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D. P. Devanand, MD; Gregory H. Pelton, MD; Diana Zamora, BA; Xinhua Liu, PhD; Matthias H. Tabert, PhD; Madeleine Goodkind, BA; Nikolaos Scarmeas, MD; Ilana Braun, MD; Yaakov Stern, PhD; Richard Mayeux, MD

Arch Neurol. 2005;62:975-980.

Background  In cognitively impaired patients without dementia, the utility of apolipoprotein E (APOE) genotyping is unclear.

Objective  To evaluate the predictive utility of the APOE 4 genotype for conversion to probable Alzheimer disease (AD).

Design  Naturalistic, longitudinal study.

Setting  Memory disorders outpatient clinic.

Patients  A total of 136 patients with memory complaints were determined to have mild cognitive impairment and were evaluated every 6 months. Fifty-seven age- and sex-matched healthy controls were evaluated annually.

Main Outcome Measures  Primary outcome measures included conversion to AD. Secondary outcome measures included change over time in Mini-Mental State Examination (MMSE) score and Selective Reminding Test (SRT) delayed recall score.

Results  The APOE 4 allele was present in 25% of patients and 21% of healthy controls. During a mean ± SD follow-up of 35.2 ± 24.3 months, 35 of 136 patients converted to AD. APOE 4 carrier status did not differ between converters (31%) and nonconverters to AD (23%, P = .3) and did not affect the time trend in MMSE or SRT scores in the entire sample. Four of 5 APOE 4 homozygotes converted to AD compared with 7 of 29 heterozygotes (P = .02). In a Cox proportional hazards model stratified by age quartiles, after controlling for sex, education, MMSE score, and SRT delayed recall score, APOE 4 increased the risk of AD in patients 70 to 85 years old (n = 57; risk ratio, 2.77; 95% confidence interval, 1.1-7.3; P = .03) but not in patients 55 to 69 years old (n = 79; P = .7).

Conclusions  APOE 4 carrier status was associated with conversion to AD in older outpatients after controlling for known demographic and clinical risk factors, and APOE 4 homozygosity was associated with increased risk of conversion to AD. However, APOE 4 carrier status by itself did not predict cognitive decline or conversion to AD, indicating that APOE genotyping in patients with mild cognitive impairment may have limited clinical applicability for prediction of outcome.

Author Affiliations: Department of Biological Psychiatry, New York State Psychiatric Institute (Drs Devanand, Pelton, Liu, Tabert, and Braun and Mss Zamora and Goodkind), Department of Neurology, College of Physicians and Surgeons (Drs Scarmeas, Stern, and Mayeux), Gertrude H. Sergievsky Center (Drs Scarmeas, Stern, and Mayeux), and Taub Institute for Research in Alzheimer’s Disease and the Aging Brain (Drs Devanand, Scarmeas, Stern, and Mayeux), Columbia University, New York, NY.

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