January 11, 2022
PAR-22-093, Research on Current Topics in Alzheimer's Disease and Its Related Dementias (R01 Clinical Trial Optional)
Alzheimer’s disease (AD) is a progressive, degenerative disorder of the brain and is the most common form of dementia in older adults. AD is the sixth leading cause of death in the United States. Prominent behavioral manifestations of AD include memory impairments and decline in other cognitive domains. Currently, at least 6.2 million Americans age 65 and older are living with AD.
In response to this impending public health crisis, the National Alzheimer’s Project Act (NAPA) was signed into law in 2011. As part of the strategic planning process to implement NAPA, NIH AD Research Summits identified research priorities and strategies needed to accelerate basic research and the development of effective therapies. This Notice of Special Interest (NOSI) was developed in response to recommendations from the Alzheimer’s Disease Research Summits to create new research programs aimed at understanding the integrative physiology of circadian rhythms and sleep and its impact on brain aging and the risk of AD and AD-related dementias (ADRD) at multiple levels (e.g., epigenetic, gene expression, proteomic, neuronal, network, systems) to identify new targets and approaches for AD prevention (see 2015 AD Summit: 3J; 2018 AD Summit: 5E).
An estimated 70 million people in the United States suffer from a sleep disorder. About 30 million Americans experience chronic insomnia, and approximately 18 million experience sleep apnea; however, it is estimated that fewer than 50% of those are diagnosed. Difficulties with sleep are common complaints among the aging, as more than half of older Americans report chronic sleep problems.
Individuals living with AD often exhibit sleep disturbances and circadian clock disruptions. Although this has been interpreted as a consequence of AD, there is evidence that sleep disturbances may contribute to the risk of AD. For example, it has been demonstrated that preclinical signs of AD are often associated with poor sleep quality. Moreover, A accumulation in the brain predicts and exacerbates sleep disruption in humans and in animal models, and experimental manipulations to increase sleep result in decreases in A deposition. Such findings provide support for interventions that improve sleep in older adults to reduce the risk of developing AD. Effective interventions exist to improve sleep, and these could be tested in AD prevention.
While it appears that there is a bidirectional relationship between chronic sleep and circadian disruption and AD pathogenesis, and previous studies have established that humans with AD and mice with A pathology develop sleep and circadian dysfunction, little is known about the mechanisms involved.
The aim of this NOSI is to advance basic and clinical research on the causes and consequences of sleep deficiency and circadian clock dysfunction in AD/ADRD, and the roles of sleep and the circadian clock as modifiers of the onset and progression of neurodegeneration.
National Institute of Neurological Disorders and Stroke (NINDS)
NINDS supports research to better understand the bi-directional association between sleep disturbances/circadian disruption and Alzheimer’s Disease Related Dementias (ADRD), i.e., frontotemporal dementia, Lewy body dementia, vascular contributions to cognitive impairment and dementia, and multiple etiology dementias. For applications submitted to this NOSI that propose clinical trials, NINDS will support applications that propose human mechanistic trials/studies that meet NIH's definition of a clinical trial and that fall within the NINDS research priorities.
Areas of research appropriate to this Notice include, but are not limited to, the following:
- Explore molecular mechanisms linking disordered sleep and circadian disruptions with cognitive decline and AD/ADRD.
- Determine processes interrupted by disordered sleep and circadian disruptions that lead to AD/ADRD-related pathologies such as accumulation of protein aggregates, synaptic loss, or dendritic pruning.
- Test whether, and how, molecular and cellular processes, acute or chronic disruption of sleep, and/or circadian rhythms modulate accumulation and/or spreading of pathological protein aggregates.
- Assess how various patterns of neuronal activity and sleep architecture modulate accumulation and/or spreading of pathological protein aggregates.
- Explore how lack of sleep and circadian clock disruption contribute to severity of neurodegenerative diseases.
- Assess a bidirectional interaction between sleep and/or the circadian clock with neurodegenerative processes in AD/ADRD.
- Determine whether the improvement of sleep and/or circadian rhythms alter the course of neurodegenerative conditions and represent a modifiable risk factor that can alter disease progression.
- Identify the genetic variants that promote variations of sleep and circadian rhythms that may contribute to the risk of AD/ADRD.
Application and Submission Information
This notice applies to due dates on or after March 11, 2022 and subsequent receipt dates through November 13, 2024.
Submit applications for this initiative using the following funding opportunity announcement (FOA) or any reissues of the announcement through the expiration date of this notice.
- PAR-22-093, Research on Current Topics in Alzheimer's Disease and Its Related Dementias (R01 Clinical Trial Optional)
All instructions in the SF424 (R&R) Application Guide and the funding opportunity announcement used for submission must be followed, with the following additions:
- For funding consideration, applicants must include NOT-AG21-051 (without quotation marks) in the Agency Routing Identifier field (box 4B) of the SF424 R&R form. Applications without this information in box 4B will not be considered for this initiative.
Applications nonresponsive to terms of this NOSI will not be considered for the NOSI initiative.
Scientific/Research Contact(s)
National Institute on Aging (NIA)
Telephone: 301-496-9350
Email: miroslaw.mackiewicz@nih.gov
and Human Services (HHS)
