Is Obstructive Sleep Apnea Important in the Development of Alzheimer's Disease?

Aim 1: We will assess the endotypes (mechanisms) underlying OSA in elderly individuals known to be high risk for AD (vs. non-OSA matched controls) using novel recently validated simplified techniques which do not require burdensome complex overnight experiments to assess endotypes (primary outcome loop gain). We will further assess the predicted response to O2 therapy in terms of respiratory outcomes among elderly OSA patients with varying levels of loop gain and pharyngeal collapsibility.

Hypothesis 1: A substantial proportion of high AD risk patients with OSA should be O2 responsive as predicted using pathophysiological assessments.

Aim 2: We will perform an overnight mechanistic study of oxygen therapy vs. room air in high AD risk patients with OSA (recruited from Aim 1 and others if necessary). Given the frequent intolerance of PAP in elderly patients, we anticipate that oxygen therapy may be a viable therapeutic approach in this fragile population. We will focus on respiratory outcomes (primary outcome: apnea hypopnea index) but also assess sleep dependent memory consolidation on word pairs task given the major impact in the elderly.

Hypothesis 2: O2, compared to room air, will improve OSA and neurocognitive outcomes in select elderly OSA patients at risk of AD.

Aim 3: Preclinical AD with OSA and non-OSA controls, from Aim 1 will have structural and molecular brain imaging focusing on hippocampal atrophy as a predictor of memory consolidation. We will also assess amyloid and tau in the medial temporal region as function of OSA severity and as a predictor of neurocognitive function. This aim will lay the groundwork for designing a robust clinical trial using neuroimaging outcomes.

Hypothesis 3: Impairment in memory consolidation is a function of hippocampal size in OSA patients at risk of AD.

Aim 4: We will perform a pilot randomized trial of oxygen vs. PAP therapy in OSA patients with preclinical AD.

Hypothesis 4: In preclinical AD with OSA, oxygen will be a viable therapeutic strategy to improve memory.

• Supplemental Oxygen (Other), also known as Oxygen, O2: Subjects will be instrumented with a nasal cannula to receive 2L/min supplemental oxygen. The oxygen will be kept at a fixed rate, however, the participant will be titrated to receive a max of 4 liters per min to maintain sats >90% based on oximetry readings.
• Continuous Positive Airway Pressure Machine (Device), also known as CPAP, PAP: Continuous positive airway pressure is a form of positive airway pressure ventilation in which a constant level of pressure greater than atmospheric pressure is continuously applied to the upper respiratory tract of a person.
• Room Air (Other), also known as Placebo: Subjects will be instrumented with a nasal cannula to receive 2L/min pressurized room air. The room air will be kept at a fixed rate, however, the participant will be titrated to receive a max of 4 liters per min to maintain sats >90% based on oximetry readings.

Primary outcomes

• Apnea Hypopnea Index - Crossover [Over 8 hours on each of the two crossover treatment nights]: The number of times a person stops breathing and periods of shallow breathing with a marked decrease in blood oxygen concentration every hour on average. A score lower than five indicates normal sleep (no sleep apnea), 5-15 indicates mild sleep apnea, 15-30 indicates moderate sleep apnea, and a score greater than 30 indicates severe sleep apnea. Result specified as change from room air condition to oxygen condition during the crossover trial
• Loop Gain (LG) - Crossover [Over 8 hours on each of the two crossover treatment nights]: A method used to measure respiratory stability of the negative feedback chemoreflex control system using a specialized Positive Airway Pressure machine called a pCrit. The overall loop gain of the ventilatory system reflects the ratio of the ventilatory response to the disturbance that elicited the response (LG = ventilatory response/ventilatory disturbance). The higher the loop gain, the potentially more unstable the respiratory control system becomes. Result specified as change from room air condition to oxygen condition during the crossover trial
• Neuroimaging - BRAAK12 tauPET [Two 1-hour long scans]: MRI and PET Scans. This study will examine pre-clinical Alzheimer's disease with OSA patients using brain imaging (structural MRI and amyloid/tau PET). MRI will be conducted to provide a structural image suitable for coregistering the PET image and observing white matter integrity. The scan should take 35 minutes. These will be MPRAGE images collected using the standard ADNI protocol at the in-house 3T MRI scanner at the University of California San Diego Altman Clinical and Translational Research Institute (ACTRI). The PET scan should take 70-90 minutes and uses the 18F-MK6240 tracer. Result given is the Standardized Uptake Value Ratio (SUVR) of tau protein in the BRAAK1-2 regions, the earliest regions to develop tau pathology in Alzheimer's disease

Secondary outcomes

• Epworth Sleepiness Scale (ESS) - Parallel [12 weeks]: A self-administered questionnaire with 8 questions. Respondents are asked to rate, on a 4-point scale (0-3), their usual chances of dozing off or falling asleep while engaged in eight different activities. The ESS score (the sum of 8 item scores, 0-3) can range from 0 to 24. The higher the ESS score, the higher that person's average sleep propensity in daily life. Result specified as change from week 1 to week 12 during the parallel treatment trial
• Pittsburgh Sleep Quality Index (PSQI) - Parallel [12 weeks]: A 19-item, self-rated questionnaire designed to measure sleep quality and disturbance over the past month. The sleep component scores are summed to yield a total score ranging from 0 to 21 with the higher total score (referred to as global score) indicating worse sleep quality. Result specified as change from week 1 to week 12 during the parallel treatment trial
• Insomnia Severity Index (ISI) - Parallel [12 weeks]: A 7-item self-report form to assess insomnia severity. Total score categories: 0-7 = No clinically significant insomnia, 8-14 = Subthreshold insomnia, 15-21 = Clinical insomnia (moderate severity), 22-28 = Clinical insomnia (severe). Result specified as change from week 1 to week 12 during the parallel treatment trial

Sex: All, ages: 65 Years to 85 Years

Inclusion Criteria:

1. Age 65-85 years
2. Gender: Men or Women
3. MOCA > 26
4. Independently living and able to drive
5. OSA (AHI ≥ 15/h) or no OSA
6. Subjects must consent to waiving their right to obtain their PHS score (since the score is not yet actionable and could lead to social stress and ethical dilemmas)

Exclusion Criteria:

1. Currently smoking
2. History of COPD or asthma
3. Heart Failure Class III or IV, unstable cardiovascular disease, or uncontrolled hypertension
4. Neuromuscular Disease
5. Drowsy Driving (ESS > 18/24)
6. Inability to complete study procedures, such as questionnaire that are only available/validated in English
7. Lack of decisional capacity to provide informed consent
8. Participants in whom magnetic resonance imaging Magnetic Resonance Imaging \[MRI\] is contraindicated including, but not limited to, those with a pacemaker, presence of metallic fragments near the eyes or spinal cord, or cochlear implant
9. Presence of a brain tumor or lobar stroke
10. Current drug or alcohol abuse/dependence
11. Prisoners

Participant flow

Outcome results

• Apnea Hypopnea Index - Crossover (Primary), Mean, units on a scale: Oxygen 34.9 +/- 18.1; Room Air 39.6 +/- 18.7
• Loop Gain (LG) - Crossover (Primary), Mean, ratio: Oxygen 0.52 +/- 0.15; Room Air 0.60 +/- 0.15
• Neuroimaging - BRAAK12 tauPET (Primary), Mean, Standardized Uptake Value Ratio: Non-OSA Controls 0.91 +/- 0.22; Obstructive Sleep Apnea 0.92 +/- 0.16
• Epworth Sleepiness Scale (ESS) - Parallel (Secondary), Mean, questionnaire sum score: Non-OSA Controls ; Crossover Only (Oxygen > Air) ; Crossover Only (Air > Oxygen) ; Crossover (Oxygen > Air) and Parallel (Positive Airway Pressure) -0.50 +/- 1.97; Crossover (Oxygen > Air) and Parallel (Oxygen) 0.14 +/- 2.85; Crossover (Air > Oxygen) and Parallel (Positive Airway Pressure) -0.22 +/- 1.72; Crossover (Air > Oxygen) and Parallel (Oxygen) -0.43 +/- 2.76; Parallel Only (Positive Airway Pressure) 1.00 +/- 0.82; Parallel Only (Oxygen) -1.8 +/- 1.92
• Pittsburgh Sleep Quality Index (PSQI) - Parallel (Secondary), Mean, questionnaire sum score: Non-OSA Controls ; Crossover Only (Oxygen > Air) ; Crossover Only (Air > Oxygen) ; Crossover (Oxygen > Air) and Parallel (Positive Airway Pressure) -1.29 +/- 2.36; Crossover (Oxygen > Air) and Parallel (Oxygen) -0.71 +/- 3.50; Crossover (Air > Oxygen) and Parallel (Positive Airway Pressure) 0.78 +/- 2.99; Crossover (Air > Oxygen) and Parallel (Oxygen) -1.57 +/- 3.42; Parallel Only (Positive Airway Pressure) -1.50 +/- 3.42; Parallel Only (Oxygen) 0.80 +/- 2.49
• Insomnia Severity Index (ISI) - Parallel (Secondary), Mean, questionnaire sum score: Non-OSA Controls ; Crossover Only (Oxygen > Air) ; Crossover Only (Air > Oxygen) ; Crossover (Oxygen > Air) and Parallel (Positive Airway Pressure) -1.43 +/- 0.98; Crossover (Oxygen > Air) and Parallel (Oxygen) -3.14 +/- 4.74; Crossover (Air > Oxygen) and Parallel (Positive Airway Pressure) -0.89 +/- 2.42; Crossover (Air > Oxygen) and Parallel (Oxygen) -4.00 +/- 2.83; Parallel Only (Positive Airway Pressure) -0.50 +/- 3.11; Parallel Only (Oxygen) 0.60 +/- 2.30

Adverse events

Time frame: from enrollment until end of follow-up, median duration 5 weeks

Other adverse events by term

• Results publication: Harding CD, Holloway BM, DeYoung PN, Kwan C, Djonlagic I, Ancoli-Israel S, Banks SJ, Malhotra A. Subjective daytime sleepiness, not sleep quality or hypoxia, predicts sleep-dependent memory consolidation in a cohort of older adults. J Clin Sleep Med. 2025 Jul 1;21(7):1217-1226. doi: 10.5664/jcsm.11648. PMID 40135690
• Results publication: Holloway BM, Harding CD, DeYoung P, Kwan CG, Avetisyan L, Lui KK, Ancoli-Israel S, Banks SJ, Djonlagic I, Malhotra A. Comorbid insomnia and sleep apnea is associated with worse verbal episodic memory in older females. J Clin Sleep Med. 2025 Dec 1;21(12):2129-2138. doi: 10.5664/jcsm.11902. PMID 41025403

• Study Protocol and Statistical Analysis Plan (PDF, 2025-04-24)
• Informed Consent Form (PDF, 2024-03-04)