An APOE Haplotype Associated with Decreased epsilon 4 Expression Increases the Risk of Late Onset Alzheimer's Disease

作者：Lescai Francesco^*; Chiamenti Andrea Maria; Codemo Alessandra; Pirazzini Chiara; D'Agostino Giuseppe; Ruaro Cristina; Ghidoni Roberta; Benussi Luisa; Galimberti Daniela; Esposito Federica; Marchegiani Francesca; Cardelli Maurizio; Olivieri Fabiola; Nacmias Benedetta; Sorbi Sandro; Tagliavini Fabrizio; Albani Diego; Boneschi Filippo Martinelli; Binetti Giuliano; Santoro Aurelia; Forloni Gianluigi; Scarpini Elio; Crepaldi Gaetano; Gabelli Carlo; Franceschi Claudio

来源：Journal of Alzheimer's Disease, 2011, 24(2): 235-245.

DOI：10.3233/JAD-2010-101764

• Alzheimer disease
• apolipoprotein E
• genetics
• polymorphism
• single nucleotide

This paper addresses a tenet of the literature on APOE, i.e., the relationship between the effects of the epsilon 4, one of the established genetic risk factor for Alzheimer's disease (AD), and its expression levels as determined by APOE promoter polymorphisms. Five polymorphisms (-491 rs449647, -427 rs769446, -219 rs405509, and epsilon rs429358-rs7412) were studied in 1308 AD patients and 1082 control individuals from the Central-Northern Italy. Major findings of the present study are the following: 1) the variants -219T and epsilon 4 increase the risk for late onset AD (LOAD) when they are both present in cis on the same chromosome (in phase); 2) the correlation between the haplotype (-219T/epsilon 4) and AD risk persists when the data are stratified by age; 3) this haplotype likely anticipates the age of onset of the disease. These data, while confirming the association between -219T and AD, highlight the importance of the phase of the alleles for the observed effects on AD risk, suggesting that this information has to be taken into account when assessing the AD genetic risk. Moreover, the data help to clarify the apparent discrepancy that emerges from the genetic analysis where a SNP characterizing the haplotype responsible for an increased risk for LOAD is coherently associated with a reduced expression of ApoE levels. Our data are compatible with the hypothesis of a complex role of ApoE in the AD pathogenesis, with positive and negative effects occurring concomitantly according to its expression levels and its protein-protein interactions largely unclarified.

• 出版日期2011