NIH – Role of Adaptive Immunity in Etiology of Alzheimer’s Disease and Alzheimer’s Disease-Related Dementias (R01 Clinical Trial Optional)

June 25, 2021 by


This Funding Opportunity Announcement (FOA) aims to explore the role of adaptive immunity in Alzheimer’s disease and Alzheimer’s disease-related dementias (AD/ADRD). Specifically, the FOA seeks an understanding of brain immune surveillance, the generation of CNS-directed immune responses in neurodegenerative disorders, and the functional role of adaptive immunity in AD/ADRD onset and progression.


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 5.6 million Americans age 65 and 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 Funding Opportunity Announcement (FOA) 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.

While the role of brain innate immunity and microglia in the pathogenesis of AD has been extensively studied, much less is known about the peripheral immune system in AD and Alzheimer’s disease-related dementias (ADRD) orchestrated by several cell types of the innate (i.e., macrophages, monocyte, neutrophils) and adaptive (i.e., CD4+ T cells, CD8+ T cells, B cells) branches of that system. It was nearly three decades ago when the first observations of T cells in AD brains were reported. In the years since, contrasting reports demonstrated presence or absence of T cells in the AD brain with a common ‘thread’ that T cells infiltrating the brain parenchyma in AD does not associate with either plaque or tangle pathology. Today, although still controversial, there is a growing body of evidence on the importance of the adaptive immune system in AD/ADRD pathogenesis. The sometimes conflicting results reported in animal studies emphasize the need to understand the heterogeneity of Aβ-specific T cell responses in different genetic backgrounds and major histocompatibility complex (MHC) context. The role of different CD4+ T cell types in AD/ADRD pathogenesis also remains controversial; CD4+ Th1 cells and CD4+ Th2 cells in models of AD may have different effects on pathology and behavior. Recent observations that clonally expanded CD8+ T cells are present in the cerebrospinal fluid (CSF) of AD patients suggest a role of CD8+ T cells in AD pathogenesis, though it is not clear whether CD8+ T cells are secondary to the disease process or actually play a pathogenic or disease-modifying role in AD.

The above considerations highlight the importance of the adaptive immune system in AD/ADRD as well as some unanswered questions and controversies regarding adaptive immune responses in the context of neurodegenerative diseases. A deeper mechanistic understanding of the immune processes that are at play could facilitate the development of innovative immunotherapies for AD/ADRD. This RFA opens the way to a better understanding of brain immune surveillance and the generation of CNS-directed immune responses in neurodegenerative disorders, specifically the functional role of adaptive immunity in AD onset and progression. It will 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 help with AD diagnostics, risk stratification, and discovery of immunotherapeutics.

Key Dates:

Open Date (Earliest Submission Date): September 28, 2021
Letter of Intent Due Date(s): September 28, 2021
Application Due: October 28, 2021

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Filed Under: Funding Opportunities