Notice of Special Interest (NOSI): Capturing Complexity in the Molecular and Cellular Mechanisms Involved in the Etiology of Alzheimer's Disease
Notice Number:

Key Dates

Release Date:

January 6, 2022

First Available Due Date:
March 11, 2022
Expiration Date:
November 13, 2024

Related Announcements

PAR-22-093, Research on Current Topics in Alzheimer's Disease and Its Related Dementias (R01 Clinical Trial Optional)

Issued by

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.

Research Objectives

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:

  • Molecular, cellular, and physiological studies that aim to define the function of genetic risk factors for AD, including integrative physiological mechanisms of ApoE in AD.
  • Comprehensive structural and functional characterizations of various amyloid and tau variants by high resolution X-ray crystallography, cryo-EM, solid-phase NMR, and native protein mass spectrometry to identify the structural basis underlying toxicity and spreading of misfolded protein aggregates.
  • Molecular mechanisms underlying exosome-mediated AD pathogenesis and using the 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 the 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, single cell analsis and high resolution mass spectrometry imaging ) 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 the development of genetic, molecular, and physiological milieu that mimics in vivo biology (e.g., 3D cell culture and aging).
  • Studies that 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.
  • Studies that 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.

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.

  • PAR-22-093, Research on Current Topics in Alzheimer's Disease and Its Related Dementias (R01 Clinical Trial Optional)

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

  • For funding consideration, applicants must include “NOT-AG-21-041” (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.


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

Please direct all inquiries to:

Austin Yang, Ph.D.
National Institute on Aging (NIA)
Telephone: 301-496-9350