Effects of successful OSA treatment on memory and ad biomarkers in older adults (ESSENTIAL) - the prevalence of alzheimer disease (ad) is high and projected to increase

Further, epidemiological data suggests that ~15% of ad risk may be attributed to sleep problems. Obstructive sleep apnea (OSA) is also common among the elderly (30-55%), and our prior work has established that cognitively normal older women with OSA have nearly double the 5-year risk of developing mild cognitive impairment (MCI) or dementia. Further, we showed that: I. OSA patients treated with positive airway pressure (PAP) experienced significant overnight increases in plasma neurofilament light (NFL), a marker of neural injury, with strong trends for ad- specific biomarkers (i.e. AΒ40 and TAU) after PAP withdrawal; II. OSA predicted longitudinal increases in ad biomarkers; and, III. PAP treatment delayed the onset of MCI in subjects with reported OSA. There is therefore strong evidence suggesting that OSA treatment could be an important prevention strategy for ad. However, trials for treatment of OSA to slow cognitive decline and progression to ad face a number of challenges. First, the most effective therapy (PAP) has poor adherence. A second challenge is defining the target population: prior trials targeted OSA patients with MCI/ad, who have more advanced disease and could be less amenable to treatment. A third challenge is identifying cognitive testing that is sensitive to sleep disruption, and linked to increased ad risk. (to capture effects of OSA on the offline processing phase requires sleep-dependent memory paradigms, in which the encoding and recall of information are separated by a period of sleep with/without OSA). Finally, a randomized trial of sufficient duration to test the effects of treatment of OSA on risk of incident ad is not feasible. Our proposed trial, effects of successful OSA treatment on memory and ad biomarkers in older adults (ESSENTIAL), addresses these challenges. ESSENTIAL is a 5-year study of cognitively normal older adults with newly diagnosed OSA, ages 55-75, recruited from 4 well-established sleep clinics. OSA patients (N=200) will be randomized to either: I) a 3-month OSA treatment by any combination of PAP, OAT, and positional therapy that results in an "effective" improvement in the apnea-hypopnea index (AHI); II) a waitlist control group to receive treatment at the conclusion of the 3-month intervention period. Effectively treated individuals (~150) and untreated individuals (~100) will then be followed for up to 24 months to compare whether sustained improvements in AHI are associated with better cognitive function and ad biomarker change profiles as compared to untreated controls. Participants will undergo PSG, actigraphy, cognitive tests, and blood draws at baseline, 3 and 24 months. Our aims are: 1) to compare 3-month change in plasma ad biomarkers (NFL, P-TAU, AΒ) between those randomized to OSA treatment and wait-list control groups; 2) to compare 3-month change in cognition between the OSA treatment and wait-list control groups; 3) to examine if sustained reduction in AHI over 24 months among effectively treated participants versus untreated controls is associated with better 24-month change profiles for ad biomarkers and cognition.