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 the N-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 of NAT2 as well as other drug-metabolizing-enzyme genes.

The results presented are the first to demonstrate a significant difference in the NAT2 genotype profiles of sporadic AD patients compared with the healthy population. 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 found among the AD population compared with control individuals, which was concomitant 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 most notable observation was the absence of NAT2*5B/NAT2*6 heterozygotes among 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 potential low-penetrance gene in AD pathogenesis, determining an individual susceptibility trait predisposing to this degenerative disease.