Sleep Schedule Restriction for Alzheimer's Disease

(ALPS Trial)

Overseen By Brian Lopresti, M.C.

Age: 65+

Sex: Any

Trial Phase: Phase < 1

Sponsor: University of Pittsburgh

Must not be taking: Antidepressants, Antipsychotics, Anticonvulsants, Steroids

Disqualifiers: Severe psychiatric conditions, CNS diseases, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: Unknown

Duration: 4 weeks

116 Participants Needed

Trial Summary

What is the purpose of this trial?

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.

Will I have to stop taking my current medications?

Yes, if you are currently using medications that affect sleep, such as antidepressants, antipsychotics, anticonvulsants, steroids, or sedating drugs used at bedtime, you will need to stop taking them to participate in this trial.

What data supports the effectiveness of the treatment Sleep Schedule Restriction for Alzheimer's Disease?

Research suggests that sleep disturbances are linked to Alzheimer's disease, and addressing these disruptions might help manage the disease. Studies have shown that improving sleep patterns, such as through light therapy, can reduce symptoms like agitation and improve rest-activity rhythms in Alzheimer's patients. ^{1 2 3 4 5}

Is sleep schedule restriction therapy safe for humans?

The research does not provide specific safety data for sleep schedule restriction therapy, but it discusses the importance of addressing sleep disturbances in Alzheimer's disease, suggesting that managing sleep issues is a valid treatment target. ^{1 2 4 6 7}

How is the Time in Bed Restriction treatment different from other treatments for Alzheimer's disease?

Time in Bed Restriction is unique because it focuses on improving sleep patterns by limiting the time spent in bed, which may help address sleep disturbances linked to Alzheimer's disease. Unlike medications, this treatment aims to modify the sleep-wake cycle, potentially influencing the progression of the disease by reducing sleep fragmentation and improving overall sleep quality. ^{1 2 6 8 9}

Eligibility Criteria

This trial is for older adults aged 65-85 with sleep difficulties but without severe psychiatric conditions, heavy alcohol or caffeine consumption, CNS diseases like Alzheimer's, or certain medications that affect sleep. Participants should have normal vision and hearing (with aids if necessary), a tendency to wake up often at night, and not be involved in shift work.

Inclusion Criteria

You can see and hear normally or with corrective lenses or aids.

You have trouble sleeping, as shown by your sleep diary and activity tracker, with a low sleep efficiency and long periods of being awake after falling asleep.

I am between 65 and 85 years old.

Exclusion Criteria

You have a score higher than 10 on the Epworth sleepiness test.

You drink more than 14 alcoholic drinks per week or more than 6 drinks at one time.

You have a serious mental health condition like severe depression, panic disorder, substance abuse, or bipolar disorder.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants undergo a time-in-bed restriction intervention to increase sleep efficiency and slow-wave activity

4 weeks

Weekly visits (in-person or virtual)

Follow-up

Participants are monitored for changes in cognitive function and sleep patterns after the intervention

4 weeks

Treatment Details

Interventions

• Sleep Schedule
• Time in Bed Restriction

Trial Overview The study tests whether restricting the time spent in bed can improve deep sleep and cognitive function in older adults. It aims to see if this intervention can reduce brain overactivity related to Alzheimer's disease risk by enhancing slow-wave activity during sleep.

Participant Groups

Group I: Time in Bed Restriction Experimental Treatment 2 Interventions

Time in Bed (TIB) restriction of 85% of habitual TIB.

Group II: Control Active Control 1 Intervention

Participants will follow their typical sleep schedule consistent with measured average sleep and wake times.

Who Is Running the Clinical Trial?

University of Pittsburgh

Lead Sponsor

Trials

1,820

Recruited

16,360,000+

National Institute on Aging (NIA)

Collaborator

Trials

1,841

Recruited

28,150,000+

Findings from Research

Many patients with Alzheimer's disease experience significant sleep disruptions, which may not only be a symptom of the disease but could also contribute to its progression.

Research suggests that addressing these sleep disturbances could potentially target underlying mechanisms of Alzheimer's, indicating that effective sleep interventions might help modify the disease course, although further large-scale studies are needed to confirm this.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sleep and its regulation: An emerging pathogenic and treatment frontier in Alzheimer's disease. Kent, BA., Feldman, HH., Nygaard, HB.[2022]

In a study of 46 institutionalized patients with severe Alzheimer's disease, morning bright light therapy significantly improved rest-activity rhythm in those with the most severe disruptions, indicating its potential as a targeted intervention.

However, the overall effectiveness of bright light therapy on sleep quality and rest-activity measures was limited, suggesting that it may not benefit all patients equally.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of morning bright light treatment for rest-activity disruption in institutionalized patients with severe Alzheimer's disease. Dowling, GA., Hubbard, EM., Mastick, J., et al.[2019]

In a study involving 10 Alzheimer's patients with severe sundowning, exposure to evening bright light for 2 hours a day significantly improved sleep-wake patterns in 8 out of 10 patients.

The treatment not only reduced nighttime activity but also increased the stability of the circadian rhythm, suggesting that bright light may help regulate sleep disturbances through a chronobiological mechanism.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bright light treatment of behavioral and sleep disturbances in patients with Alzheimer's disease. Satlin, A., Volicer, L., Ross, V., et al.[2015]

Accumulation of amyloid-β (Aβ) in the brain is a key factor in the development of Alzheimer's disease (AD), and sleep deprivation can increase Aβ levels, suggesting a link between sleep patterns and AD progression.

Individuals with early signs of Aβ deposition often experience sleep abnormalities, indicating that sleep disturbances may be an early indicator of Alzheimer's disease and highlighting the potential for sleep management in diagnosis and treatment strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sleep and Alzheimer disease pathology--a bidirectional relationship. Ju, YE., Lucey, BP., Holtzman, DM.[2022]

In a study involving 132 participants with Alzheimer's disease, interventions like walking, light exposure, and a combination of both showed significant improvements in total wake time compared to a control group, indicating potential benefits for sleep quality.

Better adherence to the walking and light exposure recommendations (at least 4 days a week) was linked to significantly less total wake time and improved sleep efficiency, highlighting the importance of consistent participation in these activities.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Increasing walking and bright light exposure to improve sleep in community-dwelling persons with Alzheimer's disease: results of a randomized, controlled trial. McCurry, SM., Pike, KC., Vitiello, MV., et al.[2022]

Accumulation of amyloid-β (Aβ) plaques in Alzheimer's disease is linked to increased sleep-wake disturbances, suggesting that Aβ pathology may disrupt normal sleep patterns.

Chronic sleep deprivation can worsen Alzheimer's disease by increasing amyloid plaque deposition, while improving sleep may help reduce plaque levels, indicating a potential therapeutic target for managing sleep disorders in AD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The sleep-wake cycle and Alzheimer's disease: what do we know? Lim, MM., Gerstner, JR., Holtzman, DM.[2018]

The article proposes new standards for identifying and naming sleep/wake cycle disturbances in Alzheimer's disease (AD) to improve research and treatment development, highlighting the significant impact these disturbances have on patients and caregivers.

The FDA has recognized the need for a comprehensive diagnostic system for behavioral problems in dementia, indicating that better-defined criteria could facilitate pharmacological research and lead to effective treatments for sleep disturbances in AD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Development of diagnostic criteria for defining sleep disturbance in Alzheimer's disease. Yesavage, JA., Friedman, L., Ancoli-Israel, S., et al.[2017]

In patients with moderate to severe Alzheimer's disease (AD), cerebrospinal fluid levels of orexin were significantly higher compared to controls, indicating a potential dysregulation of the orexinergic system as the disease progresses.

Higher orexin levels were correlated with greater sleep disturbances and cognitive decline, suggesting that the changes in orexin levels may contribute to the sleep-wake cycle disruptions commonly seen in AD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Orexinergic system dysregulation, sleep impairment, and cognitive decline in Alzheimer disease. Liguori, C., Romigi, A., Nuccetelli, M., et al.[2015]

In a study of 59 cognitively unimpaired older adults, traditional sleep metrics did not show differences between those with and without β-amyloid (Aβ) positivity, suggesting these measures may not be reliable indicators of preclinical Alzheimer's disease.

However, using a novel analysis method, researchers found that Aβ-positive participants exhibited distinct patterns of activity, including lower late-night activity and higher early morning activity, indicating potential alterations in rest/activity rhythms that could serve as markers for preclinical Alzheimer's.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Brain amyloid burden, sleep, and 24-hour rest/activity rhythms: screening findings from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's and Longitudinal Evaluation of Amyloid Risk and Neurodegeneration Studies. Spira, AP., Zipunnikov, V., Raman, R., et al.[2023]

References

1. England pubmed.ncbi.nlm.nih.gov

Sleep and its regulation: An emerging pathogenic and treatment frontier in Alzheimer's disease. [2022]

2. England pubmed.ncbi.nlm.nih.gov

Effect of morning bright light treatment for rest-activity disruption in institutionalized patients with severe Alzheimer's disease. [2019]

3. United States pubmed.ncbi.nlm.nih.gov

Bright light treatment of behavioral and sleep disturbances in patients with Alzheimer's disease. [2015]

4. England pubmed.ncbi.nlm.nih.gov

Sleep and Alzheimer disease pathology--a bidirectional relationship. [2022]

5. United States pubmed.ncbi.nlm.nih.gov

Increasing walking and bright light exposure to improve sleep in community-dwelling persons with Alzheimer's disease: results of a randomized, controlled trial. [2022]

6. England pubmed.ncbi.nlm.nih.gov

The sleep-wake cycle and Alzheimer's disease: what do we know? [2018]

7. United States pubmed.ncbi.nlm.nih.gov

Development of diagnostic criteria for defining sleep disturbance in Alzheimer's disease. [2017]

8. United States pubmed.ncbi.nlm.nih.gov

Orexinergic system dysregulation, sleep impairment, and cognitive decline in Alzheimer disease. [2015]

9. United States pubmed.ncbi.nlm.nih.gov

Brain amyloid burden, sleep, and 24-hour rest/activity rhythms: screening findings from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's and Longitudinal Evaluation of Amyloid Risk and Neurodegeneration Studies. [2023]