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Notice of Special Interest (NOSI): Infectious Etiology of Alzheimer's Disease

Alzheimer’s disease (AD) is a progressive, degenerative disorder of the brain and is the most common form of dementia in older adults. 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 6.1 million Americans age 65 and older are living with AD.

In response to this looming public health crisis, the National Alzheimer’s Project Act (NAPA) was signed into law in 2011. 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 Notice of Special Interest (NOSI) was developed in response to the recommendations of the 2018 Alzheimer’s Disease Research Summit to identify and understand the molecular and cellular mechanisms underlying the pathogenesis of AD.

The concept of a microbial etiology of AD was first proposed in the early 1950s, and further investigated and strengthened through studies in the early 1980s 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 microbial etiology of AD plausible, but raised questions, including whether pathogens are causal factors in AD or just ‘opportunistic passengers’ of neurodegeneration. Since the early studies on HSV-1 in the central nervous system (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 apolipoprotein E4 (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. The 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 of aggregates of various proteins in the brain, 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 NOSI 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 NOSI strongly encourages leveraging existing cohorts with available samples from plasma, cerebrospinal fluid (CSF), and brain tissue, as well as imaging data, to address the possible links between infectious agents and AD.

This notice applies to due dates on or after March 11, 2022 and subsequent receipt dates through November 13, 2024.

Application Due Date(s): March 11, 2022; July 8, 2022; Nov 14, 2022; March 10, 2023; July 10, 2023; Nov 13, 2023; March 11, 2024; July 9, 2024; Nov 12, 2024



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