title: Altered Energy Metabolism Pathways in the Posterior Cingulate in Young Adult Apolipoprotein E ɛ4 Carriers.
abstract: The APOE gene, encoding apolipoprotein E, is the primary genetic risk factor for late-onset Alzheimer's disease (AD). Apolipoprotein E ɛ4 allele (APOE4) carriers have alterations in brain structure and function (as measured by brain imaging) even as young adults. Examination of this population is valuable in further identifying details of these functional changes and their association with vulnerability to AD decades later. Previous work demonstrates functional declines in mitochondrial activity in the posterior cingulate cortex, a key region in the default mode network, which appears to be strongly associated with functional changes relevant to AD risk. Here, we demonstrate alterations in the pathways underlying glucose, ketone, and mitochondrial energy metabolism. Young adult APOE4 carriers displayed upregulation of specific glucose (GLUT1 & GLUT3) and monocarboxylate (MCT2) transporters, the glucose metabolism enzyme hexokinase, the SCOT & AACS enzymes involved in ketone metabolism, and complexes I, II, and IV of the mitochondrial electron transport chain. The monocarboxylate transporter (MCT4) was found to be downregulated in APOE4 carriers. These data suggest that widespread dysregulation of energy metabolism in this at-risk population, even decades before possible disease onset. Therefore, these findings support the idea that alterations in brain energy metabolism may contribute significantly to the risk that APOE4 confers for AD.
authors.affiliation: Midwestern University, Glendale, AZ, USA.|Arizona Alzheimer's Consortium, Phoenix, AZ, USA.
authors.forename: Michelle
authors.initials: M
authors.lastname: Perkins
authors.affiliation: University of Colorado School of Medicine, Aurora, CO, USA.
authors.forename: Andrew B
authors.initials: AB
authors.lastname: Wolf
authors.affiliation: Midwestern University, Glendale, AZ, USA.|Arizona Alzheimer's Consortium, Phoenix, AZ, USA.
authors.forename: Bernardo
authors.initials: B
authors.lastname: Chavira
authors.affiliation: Midwestern University, Glendale, AZ, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Shonebarger
authors.affiliation: Midwestern University, Glendale, AZ, USA.
authors.forename: J P
authors.initials: JP
authors.lastname: Meckel
authors.affiliation: Midwestern University, Glendale, AZ, USA.|Arizona Alzheimer's Consortium, Phoenix, AZ, USA.
authors.forename: Lana
authors.initials: L
authors.lastname: Leung
authors.affiliation: Midwestern University, Glendale, AZ, USA.
authors.forename: Lauren
authors.initials: L
authors.lastname: Ballina
authors.affiliation: Neuroscience Graduate Group, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Ly
authors.affiliation: Midwestern University, Glendale, AZ, USA.
authors.forename: Aman
authors.initials: A
authors.lastname: Saini
authors.affiliation: Midwestern University, Glendale, AZ, USA.
authors.forename: T Bucky
authors.initials: TB
authors.lastname: Jones
authors.affiliation: Midwestern University, Glendale, AZ, USA.|Arizona Alzheimer's Consortium, Phoenix, AZ, USA.
authors.forename: Johana
authors.initials: J
authors.lastname: Vallejo
authors.affiliation: Midwestern University, Glendale, AZ, USA.|Arizona Alzheimer's Consortium, Phoenix, AZ, USA.
authors.forename: Garilyn
authors.initials: G
authors.lastname: Jentarra
authors.affiliation: Midwestern University, Glendale, AZ, USA.|Arizona Alzheimer's Consortium, Phoenix, AZ, USA.
authors.forename: Jon
authors.initials: J
authors.lastname: Valla
mesh_terms: D000328:Adult; D000544:Alzheimer Disease / Q000235:genetics* / Q000473:pathology*; D027322:Amino Acid Transport System X-AG / Q000235:genetics / Q000378:metabolism; D053327:Apolipoprotein E4 / Q000235:genetics*; D004734:Energy Metabolism / Q000235:genetics*; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics*; D006179:Gyrus Cinguli / Q000378:metabolism*; D006593:Hexokinase / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008297:Male; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D027501:Monocarboxylic Acid Transporters / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D055815:Young Adult
chemical_list: D027322:Amino Acid Transport System X-AG; D053327:Apolipoprotein E4; D024101:Mitochondrial Proteins; D027501:Monocarboxylic Acid Transporters; D012333:RNA, Messenger; D006593:Hexokinase
keywords: APOE; Alzheimer’s disease; biomarker; energy metabolism; glucose; ketones; mitochondria; monocarboxylate; neurodegeneration; posterior cingulate