title: Brain differences in infants at differential genetic risk for late-onset Alzheimer disease: a cross-sectional imaging study.
abstract: OBJECTIVE
  Converging evidence suggests brain structure alterations may precede overt cognitive impairment in Alzheimer disease by several decades. Early detection of these alterations holds inherent value for the development and evaluation of preventive treatment therapies.
  
  
  OBJECTIVE
  To compare magnetic resonance imaging measurements of white matter myelin water fraction (MWF) and gray matter volume (GMV) in healthy infant carriers and noncarriers of the apolipoprotein E (APOE) ε4 allele, the major susceptibility gene for late-onset AD.
  
  
  METHODS
  Quiet magnetic resonance imaging was performed at an academic research imaging center on 162 healthy, typically developing 2- to 25-month-old infants with no family history of Alzheimer disease or other neurological or psychiatric disorders. Cross-sectional measurements were compared in the APOE ε4 carrier and noncarrier groups. White matter MWF was compared in one hundred sixty-two 2- to 25-month-old sleeping infants (60 ε4 carriers and 102 noncarriers). Gray matter volume was compared in a subset of fifty-nine 6- to 25-month-old infants (23 ε4 carriers and 36 noncarriers), who remained asleep during the scanning session. The carrier and noncarrier groups were matched for age, gestational duration, birth weight, sex ratio, maternal age, education, and socioeconomic status.
  
  
  METHODS
  Automated algorithms compared regional white matter MWF and GMV in the carrier and noncarrier groups and characterized their associations with age.
  
  
  RESULTS
  Infant ε4 carriers had lower MWF and GMV measurements than noncarriers in precuneus, posterior/middle cingulate, lateral temporal, and medial occipitotemporal regions, areas preferentially affected by AD, and greater MWF and GMV measurements in extensive frontal regions and measurements were also significant in the subset of 2- to 6-month-old infants (MWF differences, P < .05, after correction for multiple comparisons; GMV differences, P < .001, uncorrected for multiple comparisons). Infant ε4 carriers also exhibited an attenuated relationship between MWF and age in posterior white matter regions.
  
  
  CONCLUSIONS
  While our findings should be considered preliminary, this study demonstrates some of the earliest brain changes associated with the genetic predisposition to AD. It raises new questions about the role of APOE in normal human brain development, the extent to which these processes are related to subsequent AD pathology, and whether they could be targeted by AD prevention therapies.
authors.affiliation: Advanced Baby Imaging Lab, School of Engineering, Brown University, Providence, Rhode Island.
authors.forename: Douglas C
authors.initials: DC
authors.lastname: Dean
authors.affiliation: Alpert Medical School of Brown University, Providence, Rhode Island.
authors.forename: Beth A
authors.initials: BA
authors.lastname: Jerskey
authors.affiliation: Banner Alzheimer's Institute, Phoenix, Arizona4Department of Mathematics, Arizona State University, Tempe5Department of Radiology, University of Arizona School of Medicine, Tucson6Arizona Alzheimer's Consortium, Phoenix.
authors.forename: Kewei
authors.initials: K
authors.lastname: Chen
authors.affiliation: Banner Alzheimer's Institute, Phoenix, Arizona6Arizona Alzheimer's Consortium, Phoenix.
authors.forename: Hillary
authors.initials: H
authors.lastname: Protas
authors.affiliation: Banner Alzheimer's Institute, Phoenix, Arizona6Arizona Alzheimer's Consortium, Phoenix.
authors.forename: Pradeep
authors.initials: P
authors.lastname: Thiyyagura
authors.affiliation: Banner Alzheimer's Institute, Phoenix, Arizona6Arizona Alzheimer's Consortium, Phoenix.
authors.forename: Auttawat
authors.initials: A
authors.lastname: Roontiva
authors.affiliation: Advanced Baby Imaging Lab, School of Engineering, Brown University, Providence, Rhode Island7Department of Neuroimaging, King's College London, Institute of Psychiatry, London, England.
authors.forename: Jonathan
authors.initials: J
authors.lastname: O'Muircheartaigh
authors.affiliation: Advanced Baby Imaging Lab, School of Engineering, Brown University, Providence, Rhode Island.
authors.forename: Holly
authors.initials: H
authors.lastname: Dirks
authors.affiliation: Advanced Baby Imaging Lab, School of Engineering, Brown University, Providence, Rhode Island.
authors.forename: Nicole
authors.initials: N
authors.lastname: Waskiewicz
authors.affiliation: Advanced Baby Imaging Lab, School of Engineering, Brown University, Providence, Rhode Island.
authors.forename: Katie
authors.initials: K
authors.lastname: Lehman
authors.affiliation: Arizona Alzheimer's Consortium, Phoenix9Neurogenomics Division, Translational Genomics Research Institute, Phoenix, Arizona.
authors.forename: Ashley L
authors.initials: AL
authors.lastname: Siniard
authors.affiliation: Neurogenomics Division, Translational Genomics Research Institute, Phoenix, Arizona.
authors.forename: Mari N
authors.initials: MN
authors.lastname: Turk
authors.affiliation: Imaging Genetics Center, Laboratory of Neuro Imaging, Department of Neurology, University of California, Los Angeles School of Medicine, Los Angeles.
authors.forename: Xue
authors.initials: X
authors.lastname: Hua
authors.affiliation: Imaging Genetics Center, Laboratory of Neuro Imaging, Department of Neurology, University of California, Los Angeles School of Medicine, Los Angeles.
authors.forename: Sarah K
authors.initials: SK
authors.lastname: Madsen
authors.affiliation: Imaging Genetics Center, Laboratory of Neuro Imaging, Department of Neurology, University of California, Los Angeles School of Medicine, Los Angeles.
authors.forename: Paul M
authors.initials: PM
authors.lastname: Thompson
authors.affiliation: Banner Alzheimer's Institute, Phoenix, Arizona6Arizona Alzheimer's Consortium, Phoenix8Department of Neurology, University of California, San Diego School of Medicine, San Diego.
authors.forename: Adam S
authors.initials: AS
authors.lastname: Fleisher
authors.affiliation: Arizona Alzheimer's Consortium, Phoenix9Neurogenomics Division, Translational Genomics Research Institute, Phoenix, Arizona.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Huentelman
authors.affiliation: Advanced Baby Imaging Lab, School of Engineering, Brown University, Providence, Rhode Island.
authors.forename: Sean C L
authors.initials: SC
authors.lastname: Deoni
authors.affiliation: Banner Alzheimer's Institute, Phoenix, Arizona6Arizona Alzheimer's Consortium, Phoenix9Neurogenomics Division, Translational Genomics Research Institute, Phoenix, Arizona11Department of Psychiatry, University of Arizona School of Medicine, Phoenix.
authors.forename: Eric M
authors.initials: EM
authors.lastname: Reiman
mesh_terms: D017668:Age of Onset; D000483:Alleles; D000544:Alzheimer Disease / Q000175:diagnosis / Q000235:genetics / Q000473:pathology*; D053327:Apolipoprotein E4 / Q000235:genetics; D054022:Cerebrum / Q000473:pathology*; D002675:Child, Preschool; D003430:Cross-Sectional Studies; D042241:Early Diagnosis; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006579:Heterozygote; D006801:Humans; D007223:Infant; D008279:Magnetic Resonance Imaging / Q000295:instrumentation / Q000379:methods*
chemical_list: D053327:Apolipoprotein E4