APOE-ASTERISK-4-ASSOCIATED ALZHEIMERS-DISEASE RISK IS MODIFIED BY ALPHA-1-ANTICHYMOTRYPSIN POLYMORPHISM

Genetic studies on Alzheimer’s disease (AD), a devastating neurodegenerative disorder, have identified the apolipoprotein E (APOE) gene as a strong susceptibility marker for AD1–2. TheE*4 allele of APOE is a major risk factor for AD regardless of age of onset or family history3. However, the observation that the APOE*4 allele is neither necessary nor sufficient for the expression of AD emphasizes the involvement of other environmental or genetic elements that, either in conjunction with APOE*4 or alone, increase an individual’s risk of developing AD. Among the candidate genes that may affect the risk of this multifactorial disease is the gene coding for α1 -antichymotrypsin (ACT). Like APOE protein, ACT binds to β-amyloid peptide (ApP) with high affinity in the filamentous deposits found in the AD brain4–10 and serves as a strong stimulatory factor in the polymerization of AβP into amyloid filaments10. In AD brains, ACT expression is enhanced, particularly in areas that develop amyloid plaques4–8, 11–12, suggesting that ACT may play an important role in the pathogenesis of AD. Here we show that a common polymorphism in the signal peptide of ACT13 confers a significant risk for AD. Furthermore, the APOE*4 gene dosage effect associated with AD risk is significantly modified by the ACT polymorphism. We have also identified a unique combination of the ACT/AA and APOE 4/4 genotypes as a potential susceptibility marker for AD, as its frequency was 1/17 in the AD group compared to 1/313 in the general population control. Our data show that ACT behaves as a modifier gene that alters the AD risk conventionally associated with the APOE*4 allele. © 1995 Nature Publishing Group.