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Cognitive Domain Decline in Healthy Apolipoprotein E 4 Homozygotes Before the Diagnosis of Mild Cognitive Impairment

Richard J. Caselli, MD; Eric M. Reiman, MD; Dona E. C. Locke, PhD; Michael L. Hutton, PhD; Joseph G. Hentz, MS; Charlene Hoffman-Snyder, RN, CNP; Bryan K. Woodruff, MD; Gene E. Alexander, PhD; David Osborne, PhD

Arch Neurol. 2007;64(9):1306-1311.

Background  Memory declines more rapidly with age in apolipoprotein E (APOE) 4 carriers than in APOE 4 noncarriers, and APOE 4 homozygotes' cognitive performances correlate with stressors. These changes could represent presymptomatic disease in some, despite their youth.

Objective  To show that presymptomatic APOE 4 homozygotes experience greater psychometric decline at a younger age than APOE 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 4 homozygotes, 59 APOE 4 heterozygotes, and 112 APOE 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 4 homozygotes 60 years and older at entry (40.0%) compared with 5 of 66 APOE 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 4 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 4 homozygotes in their 60s have higher rates of cognitive domain decline than APOE 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.

Author Affiliations: Departments of Neurology (Drs Caselli and Woodruff and Ms Hoffman-Snyder), Psychology and Psychiatry (Drs Locke and Osborne), and Biostatistics (Mr Hentz), Mayo Clinic, Scottsdale, Arizona; Department of Psychiatry, University of Arizona, Tucson (Dr Reiman); Department of Psychology, Arizona State University, Tempe (Dr Alexander); Department of Neuroscience, Mayo Clinic, Jacksonville, Florida (Dr Hutton); and the Arizona Alzheimer's Disease Research Consortium, Maricopa County, Arizona (Drs Caselli, Reiman, Locke, Woodruff, Alexander, and Osborne and Ms Hoffman-Snyder).