Notice Number: NOT-AG-19-033

Key Dates
Release Date: August 12, 2019
First Available Due Date: November 12, 2019
Expiration Date: November 13, 2021

PAR-19-070 Research on Current Topics in Alzheimer's Disease and Its Related Dementias (R01 Clinical Trial Optional)

PAR-19-071 Research on Current Topics in Alzheimer's Disease and Its Related Dementias (R21 Clinical Trial Not Allowed)

Issued by
National Institute on Aging (NIA)

Purpose

This Notice of Special Interest specifies a high-priority topic of interest for PAR-19-070 "Research on Current Topics in Alzheimer's Disease and Its Related Dementias (R01 Clinical Trial Optional)" and PAR-19-071 Research on Current Topics in Alzheimer's Disease and Its Related Dementias (R21 Clinical Trial Not Allowed) .

Note that applications proposing exploratory or developmental projects for which there are insufficient preliminary data should consider applying to the R21 FOA, whereas projects that already have sufficient preliminary data or a very strong and well-developed scientific premise should apply to the R01 FOA.

Selective Cell and Network Vulnerability in Aging and Alzheimer’s Disease

Background

Alzheimer's disease (AD) is the leading cause of dementia in those over the age of 65, and as many as 5 million Americans age 65 and older have AD. As the population ages, the number of people age 65 and older with AD is projected to increase between two- and three-fold by 2050 without development of a curative or preventative treatment. AD is one of the most persistent and devastating dementing disorders of old age because it eventually leads to a complete loss of memory and of the ability to function independently. Currently there are only a few interventions that have been approved for the treatment of AD. Those approved have demonstrated only modest effects in modifying the clinical symptoms for relatively short periods, and none has shown a clear effect on disease progression. In response to this looming public health crisis in the United States, the National Alzheimer's Project Act (NAPA) was signed into law in 2011. The primary research goal of the NAPA is to find effective interventions to treat and prevent AD and AD-related dementias (AD/ADRD) by 2025. As part of the strategic planning process for the implementation of the NAPA, two Alzheimer's Disease Research Summits entitled "Path to Treatment and Prevention" were held in 2012 and 2015. The overarching goal of the Summits was to bring together leading experts on AD to identify research priorities and strategies needed to accelerate the development of effective therapies across the disease continuum.

AD is a heterogeneous, multifactorial disease that selectively affects certain regions of the brain (e.g. the entorhinal cortex, hippocampus, and prefrontal cortex) while other areas, such as the cerebellum, remain unaffected. Selective vulnerability in the nervous system refers to the fact that subpopulations of neurons in different brain areas may be more or less susceptible to specific types of environmental or pathological insults leading to cell dysfunction or death. The factors underlying this selectivity in AD remain unclear. Recent studies on the staging of AD neuropathology showed AD-related tauopathy begins in the locus coeruleus, followed by neurofibrillary tangles in the entorhinal cortex, then hippocampal pyramidal neurons, and then neocortical neurons. Why is pathology seen in the locus coeruleus and entorhinal cortex at early stages of the disease? Why are specific neuronal cell types in these and other brain regions preferentially affected? What is it about these cells and their projections that make them susceptible to amyloid and tau pathology? Recent studies using an epigenetic biomarker of tissue age (known as the epigenetic clock), which is based on DNA methylation levels, showed that the cerebellum ages more slowly than other parts of the human body in a population of supercentenarians. How the cerebellum epigenetic clock compares with other brain area epigenetic biomarkers is unknown. Neuroimaging and anatomical studies have shown shrinkage or atrophy and synaptic changes in certain regions of the brain in aging and AD. Functional imaging studies are defining changes in large-scale neural and cognitive networks in the aging human brain and have shown, for example, specific disruption of the resting-state default mode network, compared to other networks, in AD. Glia cells--astrocytes, microglia, oligodendrocytes--are critical for many normal brain functions; for example, astrocytes and microglia modulate the sculpting and turnover of synapses in development, adulthood, and aging. Glial cell function changes with age and in AD; are specific types of glial cells or their regional diversity susceptible to AD pathological processes? Understanding the differential rate of brain regional and cellular aging will lead to novel insights into the molecular mechanisms of selective cell and network vulnerability to AD.

The selective vulnerability of specific cell types, and hence neural connectivity and network activity, is most likely due to the unique molecular properties of the affected cells. Molecular characterization of neurons at the single-cell level using immunolabeling, RNA in situ hybridization, and transgenic labeling approaches has provided unique insight into individual gene expression in different cell types in different areas of the mouse brain. Current single-cell gene expression profiling approaches can measure genome-wide transcriptomics in single cells. Integrated approaches have been described to sequence both genomic DNA and mRNA from the same cell, which would allow direct comparison of genomic variation and transcriptomic profiles in single cells. These single-cell genomic and molecular profiling approaches are critical to define and characterize mechanisms underlying selective cell vulnerability in aging and AD. Such molecular signatures will suggest or confirm cellular pathways that may mediate vulnerability to, or resistance against, pathological processes in specific brain cells and regions in aging and AD. For example, differential cell vulnerability might be expressed as differential adaptive responses to cell stressors (both internal and cell non-autonomous), calcium dyshomeostasis, mitochondrial/energy dysfunction, macromolecular damage, proteostasis disruption, and protein misfolding and aggregation. Differential excitability and connectivity properties of neuronal subpopulations and their sensitivity to stress and environmental factors may contribute to and control selective network vulnerability in AD.

Research Objectives

The goal of this initiative is to define and characterize neural cell populations (neurons and glia), neural activity and circuits, structural and functional networks, and brain regions that are vulnerable in brain aging and AD and the mechanisms underlying such selective vulnerability. Genetic and molecular signatures of different types of neurons and glial cells across the adult lifespan, in AD compared to other dementias of aging, and in different stages of AD will implicate cell processes and pathways mediating selective vulnerability to AD. Defining cell types by physiological measures such as electrophysiology and connectivity and manipulating neural activity in circuits and networks will provide a functional index of selective vulnerability. Applications are encouraged to use new approaches to generate sophisticated data on molecular signatures of brain cells and on structure and function of brain circuits and networks. Understanding the mechanisms underlying selective vulnerability from cells to networks in AD is critical to fully define the disease process and to develop effective therapies.

Areas of research interest and opportunity include, but are not limited to, the following:

• Identification of neural cell populations, brain regions, neural circuits, and/or large-scale networks (connectomes) that contribute to vulnerability in brain aging and AD.
• Comprehensive single-cell transcriptomics (e.g. RNAseq), epigenetics (e.g. chromatin remodeling, DNA methylation), and/or genomics (e.g. sequencing for somatic mutations) of neurons and glial cells in different brain regions at different ages and pathological stages of AD.
• Multidisciplinary and multiplexed technological approaches to single-cell 'omics,' electrophysiology, and connectivity for comprehensive and integrative studies of selective vulnerability to neuro- and glial-degeneration in aging and AD.
• Mechanisms underlying selective cell sensitivity to beta-amyloid, tau, and other proteinopathies, including cell-to-cell spread of pathogenic proteins and the role of proteostasis network function in selective cell and circuitry vulnerability.
• Role of cell-intrinsic versus cell non-autonomous and/or environmental factors in selective vulnerability or adaptive responses to cell or network stressors or neurodegenerative events.
• Role of differential activity and connectivity properties of neuronal populations, circuits, and networks in vulnerability (or resiliency) to aging and AD.
• Characterization of the molecular, cellular, synaptic, and neural circuitry mechanisms underlying brain plasticity and resilience in counteracting vulnerability to neurodegeneration in aging and AD.

Application and Submission Information

This Notice applies to due dates on or after November 12, 2019 and subsequent receipt dates through November 13, 2021.

Submit applications for this initiative using one of the following funding opportunity announcements (FOAs) or any reissues of these announcement through the expiration date of this Notice:

• PAR-19-070 - Research on Current Topics in Alzheimer's Disease and Its Related Dementias (R01 Clinical Trial Optional)
• PAR-19-071 - Research on Current Topics in Alzheimer's Disease and Its Related Dementias (R21 Clinical Trial Not Allowed)

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-AG-19-033 (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.

Inquiries

Please direct all inquiries to:

Bradley Wise, Ph.D.
National Institute on Aging (NIA)
Telephone: 301-496-9350
Email: [email protected]