17q21.31 duplication causes prominent tau-related dementia with increased MAPT expression

Mol Psychiatry. 2017 Aug;22(8):1119-1125. doi: 10.1038/mp.2016.226. Epub 2016 Dec 13.


To assess the role of rare copy number variations in Alzheimer's disease (AD), we conducted a case-control study using whole-exome sequencing data from 522 early-onset cases and 584 controls. The most recurrent rearrangement was a 17q21.31 microduplication, overlapping the CRHR1, MAPT, STH and KANSL1 genes that was found in four cases, including one de novo rearrangement, and was absent in controls. The increased MAPT gene dosage led to a 1.6-1.9-fold expression of the MAPT messenger RNA. Clinical signs, neuroimaging and cerebrospinal fluid biomarker profiles were consistent with an AD diagnosis in MAPT duplication carriers. However, amyloid positon emission tomography (PET) imaging, performed in three patients, was negative. Analysis of an additional case with neuropathological examination confirmed that the MAPT duplication causes a complex tauopathy, including prominent neurofibrillary tangle pathology in the medial temporal lobe without amyloid-β deposits. 17q21.31 duplication is the genetic basis of a novel entity marked by prominent tauopathy, leading to early-onset dementia with an AD clinical phenotype. This entity could account for a proportion of probable AD cases with negative amyloid PET imaging recently identified in large clinical series.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Alzheimer Disease / genetics*
  • Brain / metabolism
  • Case-Control Studies
  • Chromosomes, Human, Pair 17 / genetics*
  • DNA Copy Number Variations / genetics
  • Dementia / genetics*
  • Female
  • Gene Dosage
  • Gene Duplication / genetics
  • Humans
  • Male
  • Middle Aged
  • Neurofibrillary Tangles / pathology
  • Neuroimaging
  • Tauopathies / genetics
  • tau Proteins / genetics
  • tau Proteins / metabolism


  • MAPT protein, human
  • tau Proteins