Journal Article

DZNE-2026-00288

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png 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. ; Saraiva-Pereira, M.-L. ; Cornejo-Olivas, M. R. ; Bauer, P. ; Schöls, L.DZNE* ; van de Warrenburg, B. P. ; Durr, A. ; Brice, A. ; Klockgether, T.DZNE* ; Jardim, L. B. ; Riess, O. ; Network, E. (Collaboration Author) ; Schmidt, T. ; Bauer, P. (Contributor) ; Berciano, J. (Contributor) ; Boesch, S. (Contributor) ; Brice, A. (Contributor) ; Durr, A. (Contributor) ; Forlani, S. (Contributor) ; Giunti, P. (Contributor) ; Jacobi, H. (Contributor) ; Klockgether, T. (Contributor)Extern* ; Melegh, B. (Contributor) ; Pandolfo, M. (Contributor) ; Riess, O. (Contributor) ; Schmitz-Hübsch, T. (Contributor) ; Schöls, L. (Contributor)Extern* ; Schulz, J. B. (Contributor) ; Stevanin, G. (Contributor) ; Szymanski, S. (Contributor) ; du Montcel, S. T. (Contributor) ; Timmann, D. (Contributor) ; van de Warrenburg, B. P. C. (Contributor)

2026
Oxford Univ. Press Oxford

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Please use a persistent id in citations: doi:10.1093/hmg/ddag016

Abstract: 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.

Keyword(s): Humans (MeSH) ; Age of Onset (MeSH) ; Female (MeSH) ; Male (MeSH) ; Machado-Joseph Disease: genetics (MeSH) ; Machado-Joseph Disease: epidemiology (MeSH) ; Middle Aged (MeSH) ; Homozygote (MeSH) ; Adult (MeSH) ; Haplotypes (MeSH) ; Apolipoprotein E4: genetics (MeSH) ; Aged (MeSH) ; Ataxin-3 (MeSH) ; Alleles (MeSH) ; Repressor Proteins (MeSH) ; Spinocerebellar Ataxia 3 ; genetic modifier ; genetic risk factor ; neurodegeneration ; neurogenetics ; Apolipoprotein E4 ; Ataxin-3 ; ATXN3 protein, human ; Repressor Proteins

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Contributing Institute(s):

1. Clinical Neurogenetics (AG Schöls)
2. Patient Studies (Bonn) (Patient Studies (Bonn))

Research Program(s):

1. 353 - Clinical and Health Care Research (POF4-353) (POF4-353)

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; Essential Science Indicators ; IF < 5 ; JCR ; Nationallizenz ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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