The Effects of Successful OSA Treatment on Memory and AD Biomarkers in Older Adults Study (ESSENTIAL)

The Effects of Successful OSA Treatment on Memory and AD Biomarkers in Older Adults (ESSENTIAL) Study

Icahn School of Medicine at Mount Sinai, New York University, University of Arizona, University of Pittsburgh, National Institute on Aging (NIA)

The Effects of Successful OSA TreatmENT on Memory and AD BIomarkers in Older AduLts (ESSENTIAL) study is a 5-year, multicenter randomized open-label trial that will screen 400 cognitively normal older adults recruited from well-established sleep clinics at 4 academic medical centers, with newly diagnosed moderate-severe OSA. An expected 200 OSA patients will be then randomized to one of two groups: i) a 3-month OSA treatment by any combination of PAP, OAT, and positional therapy that results in an "effective" AHI4%< 10/hour and AHI3A<20/hour (see below); ii) a waitlist control group to receive treatment at the conclusion of the 3-month intervention period. Both groups will continue follow-up for 24 months on stable therapy to determine if sustained improvements in sleep are associated with improvement in cognitive function and AD biomarkers.

The prevalence of Alzheimer disease (AD) is high and projected to increase. While there are multiple risk factors for AD, epidemiological data suggests that ~15% of AD risk may be attributed to sleep problems. Obstructive sleep apnea (OSA) is common among the elderly (30-55%), and the investigators have shown that cognitively normal older women with OSA have nearly double the risk of developing mild cognitive impairment (MCI) or dementia over 5 years. Further, the investigators have shown that in normal elderly, OSA predicts longitudinal increases in AD biomarkers. Our preliminary data also show that after positive airway pressure (PAP) withdrawal, OSA patients treated with PAP experienced significant overnight increases in plasma neurofilament light (NfL), a marker of neural injury. The present study is designed to overcome challenges identified in previous trials of treatment of OSA to slow cognitive decline and progression to AD. First, the most effective treatment for OSA, PAP therapy, has poor adherence (typically only 50% are adequately treated). Other common therapies include oral appliance therapy (OAT) which tends to be better tolerated but less effective. The investigators have piloted and propose for this study a rapid multimodal therapy initiation (RMMT) which ensures subjects will have effective therapy for their OSA that reduces OSA severity to AHI4%<10/hour and AHI3A (AKA pRDI) < 20/hour within 4 months. Second, most prior OSA treatment trials have focused primarily on symptomatic older adults (e.g. patients with MCI recruited from memory clinics), whereas early intervention in pre-symptomatic individuals may have stronger impact in preventing progression to AD. The investigators propose to enroll cognitively normal adults with newly diagnosed moderate-severe OSA (AHI4% >20/hour or AHI3A > 40/hour). Finally, selection of cognitive outcomes most responsive to OSA therapy has proved challenging. The Effects of Successful OSA TreatmENT on Memory and AD BIomarkers in Older AduLts (ESSENTIAL) study is a 5-year, multicenter randomized open-label trial that will screen 400 cognitively normal older adults (MoCA≥24, Clinical Dementia Rating [CDR]=0), ages 55-75, recruited from well-established sleep clinics at 4 academic medical centers, with newly diagnosed moderate-severe OSA (AHI4% >20/hour or AHI3A > 40/hour). An expected 200 OSA patients will be then randomized to one of two groups: i) a 3-month OSA treatment by any combination of PAP, OAT, and positional therapy that results in an "effective" AHI4%< 10/hour and AHI3A<20/hour (see below); ii) a waitlist control group to receive treatment at the conclusion of the 3-month intervention period. Both groups will continue follow-up for 24 months on stable therapy to determine if sustained improvements in sleep are associated with improvement in cognitive function and AD biomarkers. Both arms will include PSG and actigraphy, sleep-dependent memory and other cognitive evaluations, and blood draws at baseline, 3 and 24 months, with cognitive evaluation only at 12 months. Structural brain MRI will be performed at baseline. Because the investigators anticipate that 150 of 200 subjects will be well treated at 24 months, and 50 will not be, the investigators will additionally recruit ~50 subjects (on average 13 subjects per clinical site) with the same inclusion criteria who refuse treatment. These 50 subjects will perform baseline (blood draw and cognitive evaluations), 12-month (cognitive evaluation only), and 24-month (blood draw and cognitive evaluations) visits, allowing for a 24-month comparison of ~150 subjects with adequate treatment over 24 months to 100 subjects with inadequate treatment over 24 months. Our aims are: 1) To compare 3-month change in plasma AD biomarkers (NfL, p-tau, Aβ) in those randomized to OSA treatment and wait-list control groups (via both intention-to-treat and per-protocol analyses); 2) To test differences at 3 months in sleep-dependent declarative memory and cognitive scores (PACC and sub-domains) between the OSA treatment and wait-list control groups (via both intention-to-treat and per-protocol analyses); 3) To compare 24-month changes in AD biomarkers (NfL, p-tau, Aβ) and cognition in all successfully treated subjects and untreated controls.

Obstructive Sleep Apnea, OSA, Cognitive decline, Alzheimer Disease, AD, AD biomarkers, Positive Airway Pressure, PAP, CPAP, Oral appliance therapy, OAT, Positional therapy, Sleep-dependent memory

Approximately 250 total patients (~63 per site) will be enrolled. In the 3-month wait-list control randomized trial, 200 patients will be randomized to one of two groups: i) a 3-month OSA treatment by any combination of PAP, OAT, and positional therapy that results in an "effective" AHI3a<15 (rapid multi-modal treatment RMMT); ii) a waitlist control group to receive treatment at the conclusion of the 3-month intervention period. The remaining 50, plus an additional ~50 (n~100 total) participants who declined treatment and were not interested in being randomized for the 3-month trial, or who have tried but failed treatment in the past, will serve as the "control" group for the 24-month follow-up period.

A 3-month OSA treatment by any combination of PAP, OAT, and positional therapy that results in an "effective" AHI3a<15 (rapid multi-modal treatment RMMT).

Positive airway pressure (PAP) therapy is a sleep apnea treatment that uses a stream of compressed air to support the airway during sleep. With PAP therapy, a mask is worn during sleep and a portable machine gently blows pressurized room air from into your upper airway through a tube connected to the mask. This positive airflow helps keep the airway open, preventing the collapse that occurs during apnea, thus allowing normal breathing.

Oral appliance therapy involves the use of a dental appliance or oral mandibular advancement device that prevents the tongue from blocking the throat and/or advances the lower jaw forward. These devices help keep the airway open during sleep.

A NightShift Sleep Positioner (Advanced Brain Monitoring) is a neck vibration device, FDA approved to treat positional sleep apnea. The device detects patient supine position and delivers a small vibratory signal to the back of the neck to prompt position change.

Severity of cognitive impairment based on normed cutoffs with the National Alzheimer's Coordinating Centers Uniform Data Set-3 (UDS-3) assessment.

Severity of cognitive impairment based on normed cutoffs with the National Alzheimer's Coordinating Centers Uniform Data Set-3 (UDS-3) assessment.

Clinical Dementia Rating on a scale of 0-3 based on clinical assessment, 0 being no impairment, and 3 being severe impairment.

Scores of 0-4 are considered normal, depending on age, education, and complaints; 5-8 indicate mild depression; 9-11 indicate moderate depression; and 12-15 indicate severe depression.

Each item is scored on a scale of 0 (not present) to 4 (severe), with a total score range of 0-56, where <17 indicates mild severity, 18-24 mild to moderate severity and 25-30 moderate to severe.

CAPS-5 symptom cluster severity scores are calculated by summing the individual item severity scores for symptoms corresponding to a given DSM-5 cluster: Criterion B (items 1-5); Criterion C (items 6-7); Criterion D (items 8-14); and, Criterion E (items 15-20). Severity scores range from 0-4, with 0 being absent to 4 being extreme/incapacitating.

Inclusion Criteria: Cognitively normal (MoCA≥24, Clinical Dementia Rating [CDR]=0) with a minimum of 12 years of education Males and females, 55-75 years Moderate - severe OSA defined as AHI4 ≥20 events/hour or AHI3A>40/hr using a Hypopnea criterion of a 4% oxygen desaturation (AHI4) or 3% oxygen desaturation and/or EEG arousal (AHI3A) No OSA treatment Able and willing to be treated for OSA Fluency in English or Spanish Exclusion Criteria: Any other sleep or breathing disorder requiring supplemental oxygen. This includes circadian rhythm abnormalities, including irregular sleep-wake cycles defined as self-reported '≥3 sleep episodes per 24-hr period' or 'day to day irregularity of sleep/wake times greater than 2 hours' Anticipated scheduled bariatric surgery Chronic use of any sedative, stimulant, neuroleptic drugs, or other medications limiting validity of cognitive tests The presence of critical comorbid conditions, including clinically relevant endocrine or hematological conditions, substance abuse, preexisting cognitive, psychiatric, or neurological conditions, and pregnancy. History of stroke or MRI evidence of vascular damage, history of transient ischemic attacks or extensive white matter lesions (Fazekas scale >2) will also be excluded.

The final research data will be available in acceptable formats commonly accepted for documenting and supporting research findings. All data will be released and/or shared as soon as feasible without compromising privacy concerns, federal and state confidentiality concerns, proprietary interests, national security interests, or law enforcement activities. The final research data will not contain any patient identifiers. Even though the final dataset will be stripped of identifiers prior to release for sharing, we believe that there remains the possibility of deductive disclosure of subjects with unusual characteristics. Thus, we will make the data and associated documentation available to users only under a data-sharing agreement.

Research data that documents, supports, and validates research findings will be available after the main findings from the final research data set are accepted for publication. We anticipate data will be available starting in January 2029 and will be available on an NIH-sponsored platform for as long as the agency supports it.

Data and associated documentation available to users only under a data-sharing agreement that provides for: (1) a commitment to using the data only for research purposes and not to identify any individual participant; (2) a commitment to securing the data using appropriate computer technology; and (3) a commitment to destroying or returning the data after analyses are completed.