Familial early-onset dementia with complex neuropathologic phenotype and genomic background

Neurobiol Aging. 2016 Jun;42:199-204. doi: 10.1016/j.neurobiolaging.2016.03.012. Epub 2016 Mar 21.


Despite significant progress in our understanding of hereditary neurodegenerative diseases, the list of genes associated with early-onset dementia is not yet complete. In the present study, we describe a familial neurodegenerative disorder characterized clinically as the behavioral and/or dysexecutive variant of Alzheimer's disease with neuroradiologic features of Alzheimer's disease, however, lacking amyloid-β deposits in the brain. Instead, we observed a complex, 4 repeat predominant, tauopathy, together with a TAR DNA-binding protein of 43 kDa proteinopathy. Whole-exome sequencing on 2 affected siblings and 1 unaffected aunt uncovered a large number of candidate genes, including LRRK2 and SYNE2. In addition, DDI1, KRBA1, and TOR1A genes possessed novel stop-gain mutations only in the patients. Pathway, gene ontology, and network interaction analysis indicated the involvement of pathways related to neurodegeneration but revealed novel aspects also. This condition does not fit into any well-characterized category of neurodegenerative disorders. Exome sequencing did not disclose a single disease-specific gene mutation suggesting that a set of genes working together in different pathways may contribute to the etiology of the complex phenotype.

Keywords: Alzheimer disease; Early-onset dementia; Exome sequencing; LRRK2; TDP-43; Tau.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / genetics*
  • Alzheimer Disease / pathology*
  • Brain / pathology
  • Exome / genetics
  • Female
  • Genome-Wide Association Study*
  • Humans
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / genetics
  • Male
  • Microfilament Proteins / genetics
  • Molecular Chaperones / genetics
  • Mutation
  • Nerve Tissue Proteins / genetics
  • Nuclear Proteins / genetics
  • Phenotype
  • Sequence Analysis, RNA
  • TDP-43 Proteinopathies
  • Tauopathies


  • Microfilament Proteins
  • Molecular Chaperones
  • Nerve Tissue Proteins
  • Nuclear Proteins
  • SYNE2 protein, human
  • TOR1A protein, human
  • LRRK2 protein, human
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2