N-acetyltransferase (NAT2) genotype and susceptibility to sporadic Alzheimer's disease

The importance of environmental aggression and individual susceptibility to develop Alzheimer's Disease (AD) has been suggested by epidemiological stu dies on both typical familial and sporadic AD cases. In order to elucidate functions that can influence the susceptibility to AD pathogenesis, we geno typed a group of 53 sporadic late-onset AD patients, matched control indivi duals and a larger randomly selected non-demented population for the N-acet yltransferase (NAT2). We determined the relative frequencies of individual allele combinations that define a broad range of acetylator phenotypes. Int er-individual variability in the cytotoxic and genotoxic responses to a nid e diversity of environmental chemicals is known to result from the polymorp hism of NAT2 as well as other drug-metabolizing-enzyme genes. The results p resented are the first to demonstrate a significant difference in the NAT2 genotype profiles of sporadic AD patients compared with the healthy populat ion. A lower frequency of the recessive alleles NAT2*6 (chi-squared 1 d.f. = 12.56, P < 0.0004) and NAT2*5B (chi-squared 1 d.f = 6.72, P < 0.01) was f ound among the AD population compared with control individuals, which was c oncomitant with a significantly higher number of NAT2*4 fully active allele homozygotes and heterozygotes (chi-squared 1 d.f = 5.69, P = 0.017). The m ost notable observation was the absence of NAT2*5B/NAT2*6 heterozygotes amo ng cases while being present in 22.5% of control individuals (chi-squared 1 d.f. = 13.08, P = 0.0003). These observations indicate that NAT2 is a pote ntial low-penetrance gene in AD pathogenesis, determining an individual sus ceptibility trait predisposing to this degenerative disease. Pharmacogeneti cs 9:9-15 (C) 1999 Lippincott Williams & Wilkins.