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

John Alexander, Ognian Kalev, Shima Mehrabian, Latchezar Traykov, Margariata Raycheva, Dimitrios Kanakis, Petros Drineas, Mirjam I. Lutz, Thomas Ströbel, Thomas Penz, Michael Schuster, Christoph Bock, Isidro Ferrer, Peristera Paschou, Gabor G. Kovacs

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11 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)199-204
Number of pages6
JournalNeurobiology of Aging
Publication statusPublished - 1 Jun 2016


  • Alzheimer disease
  • Early-onset dementia
  • Exome sequencing
  • LRRK2
  • Tau
  • TDP-43

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    Alexander, J., Kalev, O., Mehrabian, S., Traykov, L., Raycheva, M., Kanakis, D., Drineas, P., Lutz, M. I., Ströbel, T., Penz, T., Schuster, M., Bock, C., Ferrer, I., Paschou, P., & Kovacs, G. G. (2016). Familial early-onset dementia with complex neuropathologic phenotype and genomic background. Neurobiology of Aging, 42, 199-204. https://doi.org/10.1016/j.neurobiolaging.2016.03.012