Taking a LOAD off your mind


Kelsey Kaustinen
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NEW YORK—A team of researchers from the Icahn School ofMedicine at Mount Sinai, together with the Icelandic Heart Association, SageBionetworks and other institutions, has announced the discovery that a networkof genes known to play a role in the brain's inflammatory response also existsas a key mechanism in the development of late-onset Alzheimer's disease (LOAD).
The study focused on the TREM2-TYROBP pathway. TYROBP is aninflammatory gene involved in this pathway, but previously, it had not beenlinked to the disease. TYROBP is known to interact with TREM2, a gene recentlydiscovered to be associated with Alzheimer's disease by Rita Guerreiro ofUniversity College London, Thorlakur Jonsson of deCODE Genetics and their colleagues.
This work began with an integrated analysis performed on theDNA of 376 deceased patients with LOAD, as well as gene expression data, whichrevealed the relationships between a network of genes that drive centralpathways of Alzheimer's. The researchers then created a biological networkmodel, integrating the genes key to Alzheimer's disease and the biologicalpathways they control.
"In the same way that sophisticated predictive mathematicalmodels drive decision making in the global financial markets … the field ofmedical research has begun to rely on network models such as this to derivemeaning from vast amounts of patient data, enabling better understanding andtreatment of human disease," Dr. Christopher Gaiteri, a co-lead author ofthe study and senior scientist at Sage Bionetworks, commented in a pressrelease.
Dr. Eric Schadt, an author of the study and director ofthe Icahn Institute for Genomics and Multiscale Biology and chair of theDepartment of Genetics and Genomic Sciences at Mount Sinai, called the model "alandmark achievement, yielding valuable insights into the complex mechanism ofthe disease."
LOAD is the most common form of Alzheimer's disease, anddespite extensive research, the cause of the disease is unknown, though it is attributedto a combination of "genetic, environmental and lifestyle factors," accordingto the National Institute on Aging. What is known, however, is that having theE4 allele of the apolipoprotein gene—a gene found on chromosome 19 that carriesinstructions for the coding of a protein that transports cholesterol and fatsin the bloodstream—is a genetic risk factor for the likelihood of developingLOAD. No effective preventative or disease-modifying therapies exist for thedisease, and the incidence of LOAD is expected to double by 2050.
One of the key points of interest with this discovery, saysSchadt, is the fact that "the microglia in the brain drive immune/inflammationprocesses that are causally associated with LOAD." Prior to this work,inflammation was believed to be a result of Alzheimer's disease damaging thebrain, but their work "demonstrates that it is a driver, not a consequence ofLOAD." 
"Defining the precise steps of the inflammatory responsecrucial to causing Alzheimer's disease has been elusive. We are pleased to discover these novelinsights into that process," Dr. Bin Zhang, a co-lead author of the studyand an associate professor of genetics and genomic sciences at Mount Sinai,said in a press release. "As a next step, we will evaluate drugs that impactthe TREM2-TYROBP pathway as potential therapies for the disease. This discoveryenables us to design more specific compounds that target these key stepsprecisely, in contrast to existing anti-inflammatory drugs that may be less idealfor hitting this target. "
"Currently, we see a long lag time between appearance ofamyloid on brain scans of patients and the appearance of clinical symptoms,"added Dr. Valur Emilsson, head of systems medicine at Icelandic HeartAssociation and a senior author of the paper. "An individual's inflammatoryresponse could well play a role in the disease progression, and an appropriateanti-inflammatory drug, given after amyloid is detected but before symptomsbegin, could be an important part of dementia prevention."
Schadt says their prediction is that if the TYROBP pathwayis down-regulated, the progression of Alzheimer's disease should be slowed orstopped, with the possibility that if the pathway is suppressed early enough,it might prevent the disease. In terms of therapies that could affect thenetwork, Schadt notes that there are several possibilities, "even drugs such asanti-inflammatories." This work has potential outside of Alzheimer's disease aswell, as Schadt says they are applying this approach to autism, Huntington'sdisease and schizophrenia as well.
Moving forward, Schadt says the team will continue toidentify and validate therapeutics that can molecularly affect this network,adding that they are set up to test the candidates in animal models. Theresearchers will also "explore pharma partnership to develop novel therapeuticsagainst this work."
Authors for the study, "Integrated Systems ApproachIdentifies Genetic Nodes and Networks in Late-Onset Alzheimer's Disease,"include researchers from Icelandic Heart Association; Sage Bionetworks, MerckResearch Laboratories, University of Bonn, Fred Hutchinson Cancer ResearchCenter, Massachusetts General Hospital, University of Miami, Rush UniversityMedical Center and GNF Novartis. The study appeared in Cell in late April.

Kelsey Kaustinen

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