January 7, 2022
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 Not Allowed)
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:
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.
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.
John Hsiao, M.D.
National Institute on Aging (NIA)