Repeat length variations in ATXN1 and AR modify disease expression in Alzheimer's disease

Neurobiol Aging. 2019 Jan:73:230.e9-230.e17. doi: 10.1016/j.neurobiolaging.2018.09.007. Epub 2018 Sep 15.


Genomewide association studies (GWASs) have contributed greatly to unraveling the genetic basis of Alzheimer's disease (AD). However, a large amount of "missing heritability" remains. In this exploratory study, we investigated the effect of cytosine-adenine-guanine (CAG) repeats in polyglutamine disease-associated genes (PDAGs) on the risk of AD and its expression. In a cohort of 959 patients diagnosed with AD (Amsterdam Dementia cohort) and 4106 cognitively healthy participants (Leiden 85-plus Study and the Prospective Study of Pravastatin in the Elderly at Risk), we determined the CAG repeat sequences in ATXN1, ATXN2, ATXN3, CACNA1A, ATXN7, TBP, HTT, ATN1, and AR. We did not find a significant association between the risk of AD and variations in CAG repeat numbers of PDAGs. However, we found that differences in CAG repeat numbers in ATXN1, ATXN2, and AR were significantly associated with several clinical and imaging features in AD patients. Specifically, the association between memory performance in patients with AD and the CAG repeat size in the longer ATXN1 allele, and the association between atrophy in the medial temporal lobes and the CAG repeat number in the longer AR allele remained significant after correction for multiple testing. Our findings suggest that repeat polymorphisms in ATXN1 and AR can act as important genetic modifiers of AD, warranting further scrutiny of their role in its missing heritability and pathogenesis.

Keywords: Alzheimer's disease; CAG repeat polymorphisms; Huntington disease; Missing heritability; Polyglutamine diseases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenine
  • Adult
  • Aged
  • Aged, 80 and over
  • Alzheimer Disease / genetics*
  • Alzheimer Disease / pathology
  • Ataxin-1 / genetics*
  • Cytosine
  • Female
  • Genetic Variation / genetics*
  • Genome-Wide Association Study*
  • Guanine
  • Humans
  • Male
  • Middle Aged
  • Polymorphism, Genetic / genetics*
  • Receptors, Androgen / genetics*
  • Repetitive Sequences, Nucleic Acid
  • Temporal Lobe / pathology


  • AR protein, human
  • ATXN1 protein, human
  • Ataxin-1
  • Receptors, Androgen
  • Guanine
  • Cytosine
  • Adenine