title: Testosterone modifies the effect of APOE genotype on hippocampal volume in middle-aged men.
abstract: BACKGROUND
  The APOE epsilon4 allele is an established risk factor for Alzheimer disease (AD), yet findings are mixed for how early its effects are manifest. One reason for the mixed results could be the presence of interaction effects with other AD risk factors. Increasing evidence indicates that testosterone may play a significant role in the development of AD. The aim of the present study was to examine the potential interaction of testosterone and APOE genotype with respect to hippocampal volume in middle age.
  
  
  METHODS
  Participants were men from the Vietnam Era Twin Study of Aging (n = 375). The mean age was 55.9 years (range 51-59). Between-group comparisons were performed utilizing a hierarchical linear mixed model that adjusted for the nonindependence of twin data.
  
  
  RESULTS
  A significant interaction was observed between testosterone and APOE genotype (epsilon4-negative vs epsilon4-positive). Those with both low testosterone (> or =1 SD below the mean) and an epsilon4-positive status had the smallest hippocampal volumes, although comparisons with normal testosterone groups were not significant. However, individuals with low testosterone and epsilon4-negative status had significantly larger hippocampal volumes relative to all other groups. A main effect of APOE genotype on hippocampal volume was observed, but only when the APOE-by-testosterone interaction was present.
  
  
  CONCLUSIONS
  These findings demonstrate an interaction effect between testosterone and the APOE epsilon4 allele on hippocampal volume in middle-aged men, and they may suggest 2 low testosterone subgroups. Furthermore, these results allude to potential gene-gene interactions between APOE and either androgen receptor polymorphisms or genes associated with testosterone production.
authors.affiliation: Department of Psychiatry, University of California-San Diego, 9500 Gilman Drive, La Jolla, CA 9293-0738, USA. mspanizz@ucsd.edu
authors.forename: M S
authors.initials: MS
authors.lastname: Panizzon
authors.forename: R
authors.initials: R
authors.lastname: Hauger
authors.forename: A M
authors.initials: AM
authors.lastname: Dale
authors.forename: L J
authors.initials: LJ
authors.lastname: Eaves
authors.forename: L T
authors.initials: LT
authors.lastname: Eyler
authors.forename: B
authors.initials: B
authors.lastname: Fischl
authors.forename: C
authors.initials: C
authors.lastname: Fennema-Notestine
authors.forename: C E
authors.initials: CE
authors.lastname: Franz
authors.forename: M D
authors.initials: MD
authors.lastname: Grant
authors.forename: A J
authors.initials: AJ
authors.lastname: Jak
authors.forename: K C
authors.initials: KC
authors.lastname: Jacobson
authors.forename: M J
authors.initials: MJ
authors.lastname: Lyons
authors.forename: S P
authors.initials: SP
authors.lastname: Mendoza
authors.forename: M C
authors.initials: MC
authors.lastname: Neale
authors.forename: E C
authors.initials: EC
authors.lastname: Prom-Wormley
authors.forename: L J
authors.initials: LJ
authors.lastname: Seidman
authors.forename: M T
authors.initials: MT
authors.lastname: Tsuang
authors.forename: H
authors.initials: H
authors.lastname: Xian
authors.forename: W S
authors.initials: WS
authors.lastname: Kremen
mesh_terms: D000375:Aging / Q000235:genetics; D000483:Alleles; D001057:Apolipoproteins E / Q000235:genetics* / Q000378:metabolism; D005838:Genotype; D006624:Hippocampus / Q000033:anatomy & histology* / Q000378:metabolism; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009929:Organ Size; D011110:Polymorphism, Genetic; D013739:Testosterone / Q000097:blood*; D014481:United States; D014728:Veterans; D047829:Vietnam Conflict
chemical_list: D001057:Apolipoproteins E; D013739:Testosterone
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