Time-in-bed Restriction in Older Adults With Sleep Difficulties With and Without Risk for Alzheimer's Disease

Slow-wave Sleep Enhancement in Those at Risk for Alzheimer's Disease: Links With Memory, Excitotoxicity, and Plasma A-beta

Dementia caused by Alzheimer's disease affects approximately 5.6 million adults over age 65, with costs expected to rise from $307 billion to $1.5 trillion over the next 30 years. Behavioral interventions have shown promise for mitigating neurodegeneration and cognitive impairments. Sleep is a modifiable health behavior that is critical for cognition and deteriorates with advancing age and Alzheimer's disease. Thus, it is a priority to examine whether improving sleep modifies Alzheimer's disease pathophysiology and cognitive function. Extant research suggests that deeper, more consolidated sleep is positively associated with memory and executive functions and networks that underlie these processes. Preliminary studies confirm that time-in-bed restriction interventions increase sleep efficiency and non-rapid eye movement slow-wave activity (SWA) and suggest that increases in SWA are associated with improved cognitive function. SWA reflects synaptic downscaling predominantly among prefrontal connections. Downscaling of prefrontal connections with the hippocampus during sleep may help to preserve the long-range connections that support memory and cognitive function. In pre-clinical Alzheimer's disease, hyperactivation of the hippocampus is thought to be excitotoxic and is shown to leave neurons vulnerable to further amyloid deposition. Synaptic downscaling through SWA may mitigate the progression of Alzheimer's disease through these pathways. The proposed study will behaviorally increase sleep depth (SWA) through four weeks of time-in-bed restriction in older adults characterized on amyloid deposition and multiple factors associated with Alzheimer's disease risk. This study will examine whether behaviorally enhanced SWA reduces hippocampal hyperactivation, leading to improved task-related prefrontal-hippocampal connectivity, plasma amyloid levels, and cognitive function. This research addresses whether a simple, feasible, and scalable behavioral sleep intervention improves functional neuroimaging indices of excitotoxicity, Alzheimer's pathophysiology, and cognitive performance.

Inclusion Criteria:

1. Age 65-85.
2. Self-report mean sleep efficiency (the time in bed spent asleep within the time of lights out to final awakening) < 90% based on diary and actigraphy estimates and wake time after sleep onset > 20 minutes based on diary and actigraphy estimates.
3. Self-reported normal or corrected-to-normal visual and auditory acuity.

Exclusion Criteria:

1. Shift work involving night shift or regular work within the hours of 12am and 6am.
2. Presence of a chronic condition that significantly affects sleep.
3. Severe psychiatric condition including major depressive disorder, panic disorder, substance use disorders, and alcohol abuse/dependence within the past 6 months, or a lifetime history of a psychotic disorder or bipolar I disorder, based on initial online/phone self-report diagnoses, and subsequently based on a structured psychiatric interview.
4. Current use of medications affecting sleep such as antidepressants, antipsychotic medications, anticonvulsants, and steroids.
5. Current use of sedating drugs used at bedtime.
6. Consumption of > 14 alcohol drinks per week or > 6 drinks at a single sitting.
7. Consumption of > 3 caffeine drinks per day.
8. Prior diagnosis of a Central nervous system (CNS) disease, such as multiple sclerosis, stroke, Parkinson's disease, Alzheimer's disease, seizure disorder, delirium or dementia, a loss of consciousness > 24 hours, or traumatic brain injury as identified by the Cumulative Illness Rating Scale for Geriatrics (CIRS). Participants who are diagnosed with Alzheimer's disease based on neuropsychological testing will be excluded.
9. Sleep efficiency > 90% and wake time after sleep onset < 20 minutes consistent with the rationale of the inclusion criteria described above.
10. Apnea/hypopnea index greater than 15 as determined by one night of Apnea Link Plus screening.
11. Metal in the body. Rationale: Due to the nature of magnetic resonance imaging (MRI), participants cannot have any metal implants in their bodies, cannot have worked in a metal shop or been exposed to metal fragments during combat. Metal dental work (e.g. fillings crowns) may be allowed if compatible with the fMRI scanner.
12. Claustrophobia. Rationale: Could prevent the participant from completing the MRI scans.
13. Severe obesity. BMI > 40. Rationale: Could prevent the participant from completing the MRI scan.
14. Near-miss or prior automobile accident "due to sleepiness" within the past 12 months. Rationale: reduces the risk of sleepiness-related accidents.
15. Employed as a commercial driver during the study (for example, bus drivers, train engineers, airplane pilots). Rationale: reduces the risk of sleepiness-related accidents.
16. A score below 23 on the Telephone Interview for Cognitive Status. Rationale: This cut-off has been demonstrated to differentiate well between individuals with mild cognitive impairment from individuals with dementia who would have decision making impairments (Seo et al. 2011, Archives of Gerontology and Geriatrics). This ensures that decision making abilities are intact.
17. An Epworth sleepiness score greater than 10. Rationale: ensures that sleepiness is not excessive before starting the intervention that could further increase sleepiness. (Mazzotti, Diego R., et al. "Is the Epworth Sleepiness Scale sufficient to identify the excessively sleepy subtype of OSA?." Chest 161.2 (2022): 557-561; Aurora, R. Nisha, et al. "Correlating subjective and objective sleepiness: revisiting the association using survival analysis." Sleep 34.12 (2011): 1707-1714.)