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)

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 Dementia (VD)) 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 VD 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?

Objective

This Notice of Special Interest (NOSI) encourages research to enhance our understanding of how different neurodegenerative diseases interact clinically and physiologically. We need to identify, more precisely, which neurodegenerative process, or processes, are active in individuals. At the same time, we need to better understand 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 we are to answer these questions.

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.

Examples of issues appropriate to this NOSI include, but are not limited to, the following:

• Clearance of misfolded proteins and proteostasis, endoplasmic reticulum stress, and the unfolded protein response (e.g., proteasomes, lysosomes, autophagy).
• Mitochondrial function: There is considerable evidence of mitochondrial involvement in Parkinson’s Disease (a synucleinopathy), Huntington’s Disease, and Amyotrophic Lateral Sclerosis (ALS).
• RNA transcription and processing: Huntington’s and several spinal-cerebellar atrophies are neurodegenerative disorders caused by trinucleotide repeat expansions. A hexanucleotide repeat expansion in the gene associated with C9orf72 causes familial FTD and is the most frequent cause of familial ALS. TDP43 is an RNA binding protein.
• Inflammation: Microglial activation and the innate immune system play a role in AD, with evidence in other neurodegenerative diseases, as well.
• There appears to be prion-like spread of alpha-synuclein and HPF-tau. HPF-tau may be able to seed alpha-synuclein fibrilization and vice versa.
• There are distinct “strains” of HPF-tau and alpha-synuclein.
• While AD, FTD, and LBD are characterized neuropathologically by deposits of insoluble protein aggregates (amyloids), the actual neurotoxic species all appear to be 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?

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-21-037” (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

Scientific/Research Contact(s)

John Hsiao, M.D.
National Institute on Aging (NIA)
Phone: 301-496-9350
Email: [email protected]