PAR-19-071 - Research on Current Topics in Alzheimer's Disease and Its Related Dementias (R21 Clinical Trial Not Allowed)
NOT-AG-19-019 - Notice of Correction to NOT-AG-19-007, "Notice of Special Interest: High-Priority Research Topics for PAR-19-071

Issued by
National Institute on Aging (NIA)

Purpose

This Notice of Special Interest specifies two high-priority topics of interest for PAR-19-071 "Research on Current Topics in Alzheimer's Disease and Its Related Dementias (R21 Clinical Trial Optional)".

Capturing Complexity in the Molecular and Cellular Mechanisms Involved in the Etiology of Alzheimer's Disease

Background

Alzheimer’s disease (AD) is a progressive, degenerative disorder of the brain and is the most common form of dementia of the elderly. 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 five million Americans at age 65 and older suffer from AD, and it is projected that the number of new cases of AD will double by 2025. AD is clearly becoming a national health crisis affecting Americans across all regions of the country, and the total annual payments of health care for people with AD are projected to be more than $1 trillion in 2050. In response to this looming public health crisis, the National Alzheimer’s Project Act (NAPA) was signed into law in 2011. The primary research goal of NAPA is to prevent the onset of and develop effective treatments for AD by 2025. As part of the strategic planning process to implement NAPA, NIH AD Research Summits were held in 2012 and 2015 and identified research priorities and strategies needed to accelerate basic research and the development of effective therapies. A FY2017 Alzheimer’s disease bypass budget with milestones was published in 2015 (Bypass Budget Proposal for Fiscal Year 2017 | National Institute on Aging) to establish research and funding priorities in response to the NAPA and the AD Research Summits.

This high-priority topic was developed in response to the recommendations of the AD Research Summits and milestones in the AD bypass budget to support interdisciplinary research to understand the heterogeneity and multifactorial etiology of AD. Specifically, this topic encourages basic and translational research focused on the molecular, cellular and physiological processes underlying Alzheimer’s disease pathogenesis and the genetic and epigenetic determinants of Alzheimer’s disease. Areas include amyloid, tau, presenilins, ApoE and lipids, brain circuits and synapses, cell death, immunity and inflammation, bioenergetics, vascular/metabolic factors, hormones, and genetics.

AD is defined in part by the appearance of extracellular amyloid deposits and the accumulation of intracellular neurofibrillary tangles. Supported by genetic studies, the amyloid cascade hypothesis is the leading theory of the cause and pathogenesis of AD. Despite 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, and none has shown effects on disease progression. As a result, key recommendations developed from the NIH AD Summit in 2015 suggest to expand various innovative and systems-based omics approaches to identify alternative models of AD and disease-relevant therapeutic targets.

The etiology of AD is multifactorial and complex (e.g. genetic variants, protein homeostasis, vascular changes, sleep disruption, and gender differences contribute to disease phenotype). Many large-scale genome-wide association studies (GWAS) have identified a number of new genes, including BIN1, TREM2, CLU, PICALM, and CR1, that may increase a person's risk for late-onset AD, though the function of AD risk genes and genetic variants in causing or modifying AD pathology is unclear. Apolipoprotein E genotype is a major risk factor in development of sporadic and late-onset AD, yet we do not fully understand how it contributes to AD. A comprehensive understanding of how APOE and various AD risk factor genes contribute to the etiology of AD, as well as the role of sleep, vascular, and peripheral (e.g. cardiovascular, immune, metabolic and microbiome) systems and environmental factors is likely going to provide new insights in AD pathophysiology and individual susceptibility to develop AD.

Research Objectives

The goal of this high-priority topic is to support innovative research focused on understanding the molecular and cellular mechanisms underlying the heterogeneity and multifactorial nature of AD, with the potential to create new or to challenge existing scientific paradigms. This topic encourages individual and/or collaborative research projects that propose innovative approaches to understanding the complex biology of AD to fill critical knowledge gaps or to examine critical areas of AD biology that have not been adequately addressed in the past. Applicants are encouraged to use or develop state-of-the-art research and analytical tools and to integrate the use of human data and biosamples with cell-based and animal models.

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

• Molecular, cellular, and physiological studies to define the function of genetic risk factors for AD, including integrative physiological mechanisms of ApoE in AD.
• Comprehensive structural and functional characterization of various amyloid and tau variants by high resolution X-ray crystallography, cryo-EM, solid-phase NMR, and native protein mass spectrometry to identify structural basis underlying toxicity and spreading of misfolded protein aggregates.
• Molecular mechanisms underlying exosome-mediated AD pathogenesis and using exosome as a potential multicellular phenotyping tool for AD biomarker discovery.
• Molecular mechanisms underlying the propagation of pathological protein assemblies in AD, including the role of glial cells and other non-neuronal cell types in spreading of pathological protein assemblies.
• Molecular phenotyping and connectivity of single neural cells in human aging and AD brain using/developing methods (e.g. CLARITY-related approaches, axon tracing, RNAseq) for isolation and characterization (in vitro and in vivo) of neurons and glia.
• Systems biology of brain neural cells derived from human AD induced pluripotent stem cells and development of genetic, molecular and physiological milieu that mimics in vivo biology, e.g. 3D cell culture and aging.
• Define molecular omics signatures of neural cells, genotype-phenotype relationships, and environmental influences.
• Molecular mechanisms by which metabolic and vascular risk factors as well as blood brain barrier permeability impact the initiation and progression of neurodegenerative changes in AD.
• Molecular mechanisms underlying the impact of sleep deficiency and chronic circadian disruption in the etiology of AD.
• Molecular mechanisms of gender-specific differences in the initiation and progression of neurodegeneration in AD, and on modulation of genetic and environmental risk factors.
• Molecular mechanisms by which peripheral systems (e.g. immune, metabolic, microbiome) interact with the brain during aging and the impact of this interaction on the initiation and progression of neurodegeneration in AD.
• Development of standardized, cost-effective, high-throughput methods to isolate neural and glial cells for omics profiling and drug-screening.
• Determine the structural and functional roles of lipids and carbohydrates in modulating the early pathogenesis of sporadic AD.
• Development of the next generation of animal models (e.g. using genome editing) based on genetic and environmental risk and protective factors for AD.

Deciphering the Glycosylation Code of Alzheimer's Disease

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 A 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 A 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 that either propose clinical trials or do not propose clinical trials may be considered a high priority.

Submissions should indicate that they are in response to NOT-AG-19-007 in Field 4.b on the SF 424 form.

Inquiries

Please direct all inquiries to:

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