Association of rare apolipoprotein E ε4 homozygosity with an earlier age at onset in spinocerebellar ataxia type 3

Meyer C.C.; de Mattos E.P.; Burger R.M.; Blumenstock G.; Pereira Sena P.; Gordon C.; Zaltzman R.; França M.C., Jr; Saraiva-Pereira M.-L.; Cornejo-Olivas M.R.; Bauer P.; Schöls L.; van de Warrenburg B.P.; Durr A.; Brice A.; Klockgether T.; Jardim L.B.; Riess O.; Schmidt T. · Human Molecular Genetics (2026) · DOI: 10.1093/hmg/ddag016

Resumen

Spinocerebellar Ataxia Type 3 (SCA3) is an autosomal dominant neurodegenerative Polyglutamine (polyQ) disease, caused by a cytosine-adenine-guanine (CAG) repeat expansion in the ATXN3 gene, resulting in an expanded polyQ tract in the Ataxin-3 protein. Although the principal genetic determinant of the age at onset (AAO) in polyQ diseases is the expanded CAG repeat length, variability in AAO has been explained only partly, suggesting the existence of additional genetic modifiers. Apolipoprotein E (APOE) haplotypes are associated with the risk of numerous, especially degenerative, diseases. Investigations of a potential role of APOE haplotypes in AAO variability of SCA3 have resulted in partly conflicting outcomes, with current evidence lacking power and patient diversity. To further clarify a potential modifying effect of APOE haplotypes on the AAO in SCA3, over 800 SCA3 patients from different origins were enrolled in the present study. While we did not find an association of common APOE haplotypes or singular APOE alleles with AAO in SCA3, rare ε4 homozygosity was linked to an earlier AAO in individuals from Brazil, with a mean disease onset six years earlier than carriers of other APOE haplotypes. Our study thus provides initial evidence for a relevant impact of ε4 homozygosity on disease onset in SCA3 and provides evidence supporting an allele-dosage effect of APOE ε4 in polyQ diseases. © The Author(s) 2026. Published by Oxford University Press. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/pages/standard-publication-reuse-rights)

Instituciones: Universidad Científica del Sur