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.
• December 30, 2021 - Notice of Special Interest: Common Mechanisms and Interactions Among Neurodegenerative Diseases. See Notice NOT-AG-21-037. 

Issued by

National Institute on Aging (NIA)

Purpose

Background

Etiologic and therapeutic research on dementia has focused either on individual disease syndromes (e.g., Alzheimer’s disease (AD), Lewy Body Dementia (LBD), Frontotemporal Dementia (FTD), Vascular Contributions to Cognitive Impairment and Dementia (VCID) or distinct neurodegenerative processes (e.g., beta-amyloid, HPF-tau, alpha-synuclein, TDP-43, small vessel changes). Aside from descriptive, postmortem neuropathology, different neurodegenerative diseases have generally been investigated in isolation from one another. There are few models for studying whether and how neurodegenerative disease processes relate to one another.

At autopsy, many patients with dementia, particularly older individuals, exhibit multiple neuropathological changes. In addition to tau tangles and beta-amyloid plaques, vascular changes, Lewy bodies, and TDP-43 inclusions are often present. The likelihood of antemortem dementia increases with co-occurring postmortem neuropathological burden. However, despite considerable evidence of interactions between different neuropathological processes, we do not understand how different neurodegenerative illnesses interact or relate to one another.

Co-occurring pathology complicates both pathophysiological investigation and treatment development. For instance, therapies to increase beta-amyloid clearance may be less effective if there is coincident VCID or LBD. At the same time, commonalities between neurodegenerative diseases may provide clues to pathophysiological mechanisms. Can multiple neuropathological changes interact to synergistically increase disease burden and worsen cognitive impairment? Could there be common pathways leading to synapse loss and cell death that might become targets for drug development? If either speculation is correct, what molecular, cellular, or organismic processes are involved?

Research Objectives

This NOSI encourages research to enhance our understanding of how different neurodegenerative diseases interact clinically and physiologically. There is a need to identify, more precisely, which neurodegenerative process, or processes, are active in individuals. At the same time, there needs to be better understanding of how different neurodegenerative diseases resemble and differ from one another at the molecular, cellular, and organismic levels. Cellular and animal models for investigating concurrent neurodegenerative processes need to be developed if these questions are to be answered.

Many neurodegenerative diseases involve aggregation and accumulation of misfolded proteins. Could they be studied as clinical variants of common cellular and molecular biological defects? At the same time, identifying pathophysiologic mechanisms unique to one neuropathologic entity, will be as informative as identifying commonalities.

Example research areas of interest appropriate to this NOSI include, but are not limited to, the following:

• Identify mechanisms for clearance of misfolded proteins and proteostasis, endoplasmic reticulum stress, and the unfolded protein response (e.g., proteasomes, lysosomes, autophagy).
• Define abnormal mitochondrial function regarding involvement in Parkinson’s Disease (a synucleinopathy), Huntington’s Disease, and Amyotrophic Lateral Sclerosis (ALS).
• Evaluate RNA transcription and processing in AD and AD-related dementias (ADRD). 
• Examine the role of inflammation, microglial activation, and the innate immune system in AD and ADRD.
• Delineate the prion-like spread of alpha-synuclein and HPF-tau.
• Characterize the distinct “strains” of HPF-tau and alpha-synuclein.
• Identify the neurotoxic species related to AD, FTD, and LBD deposits of insoluble protein aggregates and soluble oligomers.
• The ApoE4 allele is a major genetic risk factor for both AD and LBD. How does a gene involved in lipid transport lead to increased beta-amyloid plaques, HPF-tau tangles, and alpha-synuclein Lewy Bodies?
• AD involves both beta-amyloid plaques and HPF-tau tangles. Neocortical beta-amyloid plaques are the earliest manifestation, but HPF-tau tangles are more closely associated with cognitive impairment. HPF-tau tangles in entorhinal cortex appear normally with age, and it appears that tau spread beyond entorhinal cortex requires the presence of beta-amyloid plaques. How do beta-amyloid plaques drive spread of HPF-tau tangles?
• HPF-tau is an important component of AD and a subtype of FTD (albeit with different mixes of isoforms). What else, besides beta-amyloid, distinguishes AD from other tauopathies?
• Examine cerebrovascular contributions to neurodegeneration as a shared mechanism across multiple diseases, including VCID, AD, and other neurodegenerative diseases.
• Develop experimental models of TDP-43 proteinopathies in its human context to faithfully model certain disease features.
• Develop models of TDP-43 proteinopathies that represent both nuclear loss of function and cytoplasmic accumulation toxic gain-of-function.
• Clarify pathogenic mechanisms that involve copathologies in AD by developing tools to model co-pathology of amyloid beta, tau, and TDP-43. 

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-24-031” (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)

Lisa A. Opanashuk, Ph.D.
National Institute on Aging (NIA)
Phone: 301-827-5422
Email: [email protected]