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Insulin-degrading enzyme and Alzheimer disease

A genetic association study in the Han Chinese

From the Institute for Nutritional Sciences (Drs. Bian, Yang, Guo, Sun, and He), Chinese Academy of Sciences, Bio-X Life Science Research Center (Drs. Bian, Yang, Guo, Sun, Duan, Chen, Pan, and He), Shanghai JiaoTong University, and Shanghai Institute of Mental Health (Dr. Feng), China.

Address correspondence and reprint requests to Dr. L. He, Bio-X Life Science Research Center, Shanghai Jiao Tong University, 1954 Hua Shan Rd., Shanghai 200030, P. R. China; e-mail: helin{at}sjtu.edu.cn or helin@nhgg.org

Background: The gene for insulin-degrading enzyme (IDE) represents a strong positional and biologic candidate for late-onset Alzheimer disease (LOAD) susceptibility. IDE is located on chromosome 10q23.3 close to a region of linkage for LOAD. In addition, many studies have identified a possible role of IDE in the degradation of amyloid ß-protein and the intracellular amyloid precursor protein (APP) domain released by -secretase processing.

Objective: To examine the association of IDE with AD in the Han Chinese.

Methods: Four IDE polymorphisms (three in 5'-untranslated region and one in intron 21) were analyzed, using a population of 210 patients with LOAD and 200 control subjects well matched for age, sex, and ethnic background.

Results: Among the four polymorphisms studied, only the C allele of single-nucleotide polymorphism (SNP) IDE2 showed association with AD (p = 0.005). Stratification of the data by APOE 4 status indicated that the association between IDE2 and AD was confined to APOE 4 carriers only. No association was found between all variants studied and AD within APOE 4-negative subjects. The global haplotype frequencies showed significant differences between AD patients and control subjects. Furthermore, overrepresentation of GCTG haplotype in the AD group was found. It may be a risk haplotype for AD.

Conclusions: These results suggest a possible synergic interaction between IDE and APOE 4 in the risk to develop late-onset sporadic AD. IDE might modify the effect of the APOE 4 risk factor in the Han Chinese population.

Received December 8, 2003. Accepted in final form March 4, 2004.

Additional material related to this article can be found on the Neurology Web site. Go to www.neurology.org and scroll down the Table of Contents for the July 27 issue to find the title link for this article.

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