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However, the spatiotemporal overlap of markers for pathway dysregulation in different brain regions and cell types presents a challenge for pinpointing causal versus epiphenomenal changes characterizing disease progression. To approach this problem, we performed Weighted Gene Co-expression Network Analysis and STRING interactome analysis of gene expression patterns quantified in frontal cortex samples (Brodmann area 10) from subjects who died with a clinical diagnosis of no cognitive impairment, aMCI, or mild\/moderate AD. Frontal cortex was chosen due to the relatively protracted involvement of this region in AD, which might reveal pathways associated with disease onset. A co-expressed network correlating with clinical diagnosis was functionally associated with insulin signaling, with insulin (INS) being the most highly connected gene within the network. Co-expressed networks correlating with neuropathological diagnostic criteria (e.g., NIA-Reagan Likelihood of AD) were associated with platelet-endothelium-leucocyte cell adhesion pathways and hypoxia-oxidative stress. Dysregulation of these functional pathways may represent incipient alterations impacting disease progression and the clinical presentation of aMCI and AD.<\/jats:p>","DOI":"10.1093\/cercor\/bhac001","type":"journal-article","created":{"date-parts":[[2022,1,4]],"date-time":"2022-01-04T20:09:42Z","timestamp":1641326982000},"page":"5108-5120","source":"Crossref","is-referenced-by-count":10,"title":["Co-expression network analysis of frontal cortex during the progression of Alzheimer\u2019s disease"],"prefix":"10.1093","volume":"32","author":[{"given":"John S","family":"Beck","sequence":"first","affiliation":[{"name":"Department of Translational Neuroscience , Michigan State University, Grand Rapids, MI 49503 , USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zachary","family":"Madaj","sequence":"additional","affiliation":[{"name":"Bioinformatics and Biostatistics Core , Van Andel Research Institute, Grand Rapids, MI 49503 , 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A","family":"Schneider","sequence":"additional","affiliation":[{"name":"Department of Neurological Sciences , Rush University Medical Center, Chicago, IL 60612, USA"},{"name":"Rush Alzheimer\u2019s Disease Research Center , Chicago, IL 60612, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marcia N","family":"Gordon","sequence":"additional","affiliation":[{"name":"Department of Translational Neuroscience , Michigan State University, Grand Rapids, MI 49503 , USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stephen D","family":"Ginsberg","sequence":"additional","affiliation":[{"name":"Center for Dementia Research , Nathan Kline Institute, Orangeburg, NY 10962, USA"},{"name":"Department of Psychiatry , New York University Grossman School of Medicine, New York, NY 10016, USA"},{"name":"Department of Neuroscience and Physiology , New York University Grossman School of Medicine, New York, NY 10016, USA"},{"name":"NYU Neuroscience Institute , New York University Grossman School of Medicine, New York, NY 10016, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elliott J","family":"Mufson","sequence":"additional","affiliation":[{"name":"Department of Neurobiology , Barrow Neurological Institute, Phoenix, AZ 85013, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2851-9763","authenticated-orcid":false,"given":"Scott E","family":"Counts","sequence":"additional","affiliation":[{"name":"Department of Translational Neuroscience , Michigan State University, Grand Rapids, MI 49503 , USA"},{"name":"Cell and Molecular Biology Program , Michigan State University, East Lansing, MI 48824, USA"},{"name":"Department of Family Medicine , Michigan State University, Grand Rapids, MI 49503 , USA"},{"name":"Hauenstein Neurosciences Center , Mercy Health Saint Mary\u2019s Hospital, Grand Rapids, MI 49503 , USA"},{"name":"Michigan Alzheimer\u2019s Disease Research Center , Ann Arbor, MI 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