A year-long clinical trial will test whether boosting slow-wave sleep can slow or reverse Alzheimer’s disease in people with early symptoms. Poor sleep is consistently linked to higher dementia risk, but no one knows whether improving sleep directly alters Alzheimer’s pathology in humans. This study tackles that gap head-on. It compares three interventions—a drug that increases slow-wave sleep duration, a drug that increases total sleep time without boosting slow-wave sleep, and auditory stimulation that intensifies slow-wave sleep without changing total sleep—against a placebo. Participants are people with prodromal Alzheimer’s, a window where mild cognitive problems exist but daily independence remains. The trial uses at-home sleep recordings, fluid biomarkers, MRI, EEG, and cognitive tests to track molecular and systems-level changes over one year. If slow-wave sleep modification reduces Alzheimer’s pathology, the results would de-risk a new class of treatments based on a novel mechanism. This could shift drug development toward sleep-enhancing therapies, delay disease onset, and improve quality of life for millions. The study also refines targets for preclinical models, advancing fundamental neuroscience on how sleep and neurodegeneration connect.
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Context Over 55 million people live with dementia, costing over US$1.3trillion worldwide. Alzheimer’s disease (AD), the commonest cause of dementia, is slowly progressive, with changes in the brain long before noticeable clinical symptoms. Earlier treatment is optimal for retaining independence and quality of life. There are three disease-modifying therapies licensed worldwide which slow decline by targeting the amyloid protein, but they are not very effective or widely funded, and their side-effects and cost often preclude treatment. New avenues for Alzheimer’s treatment are desperately needed. The Challenge Good sleep is not only key for general health and wellbeing. Many large-scale observational studies link poor sleep with increased future dementia risk. Disturbances to slow-wave (non-rapid eye movement; non-REM) sleep cause short-term reductions in cerebrospinal fluid dynamics and removal of potentially toxic Alzheimer’s-related proteins via the glymphatic system, and impair synaptic plasticity and memory consolidation. Interventional studies that restore slow-wave sleep may therefore slow or reverse Alzheimer's-associated pathologies in humans. Sleep is modifiable, but until the mechanism linking human slow-wave sleep to Alzheimer pathology is determined, clinical trials cannot be developed to protect against Alzheimer’s disease by enhancement of slow-wave sleep, or total sleep. The Strategy We propose a randomised, multi-arm, placebo-controlled, multi-site, one-year study of three interventions (4 arms) with defined effects on slow-wave sleep: trazodone (to increase slow-wave sleep duration); zolpidem (to increase total sleep time, but not slow-wave sleep); and phase-targeted auditory stimulation (to increase slow-wave sleep intensity without affecting total sleep duration). We will focus on individuals in the early clinical stages of Alzheimer’s (prodromal AD), a critical window for intervention where mild cognitive problems are present but daily independence is still maintained. People with mild symptoms are not routinely diagnosed or included in clinical trials, particularly those from underserved communities, despite higher impact of poor sleep on dementia risk in specific minority ethnic groups. State-of-the-art at-home sleep recordings, fluid biomarkers, Magnetic Resonance Imaging, electroencephalography and cognitive tasks combined with targeted inclusive recruitment strategies will give a window onto molecular and systems-level effects of sleep modification. Through this deep-phenotyping and proof-of-concept intervention, we build the evidence base and technological experience required for advanced and later-phase trials. Benefits We will generate crucial proof-of-concept data over an extended period which is long enough to demonstrate how sleep, and particularly slow-wave sleep, affects molecular, pathological, neurodegenerative, and synaptic changes in prodromal AD. This approach aims to de-risk and inform the development of new sleep-enhancing therapies while paving the way for larger, collaborative clinical trials with industry leaders, such as our project partner, AstronauTx. With Dementias Platform UK (DPUK), Dementia Research Institute (DRI) and Bristol Trials Centre infrastructure, expert clinicians and academics, know-how and funding from industry partners, and our diverse Patient and Public Advisory Group, our programme will be directly relevant to the drug development pathway addressing one of the biggest challenges faced by society and individuals: dementia. Our vision is a new class of tailored AD treatments based on a new mechanism of neurodegeneration. We will improve the effectiveness and accessibility of future treatments, delay disease onset and improve quality of life for millions with early AD. If slow-wave sleep modification impacts Alzheimer’s pathology, this will inform preclinical models by refining targets for drug development (e.g. 5HT2A modulation), and shaping future animal and cellular studies, advancing fundamental neuroscience.
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