Distribution of plasma alpha 1-antichymotrypsin levels in Alzheimer disease patients and controls and their genetic controls.

Alzheimer's disease (AD) is a complex multifactorial disease in which many genetic and environmental factors are involved. Recent studies have shown that alpha(1)-antichymotrypsin (ACT) is one of the candidate genes for AD. Elevated levels of ACT have been widely, but not universally reported in the cerebrospinal fluid and plasma of AD patients. The genetic association between the ACT/codon -17*A allele of the signal peptide polymorphism and AD has been shown in some studies. One hypothesis is that the ACT/codon -17*A allele is in linkage disequilibrium with unknown functional mutation(s) in the ACT gene. Alternatively, the more hydrophobic character of the alanine (codon -17*A) may enhance ACT translocation into the endoplasmic reticulum and the Golgi apparatus, thus being secreted at higher levels. Therefore, this study was undertaken to determine the distribution of ACT plasma levels in cases (n = 397) and controls (n = 118) and the impact of ACT polymorphisms, including codon -17, on plasma ACT levels. In our cohort, plasma ACT levels were significantly higher in AD patients than controls (542.13 +/- 7.11 mg/liter vs. 496.62 +/- 12.79 mg/liter; P = 0.002). The ACT/codon -17 polymorphism showed significant association with ACT levels in male AD patients, while the effect of the intron 4 polymorphism was significant in both male and female patients. Codon 227 polymorphism was associated with lower ACT levels in AD patients. In conclusion, ACT may play an important role in the AD pathogenesis and genetic variation in the ACT gene appears to have some effect on plasma ACT concentrations.