Increased brain activation during working memory in cognitively intact adults with the APOE epsilon4 allele

Am J Psychiatry. 2006 Sep;163(9):1603-10. doi: 10.1176/ajp.2006.163.9.1603.


Objective: Altered patterns of brain activity during cognitive tasks have been demonstrated using functional magnetic resonance imaging (fMRI) in mild cognitive impairment and Alzheimer's disease. However, there have been few studies of adults at genetic risk for Alzheimer's disease prior to the onset of symptoms. The purpose of this study was to determine whether brain activation patterns associated with working memory differ as a function of apolipoprotein E (APOE) genotype in cognitively intact adults.

Method: Participants were cognitively intact, healthy adults who completed genotyping, comprehensive neuropsychological testing, and structural and functional neuroimaging. Twenty-two participants had the APOE epsilon3/epsilon3 genotype, and 13 participants had the APOE epsilon3/epsilon4 genotype. The study employed an auditory verbal N-back task to probe working memory-related brain activity.

Results: The epsilon3/epsilon3 and epsilon3/epsilon4 groups did not differ in demographic characteristics, cognitive ability, mood, or in-scanner task performance. The epsilon3/epsilon4 group showed greater activity during working memory in the medial frontal and parietal regions bilaterally and in the right dorsolateral prefrontal cortex. There were no regions in which the epsilon3/epsilon3 group showed greater activation than the epsilon3/epsilon4 group.

Conclusions: These results indicate that differences in brain activity are evident in cognitively intact individuals who are at risk for late-onset Alzheimer's disease by virtue of their APOE allele status. As neuroprotective interventions become available, early detection will increase in importance. The combination of genetic and functional neuroimaging strategies may prove useful for monitoring individuals at risk for Alzheimer's disease before the onset of cognitive symptoms.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adult
  • Aged
  • Alleles
  • Alzheimer Disease / diagnosis
  • Alzheimer Disease / epidemiology
  • Alzheimer Disease / genetics*
  • Apolipoprotein E3
  • Apolipoprotein E4
  • Apolipoproteins E / genetics*
  • Brain / physiology*
  • Cognition / physiology*
  • Female
  • Functional Laterality / physiology
  • Genotype
  • Humans
  • Magnetic Resonance Imaging / statistics & numerical data
  • Male
  • Memory / physiology*
  • Neuropsychological Tests
  • Parietal Lobe / physiology
  • Prefrontal Cortex / physiology
  • Psychomotor Performance / physiology
  • Risk Factors
  • Task Performance and Analysis
  • Verbal Behavior / physiology


  • Apolipoprotein E3
  • Apolipoprotein E4
  • Apolipoproteins E