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) epsilon 4 carriers than in APOE epsilon 4 noncarriers, and APOE epsilon 4 homozygotes' cognitive performances correlate with stressors. These changes could represent presymptomatic disease in some, despite their youth. Objective: To show that presymptomatic APOE epsilon 4 homozygotes experience greater psychometric decline at a younger age than APOE epsilon 4 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 epsilon 4 homozygotes, 59 APOE epsilon 4 heterozygotes, and 112 APOE epsilon 4 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 epsilon 4 homozygotes 60 years and older at entry (40.0%) compared with 5 of 66 APOE epsilon 4 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 e4 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 epsilon 4 homozygotes in their 60s have higher rates of cognitive domain decline than APOE epsilon 4 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.