Preclinical cognitive decline in late middle-aged asymptomatic apolipoprotein E-e4/4 homozygotes: A replication study

Richard J. Caselli, David Osborne, Eric M. Reiman, Joseph G. Hentz, Carolyn J. Barbieri, Ann M. Saunders, John Hardy, Neill R. Graff-Radford, Geri R. Hall, Gene E. Alexander

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57 Scopus citations


In a previous cross-sectional study of 100 asymptomatic individuals aged 49-69, we reported age-related decline in immediate and delayed memory that was steeper in apolipoprotein E (apoE)-e4/4 homozygotes than in members of other genetic subgroups. These findings were preliminarily based upon the statistical problem of multiple comparisons. We therefore sought to replicate these findings in a new cohort. From 1998 to 2000, 80 asymptomatic residents of Maricopa County, AZ were recruited through newspaper ads. 20 apoE-e4/4 homozygotes, 20 e3/4 heterozygotes, and 40 e4 noncarriers were matched (1:1:2) by age, gender, and years of education. All had normal neurologic and psychiatric examinations, including Folstein minimental status exam (MMSE) and Hamilton depression scale, and underwent a battery of neuropsychological tests identical to those in our previous study. The groups were well-matched for age (55.9±5.9 years), gender (60% women), and education (15.9±2.2 years), and were demographically similar to our previous cohort. Complex figure test recall was lower in e3/4 heterozygotes than noncarriers, but there was no significant difference between e4/4 homozygotes and noncarriers. There were no other significant differences in mean test scores between groups, but Wechsler adult intelligence scale-revised (WAIS-R) digit span showed a significant negative correlation with age in the e4/4 homozygote group relative to e4 noncarriers (p=0.008) as we had found in our previous study. In conclusion, we found a significant negative correlation of WAIS-R digit span with age in apoE-e4/4 homozygotes relative to e4 noncarriers in two separate cohorts, possibly reflecting an age-related effect on frontal lobe function in this genetic subgroup.

Original languageEnglish (US)
Pages (from-to)93-98
Number of pages6
JournalJournal of the Neurological Sciences
Issue number1-2
StatePublished - Aug 15 2001


  • Aging
  • Alzheimer's disease
  • Apolipoprotein E
  • Frontal lobe
  • Memory
  • Preclinical

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology


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