
 
 
 
 
 
8. I got up at ______. 
(Indicate the time you got out of bed.) 
7h30 
 
 
 
 
 
9. I woke up spontaneously (i.e. without an 
alarm clock or any external noise or light) 
yes/no 
NO 
 
 
 
 
 
10. I find that my sleep has been:  
1 = very relaxing 
2 = restful 
3 = neutral 
4 = not very relaxing 
5 = not restful at all 
(Indicate the number that best describes 
your sleep). 
 
 
3 
 
 
 
 
 

 
 
 
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Sample 
Day 6 
Day 7 
Day 8 
Day 9 
Day 10 
Today’s Date 
04-05-19 
 
 
 
 
 
1. Yesterday, I took a nap for ______ 
minutes. 
(Indicate the total length of all your 
naps in minutes. Here is an example: 
15 minutes the first nap + 10 minutes 
the second nap = 25 minutes total. ) 
25 min. 
 
 
 
 
 
2. I went to bed at _____. 
22h00 
 
 
 
 
 
3. I was able to go to bed at my 
preferred time (as early or late as 
desired) 
YES 
 
 
 
 
 
4. I turned off the lights at _____. 
22h30 
 
 
 
 
 
5. Once the lights went out, I fell asleep 
in about ___min. 
30 min. 
 
 
 
 
 
6. During the night, I woke up for about 
_____ min. Here is an example: 30 
minutes the first time I woke up + 20 
minutes the second time I woke up + 5 
minutes the third time I woke up = 55 
minutes in total) 
55 min. 
 
 
 
 
 
7. This morning I woke up at _____. 
7h00 
 
 
 
 
 
8. I got up at ______. 
(Indicate the time you got out of bed.) 
7h30 
 
 
 
 
 
9. I woke up spontaneously (i.e. 
without an alarm clock or any external 
noise or light) yes/no 
NO 
 
 
 
 
 
10. I find that my sleep has been:  
1 = very relaxing 
2 = restful 
3 = neutral 
4 = not very relaxing 
5 = not restful at all 
(Indicate the number that best 
describes your sleep). 
 
 
3 
 
 
 
 
 

 
 
 
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APPENDIX C-9: MOCA ONLINE V8.1 
 

 
 
 
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APPENDIX C-10: LOGICAL MEMORY 
 

 
 
 
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APPENDIX C-11: GERIATRIC DEPRESSION SCALE (SHORT FORM) 
 

 
 
 
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APPENDIX C-12: SDMT 
 

 
 
 
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APPENDIX C-13: TRAILS A+B 
 

 
 
 
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APPENDIX C-14: DIGIT SPAN 
 

 
 
 
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APPENDIX C-15: HOPKINS VERBAL 
 

 
 
 
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APPENDIX C-16: ADAS-COG-13 
54 pages, located here: https://www.fda.gov/media/122843/download 
 

 
 
 
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APPENDIX C-17: LAWTON BRODY IADL