title: Peripheral apoE isoform levels in cognitively normal APOE ε3/ε4 individuals are associated with regional gray matter volume and cerebral glucose metabolism.
abstract: BACKGROUND
  Carriers of the APOE ε4 allele are at increased risk of developing Alzheimer's disease (AD), and have been shown to have reduced cerebral metabolic rate of glucose (CMRgl) in the same brain areas frequently affected in AD. These individuals also exhibit reduced plasma levels of apolipoprotein E (apoE) attributed to a specific decrease in the apoE4 isoform as determined by quantification of individual apoE isoforms in APOE ε4 heterozygotes. Whether low plasma apoE levels are associated with structural and functional brain measurements and cognitive performance remains to be investigated.
  
  
  METHODS
  Using quantitative mass spectrometry we quantified the plasma levels of total apoE and the individual apoE3 and apoE4 isoforms in 128 cognitively normal APOE ε3/ε4 individuals included in the Arizona APOE cohort. All included individuals had undergone extensive neuropsychological testing and 25 had in addition undergone FDG-PET and MRI to determine CMRgl and regional gray matter volume (GMV).
  
  
  RESULTS
  Our results demonstrated higher apoE4 levels in females versus males and an age-dependent increase in the apoE3 isoform levels in females only. Importantly, a higher relative ratio of apoE4 over apoE3 was associated with GMV loss in the right posterior cingulate and with reduced CMRgl bilaterally in the anterior cingulate and in the right hippocampal area. Additional exploratory analysis revealed several negative associations between total plasma apoE, individual apoE isoform levels, GMV and CMRgl predominantly in the frontal, occipital and temporal areas. Finally, our results indicated only weak associations between apoE plasma levels and cognitive performance which further appear to be affected by sex.
  
  
  CONCLUSIONS
  Our study proposes a sex-dependent and age-dependent variation in plasma apoE isoform levels and concludes that peripheral apoE levels are associated with GMV, CMRgl and possibly cognitive performance in cognitively healthy individuals with a genetic predisposition to AD.
authors.affiliation: Department of Neuroscience, Mayo Clinic College of Medicine, 4500 San Pablo Rd, Jacksonville, FL, 32224, USA. henrietta.nielsen@neurochem.su.se.|Department of Neurochemistry, Stockholm University, Svante Arrheniusväg 16B, SE-10691, Stockholm, Sweden. henrietta.nielsen@neurochem.su.se.
authors.forename: Henrietta M
authors.initials: HM
authors.lastname: Nielsen
authors.affiliation: Banner Alzheimer's Institute, Phoenix, AZ, 85012, USA.|Department of Mathematics and Statistics, Arizona State University, Tempe, AZ, 85281, USA.|Arizona Alzheimer's Consortium, Phoenix, AZ, 85012, USA.
authors.forename: Kewei
authors.initials: K
authors.lastname: Chen
authors.affiliation: Banner Alzheimer's Institute, Phoenix, AZ, 85012, USA.|Arizona Alzheimer's Consortium, Phoenix, AZ, 85012, USA.
authors.forename: Wendy
authors.initials: W
authors.lastname: Lee
authors.affiliation: Banner Alzheimer's Institute, Phoenix, AZ, 85012, USA.|Arizona Alzheimer's Consortium, Phoenix, AZ, 85012, USA.
authors.forename: Yinghua
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Banner Alzheimer's Institute, Phoenix, AZ, 85012, USA.|Department of Mathematics and Statistics, Arizona State University, Tempe, AZ, 85281, USA.|Arizona Alzheimer's Consortium, Phoenix, AZ, 85012, USA.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Bauer
authors.affiliation: Banner Alzheimer's Institute, Phoenix, AZ, 85012, USA.|Arizona Alzheimer's Consortium, Phoenix, AZ, 85012, USA.|Department of Psychiatry, University of Arizona, Tucson, AZ, 85721, USA.|Division of Neurogenomics, Translational Genomics Research Institute, Phoenix, AZ, 85004, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Reiman
authors.affiliation: Arizona Alzheimer's Consortium, Phoenix, AZ, 85012, USA.|Department of Neurology, Mayo Clinic College of Medicine, Scottsdale, AZ, 85259, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Caselli
authors.affiliation: Department of Neuroscience, Mayo Clinic College of Medicine, 4500 San Pablo Rd, Jacksonville, FL, 32224, USA. bu.guojun@mayo.edu.
authors.forename: Guojun
authors.initials: G
authors.lastname: Bu
mesh_terms: D000367:Age Factors; D000368:Aged; D053318:Apolipoprotein E3 / Q000097:blood* / Q000235:genetics*; D053327:Apolipoprotein E4 / Q000097:blood* / Q000235:genetics*; D001921:Brain / Q000000981:diagnostic imaging* / Q000378:metabolism*; D003071:Cognition; D015331:Cohort Studies; D005260:Female; D020022:Genetic Predisposition to Disease; D005947:Glucose / Q000378:metabolism; D066128:Gray Matter / Q000000981:diagnostic imaging / Q000378:metabolism; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D013058:Mass Spectrometry; D008875:Middle Aged; D009483:Neuropsychological Tests; D009929:Organ Size; D049268:Positron-Emission Tomography; D012737:Sex Factors
chemical_list: D053318:Apolipoprotein E3; D053327:Apolipoprotein E4; D005947:Glucose
keywords: Apolipoprotein E; Cognition; Dementia; Gray matter volume; Plasma