title: Reduced hippocampal activation during episodic encoding in middle-aged individuals at genetic risk of Alzheimer's disease: a cross-sectional study.
abstract: BACKGROUND
  The presence of the apolipoprotein E (APOE) epsilon4 allele is a major risk factor for the development of Alzheimer's disease (AD), and has been associated with metabolic brain changes several years before the onset of typical AD symptoms. Functional MRI (fMRI) is a brain imaging technique that has been used to demonstrate hippocampal activation during measurement of episodic encoding, but the effect of the epsilon4 allele on hippocampal activation has not been firmly established.
  
  
  METHODS
  The present study examined the effects of APOE genotype on brain activation patterns in the medial temporal lobe (MTL) during an episodic encoding task using a well-characterized novel item versus familiar item contrast in cognitively normal, middle-aged (mean = 54 years) individuals who had at least one parent with AD.
  
  
  RESULTS
  We found that epsilon3/4 heterozygotes displayed reduced activation in the hippocampus and MTL compared to epsilon3/3 homozygotes. There were no significant differences between the groups in age, education or neuropsychological functioning, suggesting that the altered brain activation seen in epsilon3/4 heterozygotes was not associated with impaired cognitive function. We also found that participants' ability to encode information on a neuropsychological measure of learning was associated with greater activation in the anterior MTL in the epsilon3/3 homozygotes, but not in the epsilon3/4 heterozygotes.
  
  
  CONCLUSIONS
  Together with previous studies reporting reduced glucose metabolism and AD-related neuropathology, this study provides convergent validity for the idea that the MTL exhibits functional decline associated with the APOE epsilon4 allele. Importantly, these changes were detected in the absence of meaningful neuropsychological differences between the groups. A focus of ongoing work in this laboratory is to determine if these findings are predictive of subsequent cognitive decline.
authors.affiliation: Geriatric Research Education and Clinical Center, William S. Middleton Veteran's Affairs Hospital, Madison, WI, USA. mt2@medicine.wisc.edu
authors.forename: Mehul A
authors.initials: MA
authors.lastname: Trivedi
authors.forename: Taylor W
authors.initials: TW
authors.lastname: Schmitz
authors.forename: Michele L
authors.initials: ML
authors.lastname: Ries
authors.forename: Britta M
authors.initials: BM
authors.lastname: Torgerson
authors.forename: Mark A
authors.initials: MA
authors.lastname: Sager
authors.forename: Bruce P
authors.initials: BP
authors.lastname: Hermann
authors.forename: Sanjay
authors.initials: S
authors.lastname: Asthana
authors.forename: Sterling C
authors.initials: SC
authors.lastname: Johnson
mesh_terms: D000328:Adult; D000368:Aged; D000483:Alleles; D000544:Alzheimer Disease / Q000235:genetics* / Q000503:physiopathology*; D001057:Apolipoproteins E / Q000235:genetics*; D003071:Cognition / Q000502:physiology; D003430:Cross-Sectional Studies; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006579:Heterozygote; D006624:Hippocampus / Q000033:anatomy & histology / Q000503:physiopathology*; D006801:Humans; D007858:Learning / Q000502:physiology; D008279:Magnetic Resonance Imaging / Q000379:methods; D008875:Middle Aged; D009483:Neuropsychological Tests; D012307:Risk Factors; D013702:Temporal Lobe / Q000033:anatomy & histology / Q000503:physiopathology
chemical_list: D001057:Apolipoproteins E