Notice to Specify High-Priority Research Topics for PAR-18-596

Notice Number: NOT-AG-18-001

Key Dates
Release Date:   February 2, 2018

Related Announcements
PAR-18-596

Issued by
National Institute on Aging (NIA)

Purpose

This Notice of change specifies the high-priority topics of interest for the research objectives of PAR-18-596, "Research on Current Topics in Alzheimer's Disease and Its Related Dementias (R01 - Clinical Trial Optional)".

To reflect the inclusion of these topics, Section I. Funding Opportunity Description: Research Objectives, has been updated as follows:

Current Language
This Funding Opportunity Announcement (FOA) is inviting applications proposing research on current topics in Alzheimer's disease (AD) and its related dementias. Further information on the high-priority topics of interest will be announced through a series of notices published in late January and early February of 2018.

Applications proposing research on topics beyond those specified in the notices will not be prioritized for funding under this FOA. Investigators proposing such applications on topics that are not high priority are encouraged to apply to the parent R01 grant or to explore whether their topics would be appropriate for NIA's other AD-focused FOAs.

Revised Language
This Funding Opportunity Announcement (FOA) is inviting applications proposing research on current topics in Alzheimer's disease (AD) and its related dementias. The high-priority topics of interest are listed below. Applications proposing research on topics beyond those specified below are not appropriate for this FOA. Investigators proposing applications on topics that are not high priority are encouraged to apply to the parent R01 grant or to explore whether their topics would be appropriate for NIA's other AD-focused FOAs.

The high-priority topics of interest are:

1) Disparities in Quality and Access to Dementia Car

Note: This is a high-priority topic for both NIA and NINDS

Many persons with dementia (PWD) encounter challenges in gaining access to long-term services and supports (LTSS). Disparities in access and utilization may lead to, or exacerbate, adverse health outcomes. Disparities in acute care among different LTSS have been well documented, but with few exceptions have not been well delineated and explained. More research is needed to examine the extent to which individual, provider, or system-level characteristics combine to produce AD-related health disparities. Research is also needed to account for differences in quality and appropriateness of care as well as access.

Previous NIA FOAs have called for research on caregiving and assessing the impact of formal and informal care with attention to disparities. Research investments in this area have primarily been small-scale, qualitative studies, which are informative for defining and characterizing sources of disparities in formal and informal caregiving. Building on these previous investments, this high-priority topic encourages research involving large-scale, population-level, longitudinal cohorts to better explain disparities in service utilization and quality across multiple services and settings, and to place emphasis on outcomes for persons with dementia. Multiple dimensions of disparity may be addressed, including income, education, race and ethnicity, region, gender and living situations, and their interactions. For example, what explains disparities in adult day care utilization: socioeconomic status, family preferences, family structure, gender, race/ethnicity, access to information about services, and/or living in a rural or under-resourced area? Research should emphasize trajectories of care, not particular episodes or events like hospital readmissions. This information will allow policymakers and practitioners to implement methods to reduce disparities in access to high-quality dementia care.

NIA will support primary or secondary data analysis addressing disparities in service access and quality for persons with dementia. Analysis may be based on individual, local, state, national, or international-level data. Applications may focus on disparities in service utilization and quality across multiple dementia-care services (e.g., home health, nursing home care, adult day care, palliative care); across settings (e.g., home and community-based settings, nursing homes); or along multiple and intersecting disparities (e.g., income, gender, urban/rural, residence, region, race and ethnicity).

Examples of studies that are considered high priority include (but are not limited to) those that:

  • Identify the mechanisms and risk factors that explain disparities in service access and quality for persons with dementia and their caregivers.
  • Consider how institutional and social contexts influence disparities in service access and quality.
  • Leverage longitudinal data (such as NIA-funded data sources) or mixed-method data collection/analysis.

Applications that solely document descriptive disparity trends without addressing potential mechanisms or explanations would not be considered a high priority, nor would applications that focus solely on caregivers without considering dyadic and group processes and outcomes for PWD.

Applications proposing clinical trials in this topic of Disparities in Quality and Access to Dementia Care would not be considered a high priority.

2) Improving the Lives of Persons with Dementia (PWD): Impacts on PWD, Families, and Communities
Note: This is a high-priority topic for both NIA and NINDS
The current state of care for persons with dementia (PWD) leaves room for improvement—there is little continuity of care, and health care and long-term services and supports are expensive but likely variable and ineffective. Projections of future growth in the population of PWD indicate that these problems will only be exacerbated. This high-priority topic encourages research to better understand the desired outcomes of care of PWD across disease stages and etiologies.

There is a need for research that focuses on person-centered outcomes, the lived experience, and psychosocial processes of PWD. There is also a need to conduct research on families, caregivers, relationships, and networks impacted by dementia. The impacts of shifting roles and trajectories of care must be explored; research should be encouraged across the whole care spectrum. Research should begin to examine the supportive components of communities, especially Dementia-Friendly Communities, to better understand the impacts of the disease.

Three specific issues addressed by this topic include: burden of disease, including costs of care and other financial implications of disease; health outcomes, including quality of life of the person living with dementia; and community support. Research investigating these outcomes, and an emphasis on developing new measures and measurement approaches in these areas, is highly encouraged.

For burden of disease factors, research is needed that extends beyond broad societal costs, looking at the entire distribution of individuals affected by the disease rather than population averages. Trends and differences in expenditures and other burdens across regions, household types, socioeconomic statuses, and racial/ethnic groups are thus encouraged. Workforce dynamics should also be examined; both the shortage of formal caregivers in the community as well as the impacts of informal caregiver responsibilities on labor force participation are areas of concern.

For health outcomes, there exists a good amount of research about caregiver health but little research on the impact of dementia on the person with dementia (e.g., quality of life). It is particularly critical to explore the impacts of dementia on persons living alone, perhaps without a caregiver at all. Research that considers health impacts and how they might shape the relationships between PWD, their families/caregivers, and their communities is highly encouraged.

For community support, insufficient research has been conducted to understand the elements of the existing infrastructure (e.g. transportation services, meals on wheels, etc.) that provide necessary support to PWD, caregivers, and their families. Gaps that this initiative could address include determinants of the availability of a range of services for PWD and determinants of service utilization.

Applications considered high priority should stimulate research involving secondary data analysis, new data collection and data linkages, and measurement development, with an emphasis on variables relevant to persons with dementia (person-centered perspective), caregivers and families, and communities. Findings from this research are expected to inform the development of clinical and pragmatic trials as well as future analysis and data collection (e.g. using newly developed measures of PWD quality of life).

Examples of studies that are considered part of this high-priority topic include (but are not limited to) those that:

  • Identify costs of dementia and how they are met over the entire course of disease by individuals, families, communities, and/or health systems.
  • Identify trajectories of illness and impact on PWD.
  • Identify how impacts of LTSS differ for people living alone.
  • Identify how PWD, their families and caregivers define quality of life and health.
  • Identify which aspects of the community provide support to caregivers, families, and PWD.
  • Identify how regulatory and economic incentives affect access, quality, and health outcomes in health and long-term care systems for PWD.

Applications proposing clinical trials in the area of Improving the Lives of Persons with Dementia (PWD): Impacts on PWD, Families, and Communities would not be considered a high priority.

3) in vivo Synaptic Function in Alzheimer's Disease and Related Dementias
Note: This is a high-priority topic for both NIA and NINDS
Recent development of PET radioligands for a synaptic protein, SV2A, has established proof of concept for studying the synapse in living humans. This high-priority topic encourages the rapid testing and development of this potentially game-changing biomarker in AD and AD-related dementias (ADRD). This high-priority topic also seeks to advance the development of other methods to study synaptic structure and function in living humans.

The synapse is fundamental to brain function. Phenomena like long-term potentiation, neurotransmitter release, second messenger activation, and formation and pruning of dendrites during development all involve the synapse. Many tools have been developed to study synaptic morphology and function in living animals. Using intracranial confocal, 2 photon, and other in vivo microscopy methods, synaptic structure and function have been studied in animal models of neurodegeneration. However, nothing comparable has been possible in humans. Our understanding of synapses in the human brain has been limited to post-mortem examinations. We have not been able to study synaptic structure or function in living humans.

Scientists have developed PET radioligands based on levetiracetam (Keppra), an anticonvulsant that acts at synaptic vesicular protein 2A (SV2A). Since SV2A is found in presynaptic nerve terminals throughout the brain, it could serve as a marker of synaptic density or integrity. Loss of synapses should be reflected in decreased SV2A binding. 

11C-UCB-J binds with high affinity to SV2A. Recent data, including preliminary studies in AD, using 11C-UCB-J PET have been tantalizing but require replication, validation, and exploration, particularly longitudinal studies in larger cohorts. As demonstrated in the 1990s and reconfirmed in the 2000s, the earliest change in AD (detectable post mortem) appears to be loss of presynaptic terminals. Important, unanswered question include: when does synapse loss occur in relation to the appearance of ß-amyloid plaques, tau tangles, and other biomarkers? What are the regional relationships? What happens in normal aging or in other neurodegenerative diseases? What are the limitations of 11C-UCB-J PET: does it provide unique information, not available from existing methods, like FDG PET or volumetric MRI?

11C-UCB-J PET provides proof of concept for in vivo study of synapses in human. A second goal of this high-priority topic is to encourage the development of other methods to study in vivo synaptic structure or function in humans, using, for example, novel neuroimaging, PET and MRI methods, neurophysiological (EEG, MEG, ERPs) measures, or some other new technique. Studies of neurotransmitter receptors (e.g., raclopride D2 PET, or DASB SERT PET) would not be considered high priority, unless the research aim is to understand synaptic structure or function. The development of novel fluid biomarkers measuring overall synaptic damage (e.g., CSF NfL) would also not be considered high priority.

Preclinical or animal studies could be appropriate for either of this topic's aims. This topic is appropriate for applications that already have preliminary data.

Applications proposing clinical trials in the area of in vivo Synaptic Function in Alzheimer's Disease and Related Dementias would not be considered a high priority.

4) Genetic Underpinnings of Endosomal Trafficking as a Pathological Hub in Alzheimer's Disease and Alzheimer's Disease-Related Dementias (AD/ADRD)
Note: This is a high-priority topic for both NIA and NINDS
AD is defined, in part, by the appearance of extracellular amyloid deposits. Supported by genetic studies, the amyloid cascade is the leading hypothesis for the cause and pathogenesis of AD. Despite the intensive efforts that have been made in understanding amyloid and other pathological processes in AD, current approved interventions for AD have shown only modest effects in modifying clinical symptoms; none have been efficacious for slowing disease progression.

Recent developments in the field of genetics have significantly advanced understanding of the etiology of AD; more than two dozen genes are now known to be associated with late-onset AD (LOAD). Using a combination of genome wide association study (GWAS), exome chip, imputation, whole exome sequencing (WES), and whole genome sequencing (WGS), a number of AD genetic “hubs” have recently begun to emerge that may explain some of the bases for the development of the disease. Hubs include the well-known amyloid precursor processing (APP) pathway and the less understood genetic and genomic events associated with cholesterol metabolism, neuroinflammation and cellular immunity, and endocytosis pathways. Known genes that appear to be directly or indirectly associated with the endosomal compartment include APOEe4, SORL1, BIN1, ABCA7, EPHA1, and CD2AP. Some genes are observed in more than one pathway, leaving open the possibility that individuals with multiply affected pathways may be more vulnerable to the pathophysiology associated with AD.

A newly emerging model proposes that alterations in the way the cellular endosomal compartment processes amyloid precursor protein (APP) may represent a pathogenic hub for AD. This model suggests that therapies directed against extracellular amyloid plaques may fail because they are being administered too late in the disease process. Many AD genes directly or indirectly converge upon the endosomal genetic hub. Thus, the hub may act as a common pathway through which many downstream pathophysiological effects can be mediated. In-depth assessment of the genetic components related to the endosomal cellular trafficking pathway may help direct the research community toward novel alternative biological targets for therapeutic interventions.   

The goals of this high-priority topic are to encourage basic and translational research focused on the molecular, cellular, and physiological processes associated with the endosomal compartment in AD/ADRD. Studies funded under this topic will support research into AD/ADRD pathogenesis related to enhancing our understanding of how the genetic underpinnings of endosomal trafficking in AD/ADRD may act as a hub in the pathophysiological changes associated with the disease. The impact of changes in endosomal genetics on functional events, for example upon the generation of amyloid Beta (Aß) cellular processing, are important factors to be evaluated. This includes both the amyloidogenic and non-amyloidogenic pathways. All phases of endosomal processing during early through late processing stages are of interest, including those genes/events that may affect the cell membrane; early, mature, and late endosomes; the retromer/recycling pathway; the retrograde pathway/trans Golgi network; the lysosome, endolysosome, and multi-vesicular body; receptors related to cellular trafficking and cell sorting; and other related cell processing components. Applications that delineate cellular gene ontology networks and determine the weight of their impact upon endosomal processing are of interest.

Areas of research interest and opportunity that would be considered high priority under this topic include, but are not limited to:

  • Improved characterization (in vivo/in vitro) of the functions of known endosomal genes and their impact upon AD/ADRD pathophysiology.
  • Identification and characterization of novel genes not presently known to be associated with the endosomal compartment. 
  • Analysis of existing whole genome and whole exome sequence data such as that generated by the Alzheimer's Disease Sequencing Project (ADSP; see ADSP Study Design) to identify genetic variants and their function in known and novel endosomal genes. 
  • Determination of the impact of changes in endosomal genetics on functional events (amyloidogenic and non-amyloidogenic) in cellular trafficking in AD/ADRD.
  • Definition and characterization of the relationship between genes associated with AD/ADRD and endosomal processing in specific neural cell populations; this includes neurons (soma, axonal, and/or dendritic) and glia.
  • Characterization of cell types affected by changes in endosomal processing by physiological measures such as changes in neural activity.
  • Identification and characterization of the impact of genes and networks of genes that are outside of the endosomal pathway to determine their links to endosomal trafficking in AD/ADRD.
  • Delineation of cellular gene ontology networks related to endosomal processing and determination of the weight of their impact upon endosomal processing and pathophysiology.
  • Identification of cellular networks and brain regions that are selectively vulnerable to changes in endosomal processing in AD/ADRD.
  • Improvement of our understanding of how clusters of genes in the endosomal pathway may change endosomal trafficking resulting in pathological events in AD/ADRD; this includes a better understanding of how genes that act in more than one pathway impact endosomal processing, and a better understanding of converging and cascading pathways related to the endosomal compartment and how they may impact AD/ADRD pathophysiology.
  • Analysis of in vivo and in vitro outcomes of interventions that are directly designed to increase traffic flow through the endosomal compartment and that may serve as models for therapeutic approaches in AD/ADRD.
  • Identification of novel therapeutic targets associated with the endosomal compartment using existing and new in vivo and/or in vitro approaches. 
  • Improvement of our understanding of how known and newly identified protective variants associated with the endosomal compartment may be leveraged into therapeutic targets for AD/ADRD.
  • Determination of whether the amyloid hypothesis, when seen through the lens of genetic changes in endosomal processing, can identify useful therapeutic targets that can be applied at the earliest possible stage in the disease process.
  • Determination of whether/how the endosomal compartment may act as a common pathway through which downstream pathophysiological events in AD/ADRD can be mediated.
  • Comprehensive analysis of how single-cell transcriptomic (e.g. RNAseq), epigenetic (e.g. chromatin remodeling, DNA methylation), and/or genomic (e.g. sequencing for mutations) events impact neurons and glial cells and are related to changes in the endosomal compartment.
  • Novel multidisciplinary technological approaches to assess changes in the endosomal compartment in AD/ADRD.
  • Analysis of trans-synaptic spread (e.g. by exosomes) in AD/ADRD that may be mediated by genetically modulated changes in endosomal trafficking.

Applications proposing clinical trials in the area of Genetic Underpinnings of Endosomal Trafficking as a Pathological Hub in AD/ADRD would not be considered a high priority.

5) Collaborative Studies on Alzheimer's Disease and Alzheimer's Disease-Related Dementias (AD/ADRD)
Note: This is a high-priority topic for both NIA and NINDS
The National Institute on Aging engaged leading experts from academia, industry and non-profit foundations, working in Alzheimer’s and other complex diseases, in a strategic planning process to help ensure that the next generation of Alzheimer's Disease Centers (ADCs) is poised to accomplish the goals of the National Alzheimer’s Plan. The resulting recommendations included several specific ideas centered around collaboration, including developing greater opportunities for collaborations across the ADCs, increasing interactions with other center programs, and making the resources at the ADCs available to outside investigators.

Building on this notion, this high-priority topic provides the opportunity to facilitate collaborative cross-disciplinary and multi-institutional approaches that will contribute new and vital information about the clinical and pathological course of both normal aging and AD/ADRD. Scientists within and outside the ADCs can gain access to unique resources (such as the availability of neuropathological data on thousands of participants) as well as support the collection and integration of new data and samples. This topic supports collaboration among investigators and a wider participation in the design, analysis and interpretation of studies utilizing these unique resources, further leveraging the existing investment. Applications may build on existing resources and data to answer a broad range of scientific questions. Project data may be used for new grants and/or provide standardization or methodologic development of value to AD and ADRD research goals.

This topic facilitates the wider sharing and leveraging of resources available through Alzheimer's Disease Centers, as well as of other existing resources, including, but not limited to: MODEL-AD, AMP-AD, M2OVE-AD, National Alzheimer's Coordinating Center (NACC), National Cell Repository for Alzheimer's Disease (NCRAD), Alzheimer's Disease Genetics Consortium, NIA Genetics of Alzheimer’s Disease Data Storage Site (NIAGADS), the Alzheimer's Disease Sequencing Project, and those available at other NIH and NIA funded centers, such as Udall Centers, Pepper Centers, Roybal Centers, Shock Centers and RCMARs. Applications considered high priorities for this topic may also leverage existing longitudinal cohort studies with data relevant to AD/ADRD (e.g., the Health and Retirement Study, the National Health and Aging Trends Study, Rochester Epidemiology Project, MIDUS and studies participating in the Integrative Analysis of Longitudinal Studies of Aging and Dementia (IALSA)).

Applications in the area of Collaborative Studies on AD/ADRD that either propose clinical trials or do not propose clinical trials may be considered a high priority.

6) Deciphering the Glycosylation Code of Alzheimer's Disease
Note: This is a high-priority topic for both NIA and NINDS
Glycosylation is a post-translational modification in which a sugar (or carbohydrate) is attached to a hydroxyl or other functional groups of a macro molecule (such as DNA, lipids and proteins). Most glycosylated proteins are glycosylated in the rough endoplasmic reticulum (ER) or Golgi by glycosyltransferases. Likewise, specific serine or threonine hydroxyl moieties on nuclear and cytoplasmic proteins can be modified by N-acetylglucosamine (O-GlcNAc) transferase (OGT), which adds a single sugar N-acetylglucosamine. Glycosylation is known to affect various cellular and physiological functions including regulation of enzymatic activities, cell differentiation and morphogenesis. 

Currently, approaches for both basic and clinical biology of AD are largely focused on disease-related changes at the genomic, epigenetic, transcriptomic, and proteomic level(s). However, there are many different aspects of biology and cellular biochemistry that cannot be explained by these types of systems approaches. Glycosylation and complex carbohydrates have been reported to play many critical roles in the early pathogenesis and progression of AD, but the potential of these molecules to serve as biomarkers and targets of disease intervention remains largely unexplored. 

Recent studies have also suggested that the deficiency of a sulfotransferase for sialic acid-modified glycan could mitigate AD pathology and binding of Aß to various AD-risk glycoproteins such as TREM2, which are likely regulated by the change of glycans on these molecules as well. Small molecules that are known to block the interactions of Aß and glycans have been shown to increase survival advantage of neurons in mouse models of AD. Together, these findings indicate the potential of glycomic aberrations as potential biomarkers and targets of disease prevention. Despite the importance of glycosylation and altered glycan structures in AD, the aberrant molecular and biochemical function of these glycosylated molecules to serve as disease modifiers remain largely elusive. 

Traditionally, it has been very difficult to study and monitor the alteration of glycosylation and glycans in relation to aging and early initiation of AD. However, several recently developed technologies now allow one to systematically monitor the change of protein glycosylation and glycans in various biological fluids from large number of individuals. Therefore, the goal of this high-priority topic is to invite research projects using state-of-the-art methods of protein carbohydrate analyses to understand the potential impact of glycosylation on the etiology of AD and biomarker discovery.

Areas of high program relevance include, but are not limited to:

  • Precise biochemical and molecular mechanisms of altered glycan structures underlying the propagation of pathological protein assemblies in AD, including the role of glial cells and other non-neuronal cell types.
  • Molecular, cellular, and physiological studies of glycobiology to define the functional sequences of genetic risk factors for AD.
  • Understanding the roles of extracellular matrix and proteoglycans in modulating synaptic degeneration and accumulation of AD-related pathologies. 
  • Impact of microenvironment, such as plaque accumulation, on altered glycans and their roles as potential biomarkers and disease modifiers.
  • Consequences of aberrant glycosylation on the unfolded protein response and protein homeostasis.
  • Understanding the roles of chronic inflammation and immune surveillance in response to altered glycans during the course of AD.

Applications in the area of Deciphering the Glycosylation Code of AD that either propose clinical trials or do not propose clinical trials may be considered a high priority.

7) Geroscience Approaches to Alzheimer's Disease: Acceleration of Phenotypes in Asymptomatic Models of AD
Note: This is a high-priority topic for both NIA and NINDS
The basic biology of aging affects the functional performance of all organs in the body, including the brain. The field of geroscience aims to understand, at the cellular and molecular level, the interconnections between aging and disease/disabilities, with a focus on understanding the mechanisms by which aging is the major risk factor for most chronic diseases. The geroscience hypothesis posits that manipulation of aging will simultaneously delay the appearance or severity of multiple chronic diseases because these diseases share the same underlying major risk factor: the aging process.

Recent progress in the field of aging biology has allowed researchers to develop robust behavioral, genetic and pharmacological approaches to expand the lifespan of multiple species. Importantly, interventions that extend lifespan often result in improvements in multiple aspects of healthspan, resulting in significant delays in the appearance of pathology and frailty. Conversely, when lifespan is shortened, diseases and frailty occur earlier. In other words, disease susceptibility scales with the lifespan of the organism.

As for other chronic diseases of the elderly, AD is not an exception in that aging is the major risk factor for sporadic AD, and as mentioned, this risk is the centerpiece of the geroscience hypothesis. Importantly, modifying the rate of aging has already been shown to modify resilience to pathological challenges, including in genetic mouse models of AD. Understanding the role of the basic biology of aging thus provides new venues for research and inquiry into the etiology of this disease. A better understanding of the role of aging biology in the advent of AD might also lead to badly needed new therapeutic approaches.

AD is a progressive, multifactorial disease with multiple symptoms, the best-recognized of which is neurodegeneration. In addition to plaques and tangles formed in the brain, AD patients have symptoms in other tissues, potentially linked to the AD genes but of unknown relationship to the dementia itself, suggesting that the disease is systemic, and as such, it might be susceptible to interventions that act systemically. Indeed, there is substantial evidence in the literature indicating that Alzheimer’s patients develop multiple diseases and functional decline in peripheral systems, often before the onset of overt neurologic disease.

This high-priority topic aims to test whether interventions known to systemically affect the rate of aging are effective as modulators of the incidence, progression, etiology and treatment of AD. The goal of this topic is to fund several independent teams that will perform research to advance our understanding of the role of aging in the development and etiology of AD, using approaches that manipulate the rate of aging via behavioral, genetic, or pharmacological interventions, and using animal models developed for AD. Researchers are encouraged to test whether a more robust phenotype can be induced in genetically modified mice that were expected to be good mouse models of AD but that failed to produce the expected level of cognitive decline. Non-rodent models of AD, including invertebrates, are also welcome.

Researchers have identified a handful of hallmarks of aging, and tools exist to exacerbate these deteriorative processes in animal models, such as induction of cell senescence, inhibition of proteostasis, chronic inflammation and others. These interventions often lead to accelerated aging, appearance of disease, and decreases in resilience. Thus, the goal is to learn whether acceleration of the aging process can accelerate phenotypic deterioration in these animal models. Approaches might include modulation of one or more pillars of aging, such as reducing proteostasis or inducing inflammation, genetic manipulations such as Ercc1 KO or the IL-10+/- mice, or behavioral acceleration of aging (e.g., by high-fat diet feeding). The intent is to produce robust and more realistic animal models of the disease, where the interplay between aging and the disease-specific pathways such as Abeta and Tau can be explored, including their effect in both cognitive and peripheral functions.

In summary, this topic will support research to test whether interventions that accelerate the rate of aging can exacerbate AD-like phenotypes in animal models that do not show such phenotypes. Applications appropriate for this topic will be expected to include, at a minimum, expertise in basic aging biology, geroscience, animal models, and AD.

Applications proposing clinical trials in the area of Geroscience Approaches to Alzheimer's Disease: Acceleration of Phenotypes in Asymptomatic Models of AD would not be considered a high priority.

8) Geroscience Approaches to Alzheimer's Disease: Delay of Phenotypes in Current Models of AD
Note: This is a high-priority topic for both NIA and NINDS
The basic biology of aging affects the functional performance of all organs in the body, including the brain. The field of geroscience aims to understand, at the cellular and molecular level, the interconnections between aging and disease/disabilities, with a focus on understanding the mechanisms by which aging is the major risk factor for most chronic diseases. The geroscience hypothesis posits that manipulation of aging will simultaneously delay the appearance or severity of multiple chronic diseases because these diseases share the same underlying major risk factor: the aging process.

Recent progress in the field of aging biology has allowed researchers to develop robust behavioral, genetic and pharmacological approaches to expand the lifespan of multiple species. Importantly, interventions that extend lifespan often result in improvements in multiple aspects of healthspan, resulting in significant delays in the appearance of pathology and frailty. Conversely, when lifespan is shortened, diseases and frailty occur earlier. In other words, disease susceptibility scales with the lifespan of the organism.

As for other chronic diseases of the elderly, AD is not an exception in that aging is the major risk factor for sporadic AD, and as mentioned, this risk is the centerpiece of the geroscience hypothesis. Importantly, modifying the rate of aging has already been shown to modify resilience to pathological challenges, including in genetic mouse models of AD. Understanding the role of the basic biology of aging thus provides new venues for research and inquiry into the etiology of this disease. A better understanding of the role of aging biology in the advent of AD might also lead to badly needed new therapeutic approaches.

AD is a progressive, multifactorial disease with multiple symptoms, the best-recognized of which is neurodegeneration. In addition to plaques and tangles formed in the brain, AD patients have symptoms in other tissues, potentially linked to the AD genes but of unknown relationship to the dementia itself, suggesting that the disease is systemic, and as such, it might be susceptible to interventions that act systemically. Indeed, there is substantial evidence in the literature indicating that Alzheimer’s patients develop multiple diseases and functional decline in peripheral systems, often before the onset of overt neurologic disease.

This high-priority topic aims to test whether interventions known to systemically affect the rate of aging are effective as modulators of the incidence, progression, etiology and treatment of AD. The goal of this topic is to fund several independent teams that will perform research to advance our understanding of the role of aging in the development and etiology of AD, using approaches that manipulate the rate of aging via behavioral, genetic, or pharmacological interventions, and using animal models developed for AD.

Researchers are encouraged to use commonly used AD models that display neuronal AD phenotypes, such as triple transgenic, Tg2576, 5x FAD mice, and others. In addition, non-rodent models of AD, including invertebrates, are also welcome. NIA also strongly encourages the use of new models being developed by the MODEL-AD consortium. In other words, the goal is to test whether appearance of AD symptoms, both in the brain and the periphery, scale with lifespan in animal models of AD. Such a scaling of lifespan and healthspan has been shown to occur in other disease models and across a large portion of the phylogenetic scale. Specifically, researchers have identified a handful of hallmarks of aging, and tools exist to decelerate these deteriorative processes in multiple species, including behavioral approaches such as caloric restriction and CR-mimicking diets, as well as genetic (reduction in IGF-1 or mTOR, or activation of sirtuins, for example) and more recently, multiple pharmacological approaches, including those identified by the NIA Interventions Testing Program (rapamycin, 17alpha estradiol, acarbose) and others such as senolytics or NAD+ enhancing drugs. These interventions have been shown to lead to an apparent slowing of the aging process, accompanied by a delayed appearance of multiple diseases and improved resilience.

Projects supported through this high-priority topic are expected to include, at a minimum, expertise in basic aging biology, geroscience, animal models and AD.

Applications proposing clinical trials in the area of Geroscience Approaches to Alzheimer's Disease: Delay of Phenotypes in Current Models of AD would not be considered a high priority.

9) Data-Driven Approaches to Understand the Molecular Mechanisms of Neuropsychiatric Symptoms in Alzheimer's Disease and Related Dementias
Note: This is a high-priority topic for both NIA and NINDS
Individuals diagnosed with AD often suffer from a range of behavioral changes, referred to as neuropsychiatric symptoms (NPS); these symptoms include depression, anxiety, apathy, delusions, hallucinations, sleep disturbance, agitation, and aggression. NPS are common; they are present at all stages of the disease, including the prodromal stage, and cluster together. Components of NPS are known as mid-life risk factors associated with late-life dementia. NPS are often persistent and are associated with excess morbidity, mortality, increased health care use, and earlier institutionalization, as well as greater caregiver distress. Successful mitigation/treatment of NPS could delay disease onset and have a disease-modifying effect.

Despite having a large impact on the burden of disease, safe and effective long-term interventions for NPS are lacking. Nonpharmacological interventions are suggested as first-line treatment, but they are labor- and time-intensive and costly, resulting in pharmacological interventions consisting of off-label use of antipsychotics, sedative/hypnotics, anxiolytics, acetylcholinesterase inhibitors, memantine, and antidepressants; these treatments are often not efficacious and lead to significant adverse effects.

Lack of progress in the therapeutic arena is largely due to the poor understanding of the dynamic relationship and mechanistic links between NPS and AD. Recent advances in genetics, epigenetics/epigenomics, systems and network biology provide an opportunity to gain deep mechanistic insights in the dynamic relationship between NPS and AD and the molecular mechanisms underlying this comorbid condition.

This high-priority topic invites integrative data-driven approaches that utilize existing molecular and clinical data collected in clinical research (e.g., epidemiological studies, clinical trials for pharmacological and non-pharmacologic interventions) and/or generate rich multi-omic data and other patient-relevant data (including data collected with mobile devices and wearables) to build causal, predictive modes of the molecular interaction between NPS and AD/ADRD that can be used to identify therapeutic targets for novel drug discovery or drug repositioning aimed at ameliorating the neuropsychiatric symptoms in AD/ADRD.

The application of existing and novel computational methods for integration of multi-modal imaging data with molecular and other relevant patient data is encouraged. Applicants are also encouraged to integrate across in silico and experimental approaches and across human, cell-based, and animal model studies.

This topic aims to maximize the use of existing high-dimensional molecular and phenotypic data from aging cohorts and to leverage the use of data and biosamples from ongoing or legacy trials to generate new mechanistic insights and identify the molecular determinants of responder phenotypes.

Projects supported under this high priority topic should propose adequate annotation and curation of the molecular and clinical data types used and generated on the project to maximize the usability of the data by the broader research community for various types of meta-analysis and systems biology research.

In keeping with NIA's strategic goal to enhance transparency of reporting and enable reproducible and translatable discovery research, applicants are expected to make all data, analytical methods and outputs, and research tools available to the broad scientific community prior to publication via the NIA-supported AMP-AD Knowledge Portal or related NIA/NIH data repositories.

Applicants are strongly encouraged to consult with the NIA Scientific/Research contact staff early in the pre-submission process to ensure that their application is appropriate for the programmatic goals of this high-priority topic. 

Applications proposing clinical trials in the area of Data-Driven Approaches to Understand the Molecular Mechanisms of Neuropsychiatric Symptoms in AD/ADRD would not be considered a high priority.

 

In addition, Section II. Award Information, Funds Available and Anticipated Number of Awards is being amended to specify the funding available for each high-priority topic of interest.

Current Language
The number of awards is contingent upon NIH appropriations and the submission of a sufficient number of meritorious applications.

Revised Language
The number of awards is contingent upon NIH appropriations and the submission of a sufficient number of meritorious applications.

For the research on the high-priority topics of interest, NIA intends to commit the following funds in FY 2018:

  • Disparities in Quality and Access to Dementia Care, $3 million to fund 5-7 awards
  • Improving the Lives of Persons with Dementia: Impacts on PWD, Families, and Communities, $4,275,000 to fund 6-9 awards
  • in vivo Synaptic Function in AD/ADRD, $3 million to fund 1-3 awards
  • Genetic Underpinnings of Endosomal Trafficking as a Pathological Hub in AD/ADRD, $2.6 million to fund up to 5 awards
  • Collaborative Studies on AD/ADRD, $6 million to fund 3-5 awards. The awards are expected to vary in requested amount, dependent on the number of collaborators and size and scale of the project, including whether it will utilize existing data and/or samples or propose to develop new data and/or samples.
  • Deciphering the Glycosylation Code of AD, $6 million to fund 8-10 awards
  • Geroscience Approaches to AD: Acceleration of Phenotypes in Asymptomatic Models of AD, $2.7 million to fund 5-7 awards
  • Geroscience Approaches to AD: Delay of Phenotypes in Current Models of AD, $4 million to fund 8-10 awards
  • Data-Driven Approaches to Understand the Molecular Mechanisms of NPS in AD/ADRD, $6 million to fund 3-5 awards

All other aspects of this FOA remain unchanged.

Inquiries

For research on Disparities in Quality and Access to Dementia Care, as well as for research on Improving the Lives of Persons with Dementia: Impacts on PWD, Families, and Communities, please direct all inquiries to:
Elena Fazio, Ph.D.
National Institute on Aging (NIA)
Telephone: elena.fazio@nih.gov
Email: 301-496-3136

For research on in Vivo Synaptic Function in AD/ADRD, please direct all inquiries to:
John Hsiao, Ph.D.
National Institute on Aging (NIA)
Telephone: 301-496-9350
Email: jhsiao@nia.nih.gov

For research on Genetic Underpinnings of Endosomal Trafficking as a Pathological Hub in AD/ADRD, please direct all inquiries to:
Marilyn Miller, Ph.D.
National Institute on Aging (NIA)
Telephone: 301-496-9350
Email: millerm@nia.nih.gov

For research on Collaborative Studies on AD/ADRD, please direct all inquiries to:
Nina Silverberg, Ph.D.
National Institute on Aging (NIA)
Telephone: 301-496-9350
Email: silverbergn@mail.nih.gov

For research on Deciphering the Glycosylation Code of AD, please direct all inquiries to:
Austin Yang, Ph.D.
National Institute on Aging (NIA)
Telephone: 301-496-9350
Email: austin.yang@nih.gov

For research on Geroscience Approaches to AD: Acceleration of Phenotypes in Asymptomatic Models of AD, as well as for research on Geroscience Approaches to AD: Delay of Phenotypes in Current Models of AD, please direct all inquiries to:
Felipe Sierra, Ph.D.
National Institute on Aging (NIA)
Telephone: 301-496-6402
Email: sierraf@nia.nih.gov 

For research on Data-Driven Approaches to Understand the Molecular Mechanisms of NPS in AD/ADRD, please direct all inquiries to:
Suzana Petanceska, Ph.D.
National Institute on Aging (NIA)
Telephone: 301-496-9350
Email: petanceskas@nia.nih.gov