Cognitive domain decline in healthy apolipoprotein E ε4 homozygotes before the diagnosis of mild cognitive impairment

Background: Memory declines more rapidly with age in apolipoprotein E (APOE) ε4 carriers than in APOE ε4 noncarriers, and APOE ε4 homozygotes' cognitive performances correlate with stressors. These changes could represent presymptomatic disease in some, despite their youth. Objective: To show that presymptomatic APOE ε4 homozygotes experience greater psychometric decline at a younger age than APOE ε4 heterozygotes and noncarriers before the diagnosis of mild cognitive impairment (MCI) and Alzheimer disease (AD). Design: Prospective observational study Setting: Academic medical center. Participants: A total of 43 APOE ε4 homozygotes, 59 APOE ε4 heterozygotes, and 112 APOE ε4 noncarriers aged 50 to 69 years were cognitively healthy and matched at entry according to age, educational level, and sex. Intervention: Neuropsychological battery given every 2 years. Main Outcome Measures: Predefined test and cognitive domain decline criteria applied to consecutive epochs. Results: Of 214 participants, 48 showed no decline on any test, 126 showed decline on only 1 test in 1 or more domains, and 40 showed decline on 2 or more tests in 1 or more domains. Cognitive domain decline occurred in 4 of 10 APOE ε4 homozygotes 60 years and older at entry (40.0%) compared with 5 of 66 APOE ε4 heterozygotes and noncarriers (7.6%) (P=.02) and was more predictive of subsequent decline than nondomain decline (17 of 24 [70.8%] vs 29 of 70 [41.4%]; P=.01). Decline on any memory test was predictive of further decline (P<.001), as was memory domain decline (P=.006) in all genetic subgroups. Seven participants developed MCI (in 6) or AD (in 1), of whom 5 were APOE ε4 homozygotes (P=.008). Retrospective comparison showed that those who experienced multidomain, memory, and language domain decline had lower spatial and memory scores at entry than those who experienced no decline. Conclusions: APOE ε4 homozygotes in their 60s have higher rates of cognitive domain decline than APOE ε4 heterozygotes or noncarriers before the diagnosis of MCI and AD, thus confirming and characterizing the existence of a pre-MCI state in this genetic subset.