Preclinical memory decline in cognitively normal apolipoprotein E-epsilon 4 homozygotes

Objective: To determine, in a cross-sectional. evaluation of nondemented in dividuals, if age-related memory decline is influenced by apolipoprotein E (apoE) genotype. Background: The apoE-4 allele is an important risk factor for AD. PET in cognitively normal apoE-4 carriers (mean age, 56 years) show s reduced cerebral metabolism suggestive of very early AD that precedes cli nically evident memory loss or MRI-based hippocampal atrophy. Methods: Test s of immediate and delayed recall (primary outcome measures) and other neur opsychological measures (secondary outcome measures) were given to three ge netically defined groups of cognitively normal individuals (age, 49 to 69 y ears) including apoE-4 homozygotes (n = 25), apoE-4 heterozygotes (n = 25, all epsilon 3/4), and apoE-4 noncarriers (n = 50). Groups were matched for age, gender, and educational background. Cross-sectional comparisons betwee n the genetic subgroups of the relationship between age and test score were performed for each neuropsychological measure. Results: There were no inte rgroup differences in mean scores on any neuropsychological, measure, but t ests sensitive to immediate and delayed recall showed a significant negativ e correlation with age in the apoE-4 homozygote group relative to the nonca rrier group. Conclusion: Consistent with previous neuropsychological studie s of early AD, this cross-sectional study suggests that age-related memory decline occurs earlier in cognitively healthy apoE-4 homozygotes than in ap oE-4 heterozygotes and noncarriers, and precedes clinically detectable AD.