title: Interactive effect of apolipoprotein e genotype and age on hippocampal activation during memory processing in healthy adults.
abstract: BACKGROUND
  Although the apolipoprotein E (APOE) ϵ4 allele is a major genetic risk factor for late-onset Alzheimer disease, its effect on hippocampal function during episodic memory is controversial because studies have yielded mixed results. The age of the studied cohorts may contribute to this apparent inconsistency: activation for ϵ4 carriers tends to be increased in studies of older adults but decreased in some studies of younger adults. Consistent with differential age effects, research in transgenic mice suggests that the ϵ4 allele may particularly affect the aging process.
  
  
  OBJECTIVE
  To define the interactions of age and this allelic variation on brain activation during episodic memory across adult life in healthy individuals.
  
  
  METHODS
  Functional magnetic resonance imaging (fMRI) using an episodic memory paradigm to test for differences in neuroactivation across APOE genotypes and age groups.
  
  
  METHODS
  A federal research institute.
  
  
  METHODS
  Healthy white volunteers (APOE ϵ3 homozygotes and ϵ2 and ϵ4 heterozygotes) completed the fMRI task (133 volunteers aged 19-77 years).
  
  
  METHODS
  Memory-related regional blood oxygenation level-dependent (BOLD) activation.
  
  
  RESULTS
  Genotype affected the pattern of change in hippocampal BOLD activation across the adult lifespan: older age was associated with decreased activation in ϵ2 carriers and, to a lesser extent, in ϵ3 homozygotes, but this pattern was not observed in ϵ4 carriers. Among young participants, ϵ4 carriers had less hippocampal activation compared with ϵ3 homozygotes despite similar task performance.
  
  
  CONCLUSIONS
  The findings support the hypothesis that aging and APOE allele status have interacting effects on the neural substrate of episodic memory and lend clarification to disparities in the literature. The stepwise decrease in activation with age found among genotype groups resembles the order of susceptibility to Alzheimer disease, suggesting a compensatory neurobiological mechanism in older asymptomatic ϵ4 carriers.
authors.affiliation: Clinical Brain Disorders Branch, Genes, Cognition, and Psychosis Program, Division of Intramural Research Programs, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Nichols
authors.forename: Joseph C
authors.initials: JC
authors.lastname: Masdeu
authors.forename: Venkata S
authors.initials: VS
authors.lastname: Mattay
authors.forename: Philip
authors.initials: P
authors.lastname: Kohn
authors.forename: Matthew
authors.initials: M
authors.lastname: Emery
authors.forename: Fabio
authors.initials: F
authors.lastname: Sambataro
authors.forename: Bhaskar
authors.initials: B
authors.lastname: Kolachana
authors.forename: Brita
authors.initials: B
authors.lastname: Elvevåg
authors.forename: Shane
authors.initials: S
authors.lastname: Kippenhan
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Weinberger
authors.forename: Karen F
authors.initials: KF
authors.lastname: Berman
mesh_terms: D000328:Adult; D000367:Age Factors; D000368:Aged; D000375:Aging / Q000235:genetics; D000544:Alzheimer Disease / Q000235:genetics / Q000523:psychology; D053318:Apolipoprotein E3 / Q000235:genetics*; D053327:Apolipoprotein E4 / Q000235:genetics*; D001931:Brain Mapping / Q000379:methods*; D005260:Female; D006580:Genetic Carrier Screening; D020022:Genetic Predisposition to Disease; D006624:Hippocampus / Q000378:metabolism / Q000503:physiopathology; D006801:Humans; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D061212:Memory, Episodic; D008875:Middle Aged; D009483:Neuropsychological Tests; D012307:Risk Factors
chemical_list: D053318:Apolipoprotein E3; D053327:Apolipoprotein E4