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4 homozygotes
From the Department of Neurology (Dr. Caselli), the Division of Biostatistics (A. Weaver), and the Division of Psychology (Dr. Osborne), Mayo Clinic Scottsdale, AZ; the Department of Neurology (Drs. Graff–Radford and Lucas), Mayo Clinic Jacksonville, FL; the Department of Psychiatry (Dr. Reiman), University of Arizona and Samaritan Positron Emission Tomography Center, Phoenix, AZ; the Arizona Research Laboratories Division of Neural Systems, Memory, and Aging (Dr. Ueker), University of Arizona, Tucson, AZ; and the Department of Laboratory Medicine (Dr. Thibodeau), Mayo Clinic, Rochester, MN.
Address correspondence and reprint requests to Dr. Richard J. Caselli, Department of Neurology, Mayo Clinic Scottsdale, 13400 East Shea Boulevard, Scottsdale, AZ 85259.
OBJECTIVE: To determine, in a cross-sectional evaluation of nondemented individuals, 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) shows reduced cerebral metabolism suggestive of very early AD that precedes clinically evident memory loss or MRI-based hippocampal atrophy.
METHODS: Tests of immediate and delayed recall (primary outcome measures) and other neuropsychological measures (secondary outcome measures) were given to three genetically defined groups of cognitively normal individuals (age, 49 to 69 years) including apoE-4 homozygotes (n = 25), apoE-4 heterozygotes (n = 25, all 
3/4), and apoE-4 noncarriers (n = 50). Groups were matched for age, gender, and educational background. Cross-sectional comparisons between the genetic subgroups of the relationship between age and test score were performed for each neuropsychological measure.
RESULTS: There were no intergroup differences in mean scores on any neuropsychological measure, but tests sensitive to immediate and delayed recall showed a significant negative correlation with age in the apoE-4 homozygote group relative to the noncarrier group.
CONCLUSION: Consistent with previous neuropsychological studies of early AD, this cross-sectional study suggests that age-related memory decline occurs earlier in cognitively healthy apoE-4 homozygotes than in apoE-4 heterozygotes and noncarriers, and precedes clinically detectable AD.
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