Notice of Special Interest: High-Priority Research Topic for PAR-19-070

Notice Number: NOT-AG-19-012

Key Dates
Release Date: April 01, 2019

Related Announcements
PAR-19-070

Issued by
National Institute on Aging (NIA)

Purpose

This Notice of Special Interest specifies a high-priority topic of interest for PAR-19-070, "Research on Current Topics in Alzheimer's Disease and Its Related Dementias (R01 Clinical Trial Optional)".

Infectious Etiology of Alzheimer's Disease

Purpose

This high-priority topic aims to: (1) determine whether microbial pathogens represent a causal component of Alzheimer’s disease (AD), (2) establish mechanisms by which microbial pathogens impact neurodegenerative processes in AD, and (3) inform aspects of future translational studies in AD, including discovery of candidate therapeutics aimed at regulating pathogen-associated networks and molecules in AD.

Background

Alzheimer’s disease (AD) is a progressive, degenerative disorder of the brain and is the most common form of dementia in the elderly. AD is the sixth leading cause of death in the United States. Prominent behavioral manifestations of AD include memory impairments and decline in other cognitive domains. Currently, at least 5.6 million Americans age 65 and older suffer from AD, and it is projected that the number of patients with AD will grow to 11.6 million by 2040. AD is clearly becoming a national health crisis affecting Americans across all regions of the country, and the total annual payments of health care for people with AD are projected to be more than $1 trillion by 2050. In response to this looming public health crisis, the National Alzheimer’s Project Act (NAPA) was signed into law in 2011. The primary research goal of NAPA is to prevent the onset of, and develop effective treatments for, AD by 2025. As part of the strategic planning process to implement NAPA, NIH AD Research Summits identified research priorities and strategies needed to accelerate basic research and the development of effective therapies.

This high-priority topic was developed in response to the recommendations of the 2018 Alzheimer’s Disease Research Summit to (1) identify and understand the molecular and cellular mechanisms underlying the pathogenesis of Alzheimer's disease and (2) augment current and future human cohorts with more advanced, longitudinal immunological profiling to enable precision medicine research and to better understand the roles of the different arms of the central nervous system and peripheral immunity in brain aging and AD.

The concept of a microbial etiology of AD was first proposed in 1952, and further investigated and strengthened through studies in the early eighties on the herpes simplex virus type 1 (HSV-1) in human brains. Discovery of HSV-1 in brains of AD patients made the concept of microbiol etiology of AD plausible but raised questions such as whether pathogens are causal factors in AD or just “opportunistic passengers” of neurodegeneration. Since the early studies on HSV-1 in the CNS, numerous reports have associated AD with diverse bacterial, fungal, and viral pathogens, most frequently implicating herpes viruses. For example, it has been demonstrated that: (1) HSV-1 resides latently in the brain and can reactivate, (2) HSV-1 DNA is located within amyloid plaques, (3) HSV-1 infection of cultured human cells and of mouse brain causes AD-like changes, (4) HSV-1 DNA in the brain and ApoE4 confer a strong risk of AD, and (5) antiviral treatment greatly reduces amyloid-ß and phospho-Tau protein production. In addition to viruses, other microbial pathogens have been associated with AD, including Spirochetes, periodontal Spirochetes in particular, Chlamydia pneumoniae, and Helicobacter pylori. While studies demonstrate a strong link between AD and viral and bacterial pathogens, they neither establish a causal link nor offer insights into potential mechanisms. Molecular profiling of a large patient cohort, which incorporated multiple AD stages, brain regions, and -omic domains, provided additional evidence of Herpesviridae presence in AD and pointed toward multiple novel and testable biological mechanisms.

A hallmark of AD is the deposition in the brain of aggregates of various proteins, including aggregates composed of amyloid-ß (Aß). The term “amyloid-ß” refers to a family of polypeptides containing 37 to 49 amino acid residues produced by cleavage of the amyloid precursor protein (APP). Aß peptides share many of the same physiochemical properties and biological activities, including oligomerization and fibrillization, with the family of small peptides collectively known as antimicrobial peptides. For example, it has been demonstrated that Aß inhibits infection of cultured cells by viruses, protects cultured cells against lethal yeast and bacterial infections, and sequesters pathogens during the process of Aß fibrilization. Pathogen-mediated Aß fibrilization may be a part of the innate immune pathway which, in AD, undergoes chronic activation leading to excessive Aß deposition and the triggering of a cascade of pathologies that eventually results in dementia.

Taking into consideration the strong links between microbial pathogens and AD and the emergence of the antimicrobial protection hypothesis of AD, this high-priority topic invites research on mechanisms underpinning neurodegeneration in AD associated with microbial pathogens in the CNS. The goals include: to determine whether microbial pathogens represent a causal component of AD, to establish mechanisms by which microbial pathogens impact neurodegenerative processes in AD, and/or to inform aspects of future translational studies in AD including discovery of candidate therapeutics aimed at regulating pathogen-associated networks and molecules in AD. This high-priority topic strongly encourages leveraging existing cohorts with available samples from plasma, CSF, and brain tissue as well as imaging data to address the possible links between infectious agents and Alzheimer’s disease.

Research appropriate to this high-priority topic may include but is not limited to:

  • studies on the role of infectious agents as contributors to AD in the context of some of Koch's postulates,
  • identification of host genes and gene networks that are most commonly perturbed by pathogens in the brains of AD patients,
  • research on amyloidosis as a protective mechanism against microbial infection,
  • mechanisms linking microbial infection and systemic inflammation with peripheral amyloidosis,
  • research on mechanisms by which AD pathology may increase the vulnerability of the CNS to microbial infection, and
  • studies of host and pathogen factors contributing to breakdown of the blood-brain barrier and potential mechanisms leading to neuro-invasion of pathogens in AD.

Investigators proposing applications on research topics beyond those indicated above are encouraged to explore whether their topic would be appropriate for a different NIA AD/ADRD-focused FOA.

For funding consideration, applicants must include "NOT-AG-19-012" (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.

Inquiries

Please direct all inquiries to:

Miroslaw ("Mack") Mackiewicz
National Institute on Aging (NIA)
Telephone: 301-594-7636
Email: Miroslaw.Mackiewicz@nih.gov