January 6, 2022
National Institute on Aging (NIA)
Alzheimer’s disease (AD) is a progressive, degenerative disorder of the brain and is the most common form of dementia in older adults. In fact, 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, more than six million Americans age 65 and older live with 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, 2015, 2018, and 2021. During the summits, participants highlighted gaps and opportunities relative to basic research and the development of effective therapies. As a result of recommendations provided by participants, the AD+ADRD Research Implementation Milestones were developed. The milestones represent a research framework, and detail specific steps and success criteria that can be utilized to achieve the goal of treating and preventing AD and Alzheimer's disease-related dementias (ADRD) by 2025.
In response to the AD+ADRD Research Implementation Milestones, this Notice of Special Interest (NOSI) was developedto support interdisciplinary research to understand the heterogeneity and multifactorial etiology of AD. Specifically, this NOSI encourages basic and translational research focused on the molecular, cellular, and physiological processes underlying AD pathogenesis, and the genetic and epigenetic determinants of AD. Areas of interest 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 have shown effects on disease progression. As a result, key gaps and opportunities identified at the NIH AD Summit in 2015 suggest an expansion of 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 genes (e.g., 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. The apolipoprotein-E (APOE) genotype is a major risk factor in the 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 systems (e.g., cardiovascular, immune, metabolic, and microbiome), and environmental factors, will likely provide new insights in AD pathophysiology and individual susceptibility to develop AD.
The goal of this NOSI 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 NOSI 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, the following:
Application and Submission Information
This notice applies to due dates on or after March 11, 2022 and subsequent receipt dates through November 13, 2024.
Submit applications for this initiative using the following funding opportunity announcement (FOA) or any reissues of the announcement through the expiration date of this notice.
All instructions in the SF424 (R&R) Application Guide and the funding opportunity announcement used for submission must be followed, with the following additions:
Applications nonresponsive to terms of this NOSI will not be considered for the NOSI initiative.
Please direct all inquiries to:
Austin Yang, Ph.D.
National Institute on Aging (NIA)