title: Leveraging existing data sets to generate new insights into Alzheimer's disease biology in specific patient subsets.
abstract: To generate new insights into the biology of Alzheimer's Disease (AD), we developed methods to combine and reuse a wide variety of existing data sets in new ways. We first identified genes consistently associated with AD in each of four separate expression studies, and confirmed this result using a fifth study. We next developed algorithms to search hundreds of thousands of Gene Expression Omnibus (GEO) data sets, identifying a link between an AD-associated gene (NEUROD6) and gender. We therefore stratified patients by gender along with APOE4 status, and analyzed multiple SNP data sets to identify variants associated with AD. SNPs in either the region of NEUROD6 or SNAP25 were significantly associated with AD, in APOE4+ females and APOE4+ males, respectively. We developed algorithms to search Connectivity Map (CMAP) data for medicines that modulate AD-associated genes, identifying hypotheses that warrant further investigation for treating specific AD patient subsets. In contrast to other methods, this approach focused on integrating multiple gene expression datasets across platforms in order to achieve a robust intersection of disease-affected genes, and then leveraging these results in combination with genetic studies in order to prioritize potential genes for targeted therapy.
authors.affiliation: Immuneering Corporation, Cambridge, Massachusetts, United States of America.
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Fowler
authors.affiliation: Immuneering Corporation, Cambridge, Massachusetts, United States of America.
authors.forename: Jason M
authors.initials: JM
authors.lastname: Funt
authors.affiliation: Immuneering Corporation, Cambridge, Massachusetts, United States of America.|Department of Immunology and Pathology, Washington University in St. Louis, St. Louis, Missouri, United States of America.
authors.forename: Maxim N
authors.initials: MN
authors.lastname: Artyomov
authors.affiliation: Immuneering Corporation, Cambridge, Massachusetts, United States of America.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Zeskind
authors.affiliation: Immuneering Corporation, Cambridge, Massachusetts, United States of America.
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Kolitz
authors.affiliation: Immuneering Corporation, Cambridge, Massachusetts, United States of America.
authors.forename: Fadi
authors.initials: F
authors.lastname: Towfic
mesh_terms: D000465:Algorithms; D000544:Alzheimer Disease / Q000188:drug therapy / Q000235:genetics*; D053327:Apolipoprotein E4 / Q000378:metabolism*; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics*; D030562:Databases, Protein; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012737:Sex Factors; D050825:Synaptosomal-Associated Protein 25 / Q000235:genetics*
chemical_list: D053327:Apolipoprotein E4; D051792:Basic Helix-Loop-Helix Proteins; D050825:Synaptosomal-Associated Protein 25; C490553:NEUROD6 protein, human; C494208:SNAP25 protein, human