title: Impact of apolipoprotein E ε4 and HIV on cognition and brain atrophy: antagonistic pleiotropy and premature brain aging.
abstract: OBJECTIVE
  The apolipoprotein E (APOE) ε4 allele may accelerate the progression of HIV disease, and increase the risk for developing HIV-associated neurocognitive disorder (HAND). Whether APOEε4 allele(s) and age may influence brain atrophy in HIV patients is unknown and was evaluated.
  
  
  METHODS
  Automated morphometry on magnetic resonance images, using FreeSurfer analyses, neuropsychological testing and APOE genotyping were performed in 139 subjects [70 seronegative controls (SN); 69 clinically-stable HIV subjects].
  
  
  RESULTS
  Compared to SN, HIV subjects had smaller volumes throughout the brain regardless of their HAND status. Compared to APOEε4- subjects, SN controls with APOEε4 had better memory and larger global brain volumes (cerebral white matter and cortex) while HIV subjects with the APOEε4 allele(s) had poorer cognition (verbal fluency, learning, executive function and memory) and smaller cerebral and cerebellar white matter and subcortical structures. Further stratification of age showed that younger (<50 years) APOEε4+SN subjects had larger putamen and cerebral white matter, while younger APOEε4+HIV subjects had poorer performance on verbal fluency and smaller brain volumes [3-way (HIV-status×APOEε4×Age) interaction-p-values=0.005 to 0.03].
  
  
  CONCLUSIONS
  These findings suggest that APOEε4 allele(s) may show antagonistic pleiotropy on cognition and brain atrophy in SN controls, but may lead to premature aging with neurodegeneration in younger HIV patients prior to the development of HAND. Potential mechanisms for such interactions may include stronger neuro-inflammation or greater amyloid deposition in younger HIV subjects with APOEε4 allele(s). Early screening for the APOEε4 allele and brain atrophy with morphometry may guide neuroprotective intervention of cognitively normal HIV subjects prior to the development of HAND. Longitudinal follow-up studies and larger sample sizes are needed to validate these cross-sectional results.
authors.affiliation: Department of Medicine, John A. Burns School of Medicine, The Queen's Medical Center, Honolulu, Hawaii 96813, USA. lchang@hawaii.edu
authors.forename: L
authors.initials: L
authors.lastname: Chang
authors.forename: M
authors.initials: M
authors.lastname: Andres
authors.forename: J
authors.initials: J
authors.lastname: Sadino
authors.forename: C S
authors.initials: CS
authors.lastname: Jiang
authors.forename: H
authors.initials: H
authors.lastname: Nakama
authors.forename: E
authors.initials: E
authors.lastname: Miller
authors.forename: T
authors.initials: T
authors.lastname: Ernst
mesh_terms: D015526:AIDS Dementia Complex / Q000473:pathology* / Q000523:psychology*; D000328:Adult; D000368:Aged; D000375:Aging / Q000502:physiology; D019588:Aging, Premature / Q000209:etiology / Q000473:pathology*; D053327:Apolipoprotein E4 / Q000235:genetics*; D001284:Atrophy; D001921:Brain / Q000473:pathology*; D003071:Cognition / Q000502:physiology*; D003072:Cognition Disorders / Q000235:genetics / Q000473:pathology; D005260:Female; D007839:Functional Laterality / Q000502:physiology; D006801:Humans; D007091:Image Processing, Computer-Assisted; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D011597:Psychomotor Performance / Q000502:physiology
chemical_list: D053327:Apolipoprotein E4