Susceptibility to neurofibrillary tangles: role of the PTPRD locus and limited pleiotropy with other neuropathologies

Mol Psychiatry. 2018 Jun;23(6):1521-1529. doi: 10.1038/mp.2017.20. Epub 2017 Mar 21.


Tauopathies, including Alzheimer's disease (AD) and other neurodegenerative conditions, are defined by a pathological hallmark: neurofibrillary tangles (NFTs). NFT accumulation is thought to be closely linked to cognitive decline in AD. Here, we perform a genome-wide association study for NFT pathologic burden and report the association of the PTPRD locus (rs560380, P=3.8 × 10-8) in 909 prospective autopsies. The association is replicated in an independent data set of 369 autopsies. The association of PTPRD with NFT is not dependent on the accumulation of amyloid pathology. In contrast, we found that the ZCWPW1 AD susceptibility variant influences NFT accumulation and that this effect is mediated by an accumulation of amyloid β plaques. We also performed complementary analyses to identify common pathways that influence multiple neuropathologies that coexist with NFT and found suggestive evidence that certain loci may influence multiple different neuropathological traits, including tau, amyloid β plaques, vascular injury and Lewy bodies. Overall, these analyses offer an evaluation of genetic susceptibility to NFT, a common end point for multiple different pathologic processes.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Aged
  • Alzheimer Disease / physiopathology
  • Amyloid beta-Peptides / metabolism
  • Brain / metabolism
  • Cognitive Dysfunction / metabolism
  • Female
  • Genome-Wide Association Study
  • Hippocampus / metabolism
  • Humans
  • Male
  • Middle Aged
  • Neurofibrillary Tangles / genetics*
  • Neurofibrillary Tangles / pathology*
  • Neurons / metabolism
  • Neuropathology / methods
  • Plaque, Amyloid / metabolism
  • Prospective Studies
  • Receptor-Like Protein Tyrosine Phosphatases, Class 2 / metabolism*
  • Receptor-Like Protein Tyrosine Phosphatases, Class 2 / physiology
  • Tauopathies / metabolism
  • tau Proteins / metabolism


  • Amyloid beta-Peptides
  • tau Proteins
  • PTPRD protein, human
  • Receptor-Like Protein Tyrosine Phosphatases, Class 2