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The biological analysis of nicastrin (NCSTN) shows its crucial role in gamma-cleavage of the amyloid precursor protein. Inhibition of NCSTN demonstrated altered gamma-cleavage activity, suggesting its potential implication in Alzheimer's disease (AD). We sequenced the NCSTN gene promoter region and found two promoter single nucleotide polymorphisms (SNPs) at putative transcription binding sites, -796T/G and -1216C/A. The association study using the promoter SNPs showed no significant genetic effect upon the development of AD. Haplotype analysis with the promoter SNPs and coding SNPs demonstrated no significant difference between familial AD cases and controls. Moreover, the genotype of each promoter SNP did not have an association with age-at-onset in AD. Our investigation suggests that the two promoter SNPs are unrelated to the development of AD, however, further investigation at the promoter region of NCSTN may be necessary to address its potential implication of gene expression in AD.

Amyotrophic lateral sclerosis (ALS) is a progressive fatal disorder, which results from the degeneration of motor neurons in the brain and spinal cord. Approximately 20% of the inherited autosomal dominant cases are due to mutations within the gene coding for Cu/Zn superoxide dismutase 1 (SOD1), a cytosolic homodimeric enzyme that catalyzes the dismutation of toxic superoxide anion. We investigated the presence of SOD1 gene mutations and activity alterations in two unrelated families of ALS patients from Elba, an island of central Italy. No mutation in SOD1 exon 1 to 5 and no activity alteration were observed in all members of the two analyzed ALS families (FALS). These data show an apparent heterogeneous distribution of ALS patients with SOD1 gene mutations among different populations and suggest that another genetic locus could be involved in the disease.

We investigated the segregation of the copper chaperone for the superoxide dismutase (CCS) gene in two Italian families with amyotrophic lateral sclerosis lacking the mutations in superoxide dismutase 1 gene. We analyzed a total of 56 individuals; six people were affected. Diagnoses were made using the El Escorial criteria. The results of our study provide no evidence of a linkage between markers flanking the CCS gene and familial amyotrophic lateral sclerosis (FALS) in these FALS kindreds.

A novel polymorphism (-491 A/T) within the regulatory region on the apolipoprotein E gene has recently been reported to be associated with risk for Alzheimer disease (AD). To test this association in an independent data set, we have examined this polymorphism in a sample of 88 well-characterized AD cases and compared the allele frequency and genotype frequencies for this polymorphism with those observed in 112 cognitively normal subjects drawn from the same ethnic group. These results suggest that in the current data set at least, the -491 A/T polymorphism is not associated with risk for AD, but may be in partial linkage disequilibrium with the APOE epsilon2/epsilon3/epsilon4 polymorphism.