Journal of Neurology

, Volume 261, Issue 11, pp 2170–2177 | Cite as

Heritability in frontotemporal dementia: more missing pieces?

  • Kieren Po
  • Felicity V. C. Leslie
  • Natalie Gracia
  • Lauren Bartley
  • John B. J. Kwok
  • Glenda M. Halliday
  • John R. Hodges
  • James R. BurrellEmail author
Original Communication


Frontotemporal dementia (FTD) is reportedly highly heritable, even though a recognized genetic cause is often absent. To explain this contradiction, we explored the “strength” of family history in FTD, Alzheimer’s disease (AD), and controls. Clinical syndromes associated with heritability of FTD and AD were also examined. FTD and AD patients were recruited from an FTD-specific research clinic, and patients were further sub-classified into FTD or AD phenotypes. The strength of family history was graded using the Goldman score (GS), and GS of 1–3 was regarded as a “strong” family history. A subset of FTD patients underwent screening for the main genetic causes of FTD. In total, 307 participants were included (122 FTD, 98 AD, and 87 controls). Although reported positive family history did not differ between groups, a strong family history was more common in FTD (FTD 17.2 %, AD 5.1 %, controls 2.3 %, P < 0.001). The bvFTD and FTD-ALS groups drove heritability, but 12.2 % of atypical AD patients also had a strong family history. A pathogenic mutation was identified in 16 FTD patients (10 C9ORF72 repeat expansion, 5 GRN, 1 MAPT), but more than half of FTD patients with a strong family history had no mutation detected. FTD is a highly heritable disease, even more than AD, and patients with bvFTD and FTD-ALS drive this heritability. Atypical AD also appears to be more heritable than typical AD. These results suggest that further genetic influences await discovery in FTD.


Frontotemporal dementia Alzheimer's disease Genetics Progranulin Tau C9ORF72 repeat expansion Modified Goldman score 



This work was supported by funding to ForeFront, a collaborative research group dedicated to the study of frontotemporal dementia and motor neuron disease, from the National Health and Medical Research Council of Australia (NHMRC) program Grant (#1037746) and the Australian Research Council Centre of Excellence in Cognition and its Disorders Memory Node (#CE110001021). We are grateful to the research participants involved with the ForeFront research studies. In addition, JRB is supported by a NHMRC Early Career Fellowship (#1072451) and GMH by a NHMRC Senior Principal Research Fellow (#630434). Genomic DNA was extracted from blood samples by Genetic Repositories Australia, an Enabling Facility supported by NHMRC project Grant #401184, and by Mia McMillan in Professor Halliday’s laboratory. Genetic testing was funded by NHMRC project Grant #510218. We are grateful to Carol Dobson-Stone, Yue Huang and Mia McMillan for assistance with screening for repeat expansions in the C9ORF72 gene.

Conflicts of interest

On behalf of all authors, the corresponding author states that there is no conflict of interest.

Ethical standard

Institutional ethics approval was obtained prior to assessment and all participants, or next of kin where necessary, provided written informed consent.

Supplementary material

415_2014_7474_MOESM1_ESM.docx (91 kb)
Supplementary material 1 (DOCX 91 kb)


  1. 1.
    Gandhi S, Wood NW (2010) Genome-wide association studies: the key to unlocking neurodegeneration? Nat Neurosci 13:789–794. doi: 10.1038/nn.2584 CrossRefPubMedGoogle Scholar
  2. 2.
    Ramanan VK, Saykin AJ (2013) Pathways to neurodegeneration: mechanistic insights from GWAS in Alzheimer’s disease, Parkinson’s disease, and related disorders. Am J Neurodegener Dis 2:145–175PubMedCentralPubMedGoogle Scholar
  3. 3.
    Swerdlow RH, Corder EH (2012) For Alzheimer disease GWAS, pulling needles from the haystack is just the first step. Neurology 79:204–205. doi: 10.1212/WNL.0b013e318260581d CrossRefPubMedGoogle Scholar
  4. 4.
    Ratnavalli E, Brayne C, Dawson K, Hodges JR (2002) The prevalence of frontotemporal dementia. Neurology 58:1615–1621CrossRefPubMedGoogle Scholar
  5. 5.
    Goldman JS, Farmer JM, Wood EM et al (2005) Comparison of family histories in FTLD subtypes and related tauopathies. Neurology 65:1817–1819CrossRefPubMedGoogle Scholar
  6. 6.
    Rosso SM, Kaat LD, Baks T et al (2003) Frontotemporal dementia in The Netherlands: patient characteristics and prevalence estimates from a population-based study. Brain 126:2016–2022. doi: 10.1093/brain/awg204 CrossRefPubMedGoogle Scholar
  7. 7.
    Rohrer JD, Guerreiro R, Vandrovcova J et al (2009) The heritability and genetics of frontotemporal lobar degeneration. Neurology 73:1451–1456. doi: 10.1212/WNL.0b013e3181bf997a PubMedCentralCrossRefPubMedGoogle Scholar
  8. 8.
    Le Ber I, Guedj E, Gabelle A et al (2006) Demographic, neurological and behavioural characteristics and brain perfusion SPECT in frontal variant of frontotemporal dementia. Brain 129:3051–3065CrossRefPubMedGoogle Scholar
  9. 9.
    Mackenzie IRA, Frick P, Neumann M (2014) The neuropathology associated with repeat expansions in the C9ORF72 gene. Acta Neuropathol 127:347–357. doi: 10.1007/s00401-013-1232-4 CrossRefPubMedGoogle Scholar
  10. 10.
    Sieben A, Van Langenhove T, Engelborghs S et al (2012) The genetics and neuropathology of frontotemporal lobar degeneration. Acta Neuropathol 124:353–372. doi: 10.1007/s00401-012-1029-x PubMedCentralCrossRefPubMedGoogle Scholar
  11. 11.
    DeJesus-Hernandez M, Mackenzie IR, Boeve BF et al (2011) Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron 72:245–256. doi: 10.1016/j.neuron.2011.09.011 PubMedCentralCrossRefPubMedGoogle Scholar
  12. 12.
    Renton AE, Majounie E, Waite A et al (2011) A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD. Neuron 72:257–268. doi: 10.1016/j.neuron.2011.09.010 PubMedCentralCrossRefPubMedGoogle Scholar
  13. 13.
    Smits LL, Pijnenburg YAL, Koedam ELGE et al (2012) Early onset Alzheimer’s disease is associated with a distinct neuropsychological profile. J Alzheimers Dis 30:101–108. doi: 10.3233/JAD-2012-111934 PubMedGoogle Scholar
  14. 14.
    Rascovsky K, Hodges JR, Knopman D et al (2011) Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia. Brain 134:2456–2477. doi: 10.1093/brain/awr179 PubMedCentralCrossRefPubMedGoogle Scholar
  15. 15.
    Gorno-Tempini ML, Hillis AE, Weintraub S et al (2011) Classification of primary progressive aphasia and its variants. Neurology 76:1006–1014PubMedCentralCrossRefPubMedGoogle Scholar
  16. 16.
    Strong MJ, Grace GM, Freedman M et al (2009) Consensus criteria for the diagnosis of frontotemporal cognitive and behavioural syndromes in amyotrophic lateral sclerosis. Amyotroph Lateral Scler 10:131–146CrossRefPubMedGoogle Scholar
  17. 17.
    McKhann G, Drachman D, Folstein M et al (1984) Clinical diagnosis of Alzheimer’s disease: report of the NINCDS-ADRDA Work Group* under the auspices of Department of Health and Human Services Task Force on Alzheimer’s Disease. Neurology 34:939CrossRefPubMedGoogle Scholar
  18. 18.
    Mathew R, Bak TH, Hodges JR (2012) Diagnostic criteria for corticobasal syndrome: a comparative study. J Neurol Neurosurg Psychiatr 83:405–410. doi: 10.1136/jnnp-2011-300875 CrossRefPubMedGoogle Scholar
  19. 19.
    Burrell JR, Hornberger M, Villemagne VL et al (2013) Clinical profile of PiB-positive corticobasal syndrome. PLoS One 8:e61025. doi: 10.1371/journal.pone.0061025 PubMedCentralCrossRefPubMedGoogle Scholar
  20. 20.
    Dobson-Stone C, Hallupp M, Bartley L et al (2012) C9ORF72 repeat expansion in clinical and neuropathologic frontotemporal dementia cohorts. Neurology 79:995–1001. doi: 10.1212/WNL.0b013e3182684634 PubMedCentralCrossRefPubMedGoogle Scholar
  21. 21.
    Devenney E, Hornberger M, Irish M et al (2014) Frontotemporal dementia associated with the C9ORF72 mutation: a unique clinical profile. JAMA Neurol 71:331–339. doi: 10.1001/jamaneurol.2013.6002 CrossRefPubMedGoogle Scholar
  22. 22.
    Mahoney CJ, Beck J, Rohrer JD et al (2012) Frontotemporal dementia with the C9ORF72 hexanucleotide repeat expansion: clinical, neuroanatomical and neuropathological features. Brain 135:736–750. doi: 10.1093/brain/awr361 PubMedCentralCrossRefPubMedGoogle Scholar
  23. 23.
    Wood EM, Falcone D, Suh E et al (2013) Development and validation of pedigree classification criteria for frontotemporal lobar degeneration. JAMA Neurol 70:1411–1417. doi: 10.1001/jamaneurol.2013.3956 PubMedCentralCrossRefPubMedGoogle Scholar
  24. 24.
    Rubino E, Rainero I, Chiò A et al (2012) SQSTM1 mutations in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Neurology 79:1556–1562. doi: 10.1212/WNL.0b013e31826e25df PubMedCentralCrossRefPubMedGoogle Scholar
  25. 25.
    Van der Zee J, Van Langenhove T, Kovacs GG et al (2014) Rare mutations in SQSTM1 modify susceptibility to frontotemporal lobar degeneration. Acta Neuropathol. doi: 10.1007/s00401-014-1298-7 PubMedCentralGoogle Scholar
  26. 26.
    Le Ber I, Camuzat A, Guillot-Noel L et al (2013) C9ORF72 repeat expansions in the frontotemporal dementias spectrum of diseases: a flow-chart for genetic testing. J Alzheimers Dis 34:485–499. doi: 10.3233/JAD-121456 PubMedGoogle Scholar
  27. 27.
    Snowden JS, Rollinson S, Thompson JC et al (2012) Distinct clinical and pathological characteristics of frontotemporal dementia associated with C9ORF72 mutations. Brain 135:693–708. doi: 10.1093/brain/awr355 PubMedCentralCrossRefPubMedGoogle Scholar
  28. 28.
    Majounie E, Renton AE, Mok K et al (2012) Frequency of the C9orf72 hexanucleotide repeat expansion in patients with amyotrophic lateral sclerosis and frontotemporal dementia: a cross-sectional study. Lancet Neurol 11:323–330. doi: 10.1016/S1474-4422(12)70043-1 PubMedCentralCrossRefPubMedGoogle Scholar
  29. 29.
    Boeve BF, Boylan KB, Graff-Radford NR et al (2012) Characterization of frontotemporal dementia and/or amyotrophic lateral sclerosis associated with the GGGGCC repeat expansion in C9ORF72. Brain 135:765–783. doi: 10.1093/brain/aws004 PubMedCentralCrossRefPubMedGoogle Scholar
  30. 30.
    Cruts M, Gijselinck I, van der Zee J et al (2006) Null mutations in progranulin cause ubiquitin-positive frontotemporal dementia linked to chromosome 17q21. Nature 442:920–924. doi: 10.1038/nature05017 CrossRefPubMedGoogle Scholar
  31. 31.
    Gass J, Cannon A, Mackenzie IR et al (2006) Mutations in progranulin are a major cause of ubiquitin-positive frontotemporal lobar degeneration. Hum Mol Genet 15:2988–3001. doi: 10.1093/hmg/ddl241 CrossRefPubMedGoogle Scholar
  32. 32.
    Pickering-Brown SM, Rollinson S, Du Plessis D et al (2008) Frequency and clinical characteristics of progranulin mutation carriers in the Manchester frontotemporal lobar degeneration cohort: comparison with patients with MAPT and no known mutations. Brain 131:721–731. doi: 10.1093/brain/awm331 CrossRefPubMedGoogle Scholar
  33. 33.
    Van der Flier WM, Pijnenburg YA, Fox NC, Scheltens P (2011) Early-onset versus late-onset Alzheimer’s disease: the case of the missing APOE ɛ4 allele. Lancet Neurol 10:280–288. doi: 10.1016/S1474-4422(10)70306-9 CrossRefPubMedGoogle Scholar
  34. 34.
    Ryan NS, Rossor MN (2010) Correlating familial Alzheimer’s disease gene mutations with clinical phenotype. Biomark Med 4:99–112. doi: 10.2217/bmm.09.92 PubMedCentralCrossRefPubMedGoogle Scholar
  35. 35.
    Larner AJ, Doran M (2006) Clinical phenotypic heterogeneity of Alzheimer’s disease associated with mutations of the presenilin-1 gene. J Neurol 253:139–158. doi: 10.1007/s00415-005-0019-5 CrossRefPubMedGoogle Scholar
  36. 36.
    Godbolt AK, Beck JA, Collinge J et al (2004) A presenilin 1 R278I mutation presenting with language impairment. Neurology 63:1702–1704CrossRefPubMedGoogle Scholar
  37. 37.
    Van Blitterswijk M, Baker MC, DeJesus-Hernandez M et al (2013) C9ORF72 repeat expansions in cases with previously identified pathogenic mutations. Neurology 81:1332–1341. doi: 10.1212/WNL.0b013e3182a8250c PubMedCentralCrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Kieren Po
    • 1
    • 2
  • Felicity V. C. Leslie
    • 3
  • Natalie Gracia
    • 3
  • Lauren Bartley
    • 3
  • John B. J. Kwok
    • 1
    • 3
    • 4
  • Glenda M. Halliday
    • 1
    • 3
    • 4
  • John R. Hodges
    • 1
    • 3
    • 4
  • James R. Burrell
    • 1
    • 3
    • 4
    Email author
  1. 1.Concord Repatriation General HospitalSydneyAustralia
  2. 2.Sydney Medical SchoolUniversity of SydneySydneyAustralia
  3. 3.Neuroscience Research AustraliaSydneyAustralia
  4. 4.University of New South WalesSydneyAustralia

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