The importance of environmental aggression and individual susceptibility to develop Alzheimer's Disease (AD) has been suggested by epidemiological studies on both typical familial and sporadic AD cases. In order to elucidate functions that can influence the susceptibility to AD pathogenesis, we genotyped a group of 53 sporadic late-onset AD patients, matched control individuals and a larger randomly selected non-demented population for theN-acetyltransferase (NAT2). We determined the relative frequencies of individual allele combinations that define a broad range of acetylator phenotypes. Inter-individual variability in the cytotoxic and genotoxic responses to a wide diversity of environmental chemicals is known to result from the polymorphism ofNAT2as well as other drug-metabolizing-enzyme genes. The results presented are the first to demonstrate a significant difference in theNAT2genotype profiles of sporadic AD patients compared with the healthy population. A lower frequency of the recessive allelesNAT2*6(chi-squared 1 d.f. = 12.56,P< 0.0004) andNAT2*5B(chi-squared 1 d.f. = 6.72,P< 0.01) was found among the AD population compared with control indivduals, which was concomitant with a significantly higher number ofNAT2*4fully active allele homozygotes and heterozygotes (chi-squared 1 d.f. = 5.69,P= 0.017). The most notable observation was the absence ofNAT2*5B/NAT2*6heterozygotesamong cases while being present in 22.5% of control individuals (chi-squared 1 d.f. = 13.08,P= 0.0003). These observations indicate thatNAT2is a potential low-penetrance gene in AD pathogenesis, determining an individual susceptibility trait predisposing to this degenerative disease. Pharmacogenetics 9:9–15 © 1999 Lippincott Williams & Wilkins