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Functional Evaluation and Allele Frequencies in Alzheimer Disease

Eleni S. Athan, PhD; Joseph H. Lee, PhD; Alex Arriaga, BA; Richard P. Mayeux, MD,MPH; Benjamin Tycko, MD,PhD

Arch Neurol. 2002;59:1793-1799.

Background  Missense mutations in the amyloid precursor protein (APP) gene cause early-onset Alzheimer disease (AD). However, little is known regarding the effects of polymorphisms in regulatory sequences of APP on AD susceptibility.

Objectives  To identify polymorphisms in the APP promoter, to test these for associations with AD, and to assess their influence on APP promoter activity in transfected cells.

Setting  Community study of 1013 people of white, African American, or Caribbean Hispanic ethnicity, 65 years and older, residing in northern Manhattan.

Main Outcome Measures  The diagnosis of AD was established by stringent criteria, with multiple follow-up examinations over 7 years.

Results  We identified 2 polymorphisms in the APP promoter: a rare GC variant at –9 and a frequent GC variant at +37 relative to the transcription start site. The +37C allele was most frequent in African American patients (18% frequency), followed by Caribbean Hispanic patients (10%) and white patients of European descent (3%). This allele was overrepresented among patients with AD compared with elderly controls (odds ratio [OR], 1.57; 95% confidence interval [CI], 1.08-2.27 in the combined ethnic groups), but this was not significant after adjusting for age, sex, and education (OR, 1.41; 95% CI, 0.93-2.12). A stronger association was found in participants lacking any apolipoprotein-E 4 allele (OR, 2.12; 95% CI, 1.36-3.32 [univariate analysis]; OR, 2.08; 95% CI, 1.26-3.45 after adjusting for age, sex, and education). The –9C allele was not frequent enough to be evaluated for a disease association. Both variants were tested in promoter-reporter assays in U-87 glioma cells, and no differences in promoter activity were detected.

Conclusions  The –9G/C and +37G/C APP promoter polymorphisms are unlikely to contribute strongly to AD susceptibility or to cause major differences in APP expression, but the +37C allele warrants further study for association with AD in larger population samples.

From the Taub Institute for Research on Alzheimer's Disease and the Aging Brain (Drs Athan, Mayeux, and Tycko), Gertrude H. Sergievsky Center (Drs Lee and Mayeux and Mr Arriaga), and Departments of Neurology (Dr Mayeux) and Pathology (Dr Tycko), Columbia University College of Physicians and Surgeons, New York, NY.

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