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Notice of Special Interest (NOSI): Genetic Underpinnings of Endosomal Trafficking as a Pathological Hub in Alzheimer's Disease and Alzheimer's Disease-Related Dementias (AD/ADRD)

National Institutes of Health

Alzheimer's disease (AD) is defined, in part, by the appearance of extracellular amyloid deposits. Supported by genetic studies, the amyloid cascade is a 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 as demonstrated through clinical outcome measures.

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 studies (GWAS), exome chips, 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. These 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 Notice of Special Interest (NOSI) are to encourage basic and translational research focused on the molecular, cellular, and physiological processes associated with the endosomal compartment in AD and Alzheimer's disease-related dementias (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 (Aß) 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. Applications that apply Artificial Intelligence/Machine Learning methods to data analysis approaches in this area are welcome. Data generated under this NOSI will be shared through the NIA Genetics of Alzheimer's Disease Data Storage Site ( NIAGADS ) and/or another NIA-approved storage site.

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

NOT-AG-21-034