Predictive Utility of Apolipoprotein E Genotype for Alzheimer Disease in Outpatients With Mild Cognitive Impairment

Devanand, Devangere P.; Pelton, Gregory; Zamora, Diana; Liu, Xinhua; Tabert, Matthias H.; Goodkind, Madaleine; Scarmeas, Nikolaos; Braun, Ilana; Stern, Yaakov; Mayeux, Richard Paul

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 ε4 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 ε4 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 ε4 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 ε4 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 ε4 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 ε4 carrier status was associated with conversion to AD in older outpatients after controlling for known demographic and clinical risk factors, and APOE ε4 homozygosity was associated with increased risk of conversion to AD. However, APOE ε4 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.


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Taub Institute
American Medical Association
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January 28, 2016