Notice of Special Interest (NOSI): Novel Approaches to Diagnosing and Studying Clinical Alzheimer's Disease and Related Dementias
Notice Number:

Key Dates

Release Date:

January 7, 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)
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)



Tremendous strides have been made in recent years in the study of the clinical neurobiology of Alzheimer’s disease (AD) and Alzheimer's disease-related dementias (ADRD). Biomarkers play a key role in understanding AD/ADRD and are crucial to translating basic neuroscience research into clinical settings. As such, biomarkers have become essential components in trials of disease-modifying therapies for AD. This Notice of Special Interest (NOSI) encourages research applications that develop and apply novel biomarkers to study the biology of AD/ADRD.

In the past, a definitive diagnosis of AD was only possible postmortem. Now, however, there are several techniques that allows us to detect AD/ADRD in living individuals. For example, positron emission tomography (PET) with beta-amyloid or Tau specific radioligands, or measurements in cerebrospinal fluid (CSF), can demonstrate the presence of beta-amyloid plaques or Tau tangles in vivo. Similarly, magnetic resonance imaging (MRI) can detect structural defects due to neurodegeneration, such as the localized thinning of cortical gray matter or loss of hippocampal volume. Vascular dementia (VD) can be identified by the presence of sub-cortical, lacunar infarcts, micro-infarcts or hemorrhages, and white matter hyperintensities. Structural MRI and 18F-fluorodeoxyglucose (FDG) PET can identify tissue loss or cerebral glucose hypometabolism. With techniques such as these, we are now able to diagnose AD in living individuals, even identifying prodromal or preclinical illness. The recently developed NIA/Alzheimer's Association A-T-N research framework characterizes dementia based on biomarkers: ‘A’, beta-amyloid; ‘T’, Tau; and ‘N’, Neurodegeneration.

Unfortunately, there are currently no identified biomarkers specific to Frontotemporal Dementia (FTD) or Lewy Body Dementia (LBD) that are comparable to the PET and CSF measures of the plaques and tangles of AD, or the MRI-detected changes in VD. As such, there is a need for antemortem biomarkers that can identify non-AD proteinopathies, such as alpha-synuclein Lewy Bodies (LBD, Parkinson’s Disease (PD), and multi-system atrophy (MSA)), non-AD Tau (FTD and chronic traumatic encephalopathy (CTE)), TDP-43 (FTD, amyotrophic lateral sclerosis (ALS), and spinocerebellar atrophy (SCA)), or huntingtin (Huntington’s Disease).

This lack of identified biomarkers constrains our ability to study ADRDs and limits our understanding of how neurodegenerative illnesses interact with one another to cause brain dysfunction. Autopsy studies consistently show that dementia (particularly in the oldest old) is rarely limited to AD plaques and tangles. As people age, more and more neuropathological abnormalities – VD, LBD, and TDP-43, along with AD – become evident.

It is important to recognize, however, that plaques and tangles, vascular changes, Lewy Bodies, and TDP-43 are also found at autopsy in people who were never identified as cognitively impaired during life. Neuropathogical signs of AD, VD, FTD, or LBD indicate neurodegeneration, but they do not diagnose dementia. There is no currently identified biomarker whose presence reliably distinguishes normal from abnormal brain function or cognition, and there is no established biomarker that robustly predicts or correlates with clinical decline. Biomarkers more closely tied to cognitive function, that might even serve as surrogate endpoints in dementia treatment trials, would be tremendously valuable.


The goal of this NOSI is to encourage the development of novel approaches to characterizing, diagnosing, and predicting outcomes in AD and ADRD. Examples of research that might be supported include, but are not limited to, the following:

  • Studies that improve antemortem characterization of dementia, particularly ADRDs
  • Studies that develop antemortem biomarkers to identify non-AD proteinopathies: a-synuclein (Lewy Bodies), FTD-Tau (4R and 3R), and TDP-43
  • Studies that focus on biomarkers that characterize dementia subtypes:
    • AD: Posterior cortical atrophy (PCA), hippocampal sparing, dysexecutive, etc.
    • LBD: Parkinson’s Dementia, REM sleep disorder, fluctuating levels of consciousness, etc.
    • FTD: Pick’s, BvFTD, PSP, CBD, FTD w/ MND, etc.
      • Tau vs TDP-43 FTD
  • Studies that provide new information about the pathophysiology of AD and/or ADRD
  • Biomarkers of inflammation and microglia function altered in AD or ADRD
  • Studies that characterize brain networks altered in AD or ADRD
  • Studies that identify common neurobiological mechanisms underlying concomitant symptoms and cognitive impairment in AD and ADRD
  • Biomarkers of neuropsychiatric symptoms
  • Movement disorders: FTD vs LBD vs AD
  • Aphasias: logopenic primary progressive aphasia can be AD or FTD
  • Studies that aim to identify a surrogate marker for cognition, or a dementia/cognition “stress” test
  • Studies that address shortcomings of currently used biomarkers
  • Studies further characterizing or understanding biomarkers, already validated or studied in AD or ADRD

Both clinical and preclinical studies may be supported by this NOSI.

Applications proposing clinical trials on this topic would not be considered a high priority.

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-21-036" (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)

John Hsiao, M.D.
National Institute on Aging (NIA)
Phone: 301-496-9350