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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 \u03b54 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 \u03b54 homozygosity on disease onset in SCA3 and provides evidence supporting an allele-dosage effect of APOE \u03b54 in polyQ diseases.<\/jats:p>","DOI":"10.1093\/hmg\/ddag016","type":"journal-article","created":{"date-parts":[[2026,3,19]],"date-time":"2026-03-19T09:21:17Z","timestamp":1773912077000},"source":"Crossref","is-referenced-by-count":2,"title":["Association of rare\n                    <i>apolipoprotein E<\/i>\n                    \u03b54 homozygosity with an earlier age at onset in spinocerebellar ataxia type 3"],"prefix":"10.1093","volume":"35","author":[{"given":"Charlotte Clara","family":"Meyer","sequence":"first","affiliation":[{"name":"Institute of Medical Genetics and Applied Genomics, University of T\u00fcbingen , Calwerstrasse 7, 72076 T\u00fcbingen, Baden-W\u00fcrttemberg ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eduardo Preusser","family":"de 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