Key Dates

Related Announcements

• October 17, 2024 - Notice of NIAID Withdrawal of Participation from "Notice of Special Interest (NOSI): The Role of the Immune System in Aging Brain and Alzheimer's Disease (AD) and AD-Related Dementias (ADRD)", NOT-AG-24-010. See Notice NOT-AI-25-003.
• December 22, 2021 - Research on Current Topics in Alzheimer's Disease and Its Related Dementias (R01 Clinical Trial Optional). See NOFO PAR-22-093.
• December 22, 2021 - Research on Current Topics in Alzheimer's Disease and Its Related Dementias (R21 Clinical Trial Optional). See NOFO PAR-22-094.

Issued by

National Institute on Aging (NIA)

Purpose

Background

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 seventh leading cause of death in the United States. Prominent behavioral manifestations of AD include memory impairments and decline in other cognitive domains. Currently, more than 6 million Americans, most of them age 65 or older, suffer from 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 the recommendations of the 2018 Alzheimer’s Disease Research Summit Research Milestone 2.B: establish new research programs that employ data-driven, systems-based approaches to understand the interaction between peripheral systems (in particular: immune, metabolic, and microbiome) and the brain and the impact of this interaction on brain aging and neurodegeneration.

Neuroinflammation as a hallmark of AD and AD-related dementias (ADRD), including frontal temporal dementia, vascular contributions in dementia, and Lewy body dementias, is considered a manifestation of immune dysfunction. Innate immune cells have been considered as the primary contributors for the neuroinflammation in AD/ADRD, but recent studies point toward a significant role of the adaptive immune system. For example, it has been postulated that antigen-activated and differentiated CD8+ T cells play a role in the pathogenesis of AD mediated by their cytotoxicity and production of inflammatory cytokines. Little is known about the cross-talk between adaptive and innate immunity in the aging brain and brain with AD/ADRD.

The concept that the brain is an immune-privileged organ has been challenged. We understand today that immune privilege is conditional and that it varies regionally. It is recognized that the innate and the adaptive arms of immunity are present under the homeostasis of the central nervous system (CNS). While microglia constantly surveil the brain parenchyma, there are adaptive and innate immune cells (T and B cells, neutrophils and monocyte/macrophages) present in the parenchyma and at the brain borders. In neurodegenerative disorders, a series of changes occur in both the innate and adaptive immune system that may contribute to and/or exacerbate neurodegeneration. In AD, it is thought that the sequential extracellular depositions of amyloid beta and intracellular accumulation of hyperphosphorylated tau protein induce an innate immune response, leading eventually to changes in the integrity of the blood-brain barrier, cerebrospinal fluid (CSF)/blood, and lymphatic drainage. These changes may allow for the development of a potentially detrimental immune niche in both parenchyma and the brain borders with increasingly inflammatory signature.

This NOSI aims at a better understanding of brain immune surveillance and the generation of CNS-directed immune responses in neurodegenerative disorders, specifically the role of cross-talk between innate and adaptive immunity in AD/ADRD onset and progression. The goal is to shed light on the etiology of the immune imbalance (e.g., between peripheral adaptive and brain innate immune responses) typical of neurodegenerative disorders, with promising implications for therapy. These studies may ultimately help with AD/ADRD diagnostics, risk stratification, and discovery of immunotherapeutics.

Research Objectives

The goal of this NOSI is to explore the role of the adaptive immune system and innate immune system and their cross-talk in the etiology of AD/ADRD. This NOSI solicits human subjects and animal research across a broad range of topics and laboratory models. Research appropriate to this NOSI may include, but is not limited to, the following:

The roles of innate and adaptive immunity in the CNS in the onset and progression of AD/ADRD

Examples would include:

• Studies on the composition, phenotype (naïve, memory, activated), and antigen specificity of T and B cells in the CNS during the neurodegenerative processes.
• Characterization of T cells and microglia infiltrating protein aggregates in the aging and AD brain
• Characterization of B cells residing in AD/ADRD brain and their roles in AD onset and progression
• Role of neutrophils and mast cells in aging and AD/ADRD brain
• Characterization of antigen presenting cells (APCs) and identification of MHC class I and II peptides from APC, such as microglia and others in the aging and AD/ADRD brain
• Microglia and the role of the complement system in AD/ADRD
• Role of microglia and microglial genes in AD/ADRD pathogenesis
• Systematic characterization of disease-associated microglia (DAM) from various animal models of AD/ADRD

Additional Examples on T cells

• Systematic identification and characterization of the phenotype, differentiation state of T cells in the CSF and brain parenchyma of different AD mouse models
• Systematic identification and characterization of the clonally expanded T cells in the CSF in AD/ADRD in humans
• Systematic characterization of the specificity of clonally expanded T cell receptors (TCRs), including such approaches as machine learning to predict the potential antigens that may be recognized by these TCR sequences
• Determination of the role of clonally expanded TCRs and their targets in the pathogenesis of AD mouse models by adoptive transfer, and determination of their ability to alter the course of the disease
• Development of animal models to study the role of adaptive immunity in onset and progression of neurodegeneration (e.g., the role of CD8+ or CD4+ or MAIT or gd or Treg T cells in the pathogenesis of AD by crossing various AD models with specific T cell knockout mice)

Additional Examples on B Cells

• Systematic analysis of B cells in the brains of animal models of AD/ADRD (e.g., comparing the transcriptomes of B cells from meningeal border or brain parenchyma of AD/ADRD transgenics against the B cell subsets such as naive, activated, memory or plasma cells)
• Characterization of antibodies and antigen specificity of B cells from mouse brains of AD/ADRD models (e.g., establish single-cell Ig repertoire during onset and progression of neurodegeneration and compare it to the repertoire of pre-diseased and/or wildtype mice)
• Identification of changes to B cell subsets during AD/ADRD progression
• Characterization of human B cells in CSF from AD patients vs. healthy, age-matched controls (i.e, transcriptomic characterization of CD19/CD45+ cells)
• Characterization of antibodies and antigens from CSF of AD/ADRD patients (i.e., Ig repertoires and comparison to healthy age-matched controls)

Cross-talk between the cells of the peripheral immune system and adaptive/innate immune system in the AD/ADRD brain. The role of the peripheral immune system in the onset and progression of neurodegeneration. 

Examples would include:

• Determining the origins of the immune cells in the CNS (bone marrow vs local skull marrow, periphery vs local)
• Cell trafficking mechanisms and patterns in and out of the brain in AD vs a healthy aging brain
• Cross-talk of B and T cells AND/OR cross talk of the adaptive immune system and the innate immune system in the aging brain
• B cells as APCs, B cells and autoimmunity and AD/ADRD, origins and mechanisms of recruitment of B cells into the CNS during aging and AD/ADRD
• Studies on interactions between innate and adaptive immunity during neurodegeneration (e.g., microglia phenotypes and disease progression following manipulations of T and B cells)
• Studies on behavioral outcomes following manipulation of adaptive and innate immunity
• Development and employment of novel animal models to advance integrative research to understand how innate and adaptive immune systems interact in the CNS to impact brain aging and the initiation and progression of neurodegeneration in AD/ADRD (e.g., crosses of different animal models of AD/ADRD with animals lacking specific elements of the immune system, for example CD8+T cells or B cell-deficient AD mice)

Interactions between innate and adaptive immune systems at the brain borders (i.e, meninges, perivascular spaces, skull bone marrow, and choroid plexus) 

• Characterization in a systematic, integrative way of the nature of bi-directional communication between the central and peripheral lymphatic systems (e.g., to what extent the meningeal lymphatic vessels act as brain cellular afferent routes allowing immune cells to circulate through the meninges; mechanisms of how immune cells flow/fluctuate in meningeal lymphatic vessels during inflammation or during various stages of neurodegenerative processes; or to what extent the meningeal lymphatics play a role in trafficking of immune cells in and out of different brain compartments)
• Identification of the meningeal immune cells and establishment of their antigenic specificity, mechanisms that would maintain those cells within the meninges and meningeal lymphatics, and cytokine profiles of immune cell subtypes in the meninges and meningeal lymphatics in AD, and elucidation of whether age-related changes in brain lymphatics impact the immune cell repertoire in normal aging brain vs AD/ADRD brain
• Definition of molecular, cellular, and physiological changes in the peripheral lymphatic system during aging and their contribution to the development of AD

Application and Submission Information

This notice applies to due dates on or after November 12, 2024 and subsequent receipt dates through December 31, 2027. 

Submit applications for this initiative using one of the following notices of funding opportunities (NOFOs) or any reissues of these announcements 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)
• PAR-22-094 - Research on Current Topics in Alzheimer's Disease and Its Related Dementias (R21 Clinical Trial Optional)

All instructions in the SF424 (R&R) Application Guide and the notice of funding opportunity used for submission must be followed, with the following additions:

• For funding consideration, applicants must include “NOT-AG-24-010” (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.

Inquiries

Please direct all inquiries to the contacts in Section VII of the listed notice of funding opportunity with the following additions/substitutions:

Scientific/Research Contact(s)

Maja Maric, Ph.D.
National Institute on Aging (NIA)
Division of Neuroscience
Telephone: (301) 496-9350
Email: [email protected]

Lisa A. Opanashuk, Ph.D.
National Institute on Aging (NIA)
Division of Neuroscience
Telephone: (301) 827-5422
Email: [email protected]