An increasing number of genes have been linked to Alzheimer?s disease (AD). Recently, a new polymorphism of the human alpha2-macroglobulin gene (A2M) was proposed to be a risk factor for AD. This polymorphism is due to an A to G transition in exon 24, at position 1000 based on the cDNA sequence or at position 976 based on the mature protein. This point mutation changes Ile (ATC) to Val (GTC) near the thiolester site of alpha2-macroglobulin. The resultant polymorphism is of high frequency with an allele distribution of 60 to 70 percent A vs. 30 to 35 percent G in white populations. We developed a practicable method for detecting this polymorphism. The new method is based on semi-automated polymerase chain reaction (PCR)-single strand sequence polymorphism (SSCP) analysis and is considerably faster and/or simpler than earlier approaches such as PCR-restriction fragment length polymorphism (RFLP) analysis and direct DNA sequencing. Parallel analysis of human peripheral blood specimens with the three methods showed that the new method is as reliable diagnostically as are the earlier methods. The new method is thus particularly advantageous for large-scale studies of the relationship between this novel point mutation and AD risk.In addition to gene abnormalities, a number of infectious agents such as herpes simplex type 1 virus (HSV-1) have been suggested to participate in the development of AD. We re-investigated the possible role of this virus in the etiology of AD. We found that only a small percentage of coded brain samples from the temporal and frontal cortex of elderly AD patients and controls were positive for HSV-1 DNA. Furthermore, HSV-1 DNA was not more common in the brains of patients with AD and apolipoprotein E4 than in unaffected patients, indicating an unlikely role of HSV-1 in AD.In other collaborative studies, we continued studying the possible pathogenetic role of apolipoprotein(a) isoforms and alleles in patients with atherosclerotic heart disease and systemic lupus erythematosus.

Agency
National Institute of Health (NIH)
Institute
Clinical Center (CLC)
Type
Intramural Research (Z01)
Project #
1Z01CL010307-02
Application #
6431870
Study Section
Cognition and Perception Study Section (CP)
Project Start
Project End
Budget Start
Budget End
Support Year
2
Fiscal Year
2000
Total Cost
Indirect Cost
Name
Clinical Center
Department
Type
DUNS #
City
State
Country
United States
Zip Code
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