Molecular Genetics of Frontotemporal Dementia


Frontotemporal dementia (FTD) is a nonAlzheimer's form of dementia. Onset age lies in the mid‐to‐late 50s. FTD affects the frontal and/or the temporal lobes and is clinically divided into two main categories: behavioural variant (bvFTD) and language variant. FTD is characterised by heterogeneous pathology defined by pathogenic protein inclusions: microtubule‐associated protein tau (MAPT), ubiquitin/transactive responses (TAR) deoxyribonucleic acid (DNA)‐binding protein 43 (TDP)‐43, fused in sarcoma (FUS) and p62. MAPT, progranulin (PGRN) and, recently, C9orf72 genes represent the three main genetic markers associated with FTD. In addition, genetic variability in TDP‐43, charged multivesicular body protein 2B (CHMP2B), valosin‐containing protein (VCP), FUS and TMEM106B genes contribute to ⩽5% of cases. Research tools such as genome‐wide association studies and exome and genome sequencing hold promise to further uncover the genetic underpinnings of this complex disorder.

Key Concepts:

  • Frontotemporal dementia (FTD) is a nonAlzheimer's form of dementia; it affects behaviour, cognition and language, while memory (in the early phases).

  • The anatomical areas of the brain that are affected by atrophy are the frontal and the temporal lobes; based on this fact FTD is considered part of the spectrum called frontotemporal lobar degeneration (FTLD).

  • FTD is a complex disease with insidious onset; no therapeutic measures are available as yet.

  • Behavioural variant FTD (bvFTD) is the most common syndrome of FTD, which is associated with gradual deterioration of behaviour and cognition.

  • Different protein inclusions in the brain are used to classify the pathology associated with FTLD.

  • TDP‐43 and tau pathology represent the most common (∼90%) types of pathological signatures associated with FTLD.

  • MAPT, PGRN and C9orf72 are the major (∼95%) genetic markers associated with familial FTD.

  • TMEM106B regulates granulin protein levels.

  • Genome‐wide association studies (GWASs) and next‐generation sequencing technologies whole exome sequencing (WES) and whole genome sequencing (WGS) hold promise for dissecting the genetic aetiology of complex diseases; in molecular genetics these technologies help in screening a wide range of genetic variabilities from SNPs to CNVs in large cohorts across different populations.

Keywords: frontotemporal dementia; frontotemporal lobar degeneration; bvFTD; PPA; MAPT; PGRN; C9orf72; TMEM106B; tau pathology; TDP‐43 pathology

Figure 1.

The main clinical, pathological and genetic features associated with FTD are summarised. In each section, the most common features are located at the top in black boxes. As the features become less stable, common or frequent the boxes increasingly brighten up into lighter shades of grey. In the Genetics section TMEM106B is shown as a possible modifier of PGRN. Abbreviations: bvFTD, behavioural variant FTD; C9orf72, chromosome 9 open reading frame 72; CHMP2B, charged multivesicular body protein 2B; FUS, fused in sarcoma; FTD, frontotemporal dementia; FTLD‐FUS, frontotemporal lobar degeneration with FUS pathology; FTLD‐tau, frontotemporal lobar degeneration with tau pathology; FTLD‐TDP, frontotemporal lobar degeneration with ubiquitin/TDP‐43 pathology (that is subdivided in Types A, B, C, D – see Table ); FTLD‐UPS, frontotemporal lobar degeneration with ubiquitin/p62 pathology (which are elements of the Ubiquitin Proteasome System); LPA, logopenic progressive aphasia; MAPT, microtubule associated protein tau; PGRN, progranulin; PNFA, progressive nonfluent aphasia; PPA, primary progressive aphasia; SD, semantic dementia; TDP‐43, TAR DNA binding protein 43; TMEM106B, transmembran protein 106 B; VCP, valosin‐containing protein.

Figure 2.

The input from different fields of expertise through different forms of investigation holds promise to provide a more comprehensive perspective on the different components that contribute to the disease.



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Further Reading

Budini M, Baralle FE and Buratti E (2011) Regulation of gene expression by TDP‐43 and FUS/TLS in frontotemporal lobar degeneration. Current Alzheimer Research 8(3): 237–245. A review on how TDP‐43 and FUS might exert their pathogenic effects in FTLD.

Felten DL and Jozefowicz R (2003) Netter's atlas of Human Neuroscience (1e Netter Basic Science). For a better understanding of the brain compartments, structures and functions. Teterboro, New Jersey: Icon Learning Systems.

Frontotemporal dementia #600274. OMIM (Online Mendelian Inheritance in Men).

Goedert M (2005) Tau gene mutations and their effects. Movement Disorders 20(Suppl. 12): S45–S52. A more extensive review on tau mutations and their effects.

Kipps CM, Knibb JA, Patterson K and Hodges JR (2008) Neuropsychology of frontotemporal dementia. Handbook of Clinical Neurology 88: 527–548. An insight on neuropsychological profiles in FTD.

Morris M, Maeda S, Vossel K and Mucke L (2011) The many faces of tau. Neuron 70(3): 410–426. A more detailed and comprehensive analysis of tau protein and its functions.

Singleton A and Hardy J (2011) A generalizable hypothesis for the genetic architecture of disease: pleomorphic risk loci. Human Molecular Genetics 20(R2): R158–R162 A review addressing how the concept of genetic variability and haplotypes can underlie different phenotypic signatures.

Sorbi S, Hort J, Erkijuntti T et al. (2012) EFNS‐ENS Guidelines on the diagnosis and management of disorders associated with dementia. European Journal of Neurology 19(9): 1159–1179 Guidelines for diagnosis and management of dementias.

Sun L and Eriksen JL (2011) Recent insights into the involvement of progranulin in frontotemporal dementia. Current Neuropharmacology 9(4): 632–642. A review on PGRN and insights on its possible pathogenic effects in FTLD.

Weihl CC (2011) Valosin containing protein associated fronto‐temporal lobar degeneration: clinical presentation, pathologic features and pathogenesis. Current Alzheimer Research 8(3): 252–260. A deep analysis of the association between VCP and FTD.

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Ferrari, Raffaele, Thumma, Avinash, and Momeni, Parastoo(May 2013) Molecular Genetics of Frontotemporal Dementia. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0024457]