An APOE Haplotype Associated with Decreased ε4 Expression Increases the Risk of Late Onset Alzheimer's Disease

Article type: Research Article

Authors: Lescai, Francesco^{a; b; q; *} | Chiamenti, Andrea Maria^d | Codemo, Alessandra^{d; f} | Pirazzini, Chiara^{c; p} | D'Agostino, Giuseppe^c | Ruaro, Cristina^d | Ghidoni, Roberta^{h; i} | Benussi, Luisa^h | Galimberti, Daniela^j | Esposito, Federica^k | Marchegiani, Francesca^l | Cardelli, Maurizio^l | Olivieri, Fabiola^l | Nacmias, Benedetta^m | Sorbi, Sandro^m | Tagliavini, Fabrizioⁿ | Albani, Diego^o | Boneschi, Filippo Martinelli^k | Binetti, Giuliano^h | Santoro, Aurelia^{b; c} | Forloni, Gianluigi^o | Scarpini, Elioⁱ | Crepaldi, Gaetano^{d; g} | Gabelli, Carlo^{d; f} | Franceschi, Claudio^{b; c}

Affiliations: [a] Division of Research Strategy and UCL Cancer Institute, University College London, London, UK | [b] CIG – Interdepartmental Centre “L. Galvani” for Biocomplexity, Alma Mater Studiorum Università di Bologna, Bologna, Italy | [c] Department of Experimental Pathology, Alma Mater Studiorum Università di Bologna, Bologna, Italy | [d] Centro Regionale per lo Studio e la Cura dell'Invecchiamento Cerebrale (CRIC), Padova-Arcugnano (VI) – Consorzio di Ricerca Luigi Amaducci, Italy | [e] U.L.S.S. 16, Padova, Italy | [f] Clinica Medica 1°, Università di Padova, Padova, Italy | [g] CNR – Istituto di Neuroscienze, Sezione Invecchiamento, Padova, Italy | [h] NeuroBioGen Lab-Memory Clinic, IRCCS “Centro S. Giovanni di Dio-Fatebenefratelli”, Brescia, Italy | [i] Proteomics Unit, IRCCS “Centro S.Giovanni di Dio-Fatebenefratelli”, Brescia, Italy | [j] Department of Neurological Sciences, Centro Dino Ferrari, University of Milan, Fondazione IRCCS Fondazione Ospedale Maggiore Policlinico, Milan, Italy | [k] Institute of Experimental Neurology (INSPE) and Department of Neurology, San Raffaele Scientific Institute, Milan, Italy | [l] Italian National Research Center for Aging I.N.R.C.A., Ancona, Italy | [m] Department of Neurological and Psychiatric Sciences, University of Florence, Florence, Italy | [n] Fondazione IRCCS, Istituto Neurologico Carlo Besta, Milan, Italy | [o] “Mario Negri” Institute for Pharmacological Research, Milan, Italy | [p] Department of Pathobiology and Biomedical Methodologies, Università di Palermo, Palermo, Italy | [q] ITB-CNR, Institute of Biomedical Technology – Italian National Council of Research, Milano, Italy

Correspondence: [*] Correspondence to: Francesco Lescai, UCL Cancer Institute, University College London, Gower Street, WC1 6BT London, UK. E-mail: [email protected].

Abstract: This paper addresses a tenet of the literature on APOE, i.e., the relationship between the effects of the ε4, 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 ε 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 ε4 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/ε4) 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 an 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.

Keywords: Alzheimer disease, apolipoprotein E, genetics, polymorphism, single nucleotide

DOI: 10.3233/JAD-2011-101764

Journal: Journal of Alzheimer's Disease, vol. 24, no. 2, pp. 235-245, 2011