Key Dates

Related Announcements

• December 30, 2024 - Research on Current Topics in Alzheimer's Disease and Its Related Dementias (R21 Clinical Trial Optional). See NOFO PAR-25-331.
• December 30, 2024 - Research on Current Topics in Alzheimer's Disease and Its Related Dementias (R01 Clinical Trial Optional). See NOFO PAR-25-332.
• January 7, 2022 - Notice of Special Interest (NOSI): Novel Approaches to Diagnosing and Studying Clinical Alzheimer's Disease and Related Dementias. See Notice NOT-AG-21-036. 

Issued by

National Institute on Aging (NIA)

Purpose

Background

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

In the past, a definitive diagnosis of AD or ADRD was only possible postmortem. Now, however, there are neuroimaging and fluid biomarkers that allow the diagnosis of AD/ADRD neuropathology in living individuals, even identifying prodromal or preclinical illness. The Alzheimer's Association A-T-N research framework uses biomarkers for amyloid-beta (A), tau (T); and neurodegeneration (N), to characterize AD. 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. Blood biomarkers may perform as well as CSF for beta-amyloid, but blood phospho-tau isoforms appear to be useful primarily as biomarkers of beta-amyloid plaques. A validated blood marker specific to tau pathology is still needed. Magnetic resonance imaging (MRI) can detect structural defects due to neurodegeneration, such as localized thinning of cortical gray matter or loss of hippocampal volume, as well as white-matter abnormalities using diffusion tensor imaging (DTI). Vascular Contributions to Cognitive Impairment and Dementia (VCID) can be identified on MRI by the presence of sub-cortical and lacunar infarcts, micro-infarcts and hemorrhages, hemosiderosis, and white-matter hyperintensities. Arterial Spin Labelling (ASL) MRI, and 18F-fluorodeoxyglucose (FDG) PET can identify changes in regional glucose metabolism and blood flow, while Blood Oxygen Level Determination (BOLD) functional MRI (fMRI) can be used to characterize functional neural networks.

AD biomarkers were essential for the approval of (the first) AD disease-modifying therapies: the anti-amyloid monoclonal antibodies (mAbs), lecanemab (Leqembi); and donanemab (Kisunla). CSF and PET biomarkers were used for antemortem diagnosis and proof-of-target engagement. MRI was essential to safety-monitoring of Amyloid Related Imaging Abnormalities (ARIA).

Seeding Amplification Assay (SAA) for alpha-synuclein is a recently developed method to detect alpha-synuclein oligomers in CSF and brain Lewy Bodies (LB). This allows antemortem diagnosis of synucleinopathies such as Dementia with Lewy Bodies (DLB), Parkinson’s Disease (PD), PD Dementia (PDD), and multi-system atrophy (MSA). However, there are no blood-based or neuroimaging biomarkers (e.g., PET radiotracers) for synucleinopathies.

Currently, there are no biomarkers specific to Frontotemporal Dementia (FTD) that are comparable to the PET and CSF measures for AD plaques and tangles or the MRI changes for VCID. FTD is caused by (at least) two different neuropathologies: non-AD tau tangles (either 3R or 4R) or TDP43. TDP43 and Tau FTD may be clinically indistinguishable. There are no fluid or neuroimaging biomarkers for TDP43, or 3R-tau or 4R-tau individually (available tau radiotracers bind only to AD’s mix of 3R/4R tau). C9orf72 mutations can cause an inherited TDP43 FTD that overlaps with amyotrophic lateral sclerosis (ALS).

A new aging-related dementia, Limbic Age-related TDP43 encephalopathy (LATE) was recently described. LATE dementia is typically amnestic, mimicking AD in the oldest-old. LATE neuropathology is characterized by limbic system TDP43 and often involves hippocampal sclerosis. There are no biomarkers for LATE.

This lack of antemortem biomarkers for non-AD proteinopathies 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. More neuropathological abnormalities (e.g., VCID, LBD, and TDP-43, along with AD) become evident as people age.

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, VCID, 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.

Research Objectives

The goal of this NOSI is to encourage the development of novel approaches to characterizing, diagnosing, and predicting outcomes in AD/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 (e.g., alpha-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.
  • LATE
  • LBD: Parkinson’s Dementia, REM sleep disorder, fluctuating levels of consciousness, etc.
  • FTD: Pick’s, BvFTD, PSP, CBD, FTD w/ MND, etc., including 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
• Studies of movement disorders associated with AD/ADRD
• Studies of aphasias associated with AD/ADRD
• Studies 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, 2025 and subsequent receipt dates through November 17, 2027 . 

Submit applications for this initiative using one of the following notices of funding opportunities (NOFOs) or any reissues of these announcements through the expiration date of this notice.

• PAR-25-331 - Research on Current Topics in Alzheimer's Disease and Its Related Dementias (R21 Clinical Trial Optional)
• PAR-25-332 - Research on Current Topics in Alzheimer's Disease and Its Related Dementias (R01 Clinical Trial Optional)

All instructions in the How to Apply - Application Guide and the notice of funding opportunity used for submission must be followed, with the following additions:

• For funding consideration, applicants must include “NOT-AG-24-30” (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.

Inquiries

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

Scientific/Research Contact(s)

Alessandra Rovescalli, Ph.D.
National Institute on Aging (NIA)
Phone: 301-496-9350
Email: [email protected]