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Nicastrin regulates gamma-secretase cleavage of the amyloid precursor protein by forming complexes with presenilins, in which most mutations causing familial early-onset Alzheimer disease (EOAD) have been found. The gene encoding nicastrin (NCSTN) maps to 1q23, a region that has been linked and associated with late-onset Alzheimer disease (LOAD) in various genome screens. In 78 familial EOAD cases, we found 14 NCSTN single-nucleotide polymorphisms (SNPs): 10 intronic SNPs, 3 silent mutations, and 1 missense mutation (N417Y). N417Y is unlikely to be pathogenic, since it did not alter amyloid beta secretion in an in vitro assay and its frequency was similar in case and control subjects. However, SNP haplotype estimation in two population-based series of Dutch patients with EOAD (n=116) and LOAD (n=240) indicated that the frequency of one SNP haplotype (HapB) was higher in the group with familial EOAD (7%), compared with the LOAD group (3%) and control group (3%). In patients with familial EOAD without the APOE epsilon4 allele, the HapB frequency further increased, to 14%, resulting in a fourfold increased risk (odds ratio = 4.1; 95% confidence interval 1.2-13.3; P=.01). These results are compatible with an important role of gamma-secretase dysfunction in the etiology of familial EOAD.

Original publication

DOI

10.1086/340732

Type

Journal article

Journal

Am J Hum Genet

Publication Date

06/2002

Volume

70

Pages

1568 - 1574

Keywords

Age of Onset, Aged, Alleles, Alzheimer Disease, Amyloid Precursor Protein Secretases, Apolipoprotein E4, Apolipoproteins E, Aspartic Acid Endopeptidases, Case-Control Studies, Endopeptidases, Female, Gene Frequency, Genetic Predisposition to Disease, Genetic Variation, Haplotypes, Humans, Male, Membrane Glycoproteins, Middle Aged, Molecular Sequence Data, Netherlands, Odds Ratio, Polymorphism, Single Nucleotide