Notice of Special Interest: Understanding Alzheimer's Disease in the Context of the Aging Brain
Notice Number:

Key Dates

Release Date:

December 30, 2021

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)
PAR-22-094 - Research on Current Topics in Alzheimer's Disease and Its Related Dementias (R21 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. Prominent behavioral manifestations of AD include memory impairments and decline in other cognitive domains. Age is a major risk factor for developing dementia, with imaging and biomarker data suggesting that the pathophysiological processes of AD begin more than a decade prior to the diagnosis of dementia. AD is a heterogeneous, multifactorial disease, and a challenge in AD research is to fully understand how the multiple etiologies and age-related prodromal processes contribute to the pathophysiology of AD. Knowledge of the mechanisms underlying the shift from healthy brain aging to the neurodegeneration of AD is imperative for the design and determination of effective interventions.

Changes in brain structure and function may continue throughout life, and studies at multiple levels of analysis in model organisms and humans are helping to define the normal trajectory of changes in the brain over the adult lifespan. Structural neuroimaging and anatomical studies of brain have shown declines in total gray and white matter, along with shrinkage or atrophy and synaptic changes in certain regions of the brain during aging. Functional imaging studies are defining the workings of large-scale neural and cognitive networks in the aging human brain, and have shown, for example, disruption of the resting-state default mode network, as well as putative compensatory recruitment of brain areas to sustain cognitive function. Human and animal studies suggest that adaptive or resilient processes (i.e., brain plasticity) may be needed for maintenance of brain structure and function during normal aging. At the molecular and cellular level of analysis in animal models, brain aging is associated with changes in gene and epigenetic expression, mitochondrial and energy metabolism, calcium regulation, protein homeostasis, glia, and neural plasticity and synaptic function. What remains unclear is when these normal aging changes transition to pathological aging and disease phenotypes. Complicating the understanding of the role of aging in AD is the fact that most studies employ adult, not aged, genetic animal models of disease. Integration of research at various levels of analysis, from cells to neural networks, in older adults and in appropriate animal and cell models is needed to reach a global understanding of brain aging and its contribution to, and promotion of, pathological processes underlying AD.


The goal of this Notice of Special Interest (NOSI) is to solicit applications that aim to establish the role and underlying mechanisms by which brain aging impacts the development and progression of AD. A comprehensive and integrative characterization of brain aging, including its crosstalk with peripheral systems and factors, will help to define the mechanisms underlying the shift from normal aging to pathological processes in the etiology of AD. To gain a deeper understanding of the complex biology and physiology of healthy and pathologic brain aging, cross-disciplinary, systems-based approaches using newly developed tools and technology to integrate findings on AD with research on the basic biology and neurobiology of aging are encouraged. Animal and human studies are appropriate for this NOSI.

Areas of research interest and opportunity include, but are not limited to, the following:

  • Characterize in a systematic, integrative way how aging processes (e.g., hallmarks of aging, genomic instability, epigenetic changes, senescence, macromolecular damage, mitochondrial/energy dysfunction, proteostasis dysfunction, calcium dyshomeostasis, loss of neural stem cells, inflammation/immunity, and alterations in stress responses) impact the development and/or progression of AD pathophysiology in brain.
  • Define genetic, molecular, and metabolic neural profiles in conjunction with behavioral profiles that distinguish normal brain aging from pathological aging.
  • Employ a lifespan approach to study the genetic, epigenomic, proteomic, lipidomic, metabolic, and other molecular changes during vulnerable periods/physiological transition states to understand the mechanisms behind protective and risk factors.
  • Characterize the role of the proteostasis network, intracellular organelle interaction, or cell-cell communication in brain protection and degeneration (e.g., due to proteotoxicity) in aging and AD.
  • Characterize the impact of age-related changes in glial cells (e.g., astrocytes, microglia, oligodendrocytes) and other non-neuronal cells in AD pathophysiology.
  • Identify neural cell populations, brain regions, neural circuits, and/or large-scale networks (connectome) that are vulnerable duringbrain aging and contribute to AD.
  • Define the age-related aberrant or compensatory neural activities in epileptogenic, sensory, motor, emotional, cognitive, or sleep systems that contribute to AD.
  • Characterize the molecular, cellular, synaptic, and neural circuitry mechanisms underlying brain plasticity (e.g. neurogenesis or adaptive cell stress response pathways) in aging and AD.
  • Elucidate molecular, cellular, and physiological changes in the brain glymphatic and lymphatic transport systems during aging and their contribution to the development of AD.
  • Integrate research aimed at understanding the epigenetics, genetics, molecular and cellular networks, neural connectivity, and complex biology of brain resilience and/or cognitive resilience in aging and AD.
  • Study the integrative physiology of sleep and whether disruption of sleep and/or circadian clock accelerates brain aging and AD neurodegenerative change.
  • Elucidate the short- and long-term consequences of disrupted and optimized sleep on brain aging and AD.
  • Elucidate the impact of sex differences on the trajectories of brain aging and AD.
  • Develop integrative research to understand how aging in peripheral systems (e.g., immune, endocrine, metabolic, microbiome) interact with the CNS to impact brain aging and the initiation and progression of AD neurodegenerative changes.
  • Develop and employ novel animal models, such as rodents, canines and non-human primates, which can spontaneously develop neuropathological signs of AD at older ages.
  • Use human cell reprogramming approaches (e.g., iPSCs) and 3D or organoid culture approaches to study molecular, physiological, and systems cell biology of aging and 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 one of the following funding opportunity announcements (FOAs) or any reissues of these 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)
  • 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 funding opportunity announcement used for submission must be followed, with the following additions:

  • For funding consideration, applicants must include NOT-AG-21-039 (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:

Scientific/Research Contact(s)

Erin Gray, Ph.D.
National Institute on Aging (NIA)
Telephone: 301-451-3968