Notice Number: NOT-AG-18-046

Key Dates
Release Date: November 20, 2018

NOT-AG-22-007 - Notice to Expire NOSIs to PAR-19-070, "Research on Current Topics in Alzheimer's Disease and Its Related Dementias (R01 Clinical Trial Optional)"

NOT-AG-22-006 - Notice to Expire NOSIs to PAR-19-070, "Research on Current Topics in Alzheimer's Disease and Its Related Dementias (R01 Clinical Trial Optional)"

Issued by
National Institute on Aging (NIA)

Purpose

This Notice of Information 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)" and PAR-19-071 "Research on Current Topics in Alzheimer's Disease and Its Related Dementias (R21 Clinical Trial Not Allowed)".

Genetic Underpinnings of Endosomal Trafficking as a Pathological Hub in Alzheimer's Disease and Alzheimer's Disease-Related Dementias (AD/ADRD)
AD is defined, in part, by the appearance of extracellular amyloid deposits. Supported by genetic studies, the amyloid cascade is the leading hypothesis for the cause and pathogenesis of AD.Despite the intensive efforts that have been made in understanding amyloid and other pathological processes in AD, current approved interventions for AD have shown only modest effects in modifying clinical symptoms; none have been efficacious for slowing disease progression.

Recent developments in the field of genetics have significantly advanced understanding of the etiology of AD; more than two dozen genes are now known to be associated with late-onset AD (LOAD). Using a combination of genome wide association study (GWAS), exome chip, imputation, whole exome sequencing (WES), and whole genome sequencing (WGS), a number of AD genetic hubs have recently begun to emerge that may explain some of the bases for the development of the disease. Hubs include the well-known amyloid precursor processing (APP) pathway and the less understood genetic and genomic events associated with cholesterol metabolism, neuroinflammation and cellular immunity, and endocytosis pathways. Known genes that appear to be directly or indirectly associated with the endosomal compartment include APOEe4, SORL1, BIN1, ABCA7, EPHA1, and CD2AP. Some genes are observed in more than one pathway, leaving open the possibility that individuals with multiply affected pathways may be more vulnerable to the pathophysiology associated with AD.

A newly emerging model proposes that alterations in the way the cellular endosomal compartment processes amyloid precursor protein (APP) may represent a pathogenic hub for AD. This model suggests that therapies directed against extracellular amyloid plaques may fail because they are being administered too late in the disease process. Many AD genes directly or indirectly converge upon the endosomal genetic hub. Thus, the hub may act as a common pathway through which many downstream pathophysiological effects can be mediated. In-depth assessment of the genetic components related to the endosomal cellular trafficking pathway may help direct the research community toward novel alternative biological targets for therapeutic interventions.

The goals of this high-priority topic are to encourage basic and translational research focused on the molecular, cellular, and physiological processes associated with the endosomal compartment in AD/ADRD. Studies funded under this topic will support research into AD/ADRD pathogenesis related to enhancing our understanding of how the genetic underpinnings of endosomal trafficking in AD/ADRD may act as a hub in the pathophysiological changes associated with the disease. The impact of changes in endosomal genetics on functional events, for example upon the generation of amyloid Beta (A ) cellular processing, are important factors to be evaluated. This includes both the amyloidogenic and non-amyloidogenic pathways. All phases of endosomal processing during early through late processing stages are of interest, including those genes/events that may affect the cell membrane; early, mature, and late endosomes; the retromer/recycling pathway; the retrograde pathway/trans Golgi network; the lysosome, endolysosome, and multi-vesicular body; receptors related to cellular trafficking and cell sorting; and other related cell processing components. Applications that delineate cellular gene ontology networks and determine the weight of their impact upon endosomal processing are of interest.

Areas of research interest and opportunity that would be considered high priority under this topic include, but are not limited to:

• Improved characterization (in vivo/in vitro) of the functions of known endosomal genes and their impact upon AD/ADRD pathophysiology.
• Identification and characterization of novel genes not presently known to be associated with the endosomal compartment.
• Analysis of existing whole genome and whole exome sequence data such as that generated by the Alzheimer's Disease Sequencing Project (ADSP; see ADSP Study Design) to identify genetic variants and their function in known and novel endosomal genes.
• Determination of the impact of changes in endosomal genetics on functional events (amyloidogenic and non-amyloidogenic) in cellular trafficking in AD/ADRD.
• Definition and characterization of the relationship between genes associated with AD/ADRD and endosomal processing in specific neural cell populations; this includes neurons (soma, axonal, and/or dendritic) and glia.
• Characterization of cell types affected by changes in endosomal processing by physiological measures such as changes in neural activity.
• Identification and characterization of the impact of genes and networks of genes that are outside of the endosomal pathway to determine their links to endosomal trafficking in AD/ADRD.
• Delineation of cellular gene ontology networks related to endosomal processing and determination of the weight of their impact upon endosomal processing and pathophysiology.
• Identification of cellular networks and brain regions that are selectively vulnerable to changes in endosomal processing in AD/ADRD.
• Improvement of our understanding of how clusters of genes in the endosomal pathway may change endosomal trafficking resulting in pathological events in AD/ADRD; this includes a better understanding of how genes that act in more than one pathway impact endosomal processing, and a better understanding of converging and cascading pathways related to the endosomal compartment and how they may impact AD/ADRD pathophysiology.
• Analysis of in vivo and in vitro outcomes of interventions that are directly designed to increase traffic flow through the endosomal compartment and that may serve as models for therapeutic approaches in AD/ADRD.
• Identification of novel therapeutic targets associated with the endosomal compartment using existing and new in vivo and/or in vitro approaches.
• Improvement of our understanding of how known and newly identified protective variants associated with the endosomal compartment may be leveraged into therapeutic targets for AD/ADRD.
• Determination of whether the amyloid hypothesis, when seen through the lens of genetic changes in endosomal processing, can identify useful therapeutic targets that can be applied at the earliest possible stage in the disease process.
• Determination of whether/how the endosomal compartment may act as a common pathway through which downstream pathophysiological events in AD/ADRD can be mediated.
• Comprehensive analysis of how single-cell transcriptomic (e.g. RNAseq), epigenetic (e.g. chromatin remodeling, DNA methylation), and/or genomic (e.g. sequencing for mutations) events impact neurons and glial cells and are related to changes in the endosomal compartment.
• Novel multidisciplinary technological approaches to assess changes in the endosomal compartment in AD/ADRD.
• Analysis of trans-synaptic spread (e.g. by exosomes) in AD/ADRD that may be mediated by genetically modulated changes in endosomal trafficking.

Applications proposing clinical trials on this topic would not be considered a high priority.

Inquiries

Please direct all inquiries to:

Marilyn Miller, Ph.D.
National Institute on Aging (NIA)
Telephone: 301-496-9350
Email: millerm@nia.nih.gov