Role of common and rare APP DNA sequence variants in Alzheimer disease

Abstract

Objectives: More than 30 different rare mutations, including copy number variants (CNVs), in the amyloid precursor protein gene (APP) cause early-onset familial Alzheimer disease (EOFAD), whereas the contribution of common APP variants to disease risk remains controversial. In this study we systematically assessed the role of both rare and common APP DNA variants in Alzheimer disease (AD) families.

Methods: Families with EOFAD genetically linked to the APP region were screened for missense mutations and locus duplications of APP. Further, using genome-wide DNA microarray data, we examined the APP locus for CNVs in a total of 797 additional early- and late-onset AD pedigrees. Finally, 423 single nucleotide polymorphisms (SNPs) in the APP locus, including 2 promoter polymorphisms previously associated with AD risk, were tested in up to 4,200 individuals from multiplex AD families.

Results: Analyses of 8 21q21-linked families revealed one family carrying a nonsynonymous mutation in exon 17 (Val717Leu) and another family with a partially penetrant 3.5-Mb locus duplication encompassing APP. CNV analysis in the APP locus revealed an additional family carrying a fully penetrant 380-kb duplication, merely spanning APP. Last, contrary to previous reports, association analyses of more than 400 different SNPs in or near APP failed to show significant effects on AD risk.

Conclusion: Our study shows that APP mutations and locus duplications are a very rare cause of EOFAD and that the contribution of common APP variants to AD susceptibility is insignificant. Furthermore, duplications of APP may not be fully penetrant, possibly indicating the existence of hitherto unknown protective genetic factors.

Figure 1. Pedigree charts of families found to carry disease-causing APP mutations and locus duplications

Information for each individual is (from top to bottom): age at onset (in affected individuals) or age at last examination (unaffected individuals); APOE genotype; and APP mutation finding. Probands are indicated by arrows. No DNA or clinical information was available from the founders (?). dup = carriers of APP duplication; mut = carriers of Val717Leu mutation.

Figure 2. Delineation of the APP duplicated region identified here and those in previous studies

Approximate locations of the duplicated intervals across studies are shown. Solid arrows indicate minimal size of the duplicated interval; dotted lines indicate maximal boundaries. Note that our study is the only to use high-density genome-wide association study data, allowing a much more precise delineation of the duplicated interval than the lower-resolution microsatellite-based mapping. Physical location of duplicated segments from microarray data mapped to hg18 assembly are family (Fam.) VI (chr21: 23984747–27466529) and family BRB (chr21: 26125668–26505191).