TBK1 – Frontotemporal Dementia

TBK1-associated frontotemporal dementia (FTD) is inherited in an autosomal dominant manner due to heterozygous loss-of-function variants in the TANK-binding kinase 1 (TBK1) gene, leading to haploinsufficiency of a key regulator of autophagy and innate immunity.

In a Belgian cohort of 481 FTD patients, 5 unrelated probands carrying TBK1 LoF mutations were identified, representing 1.1% of cases, with segregation of the recurrent c.1928_1930del (p.Glu643del) variant in 6 affected relatives in a large family (PMID:26581300). The same c.1928_1930del (p.Glu643del) mutation has been observed in multiple additional FTD-ALS families, reinforcing its pathogenicity.

Exonic resequencing in a European Early-Onset Dementia Consortium cohort of 2,538 FTD, ALS, and FTD-ALS patients revealed TBK1 LoF variants in 0.4% of isolated FTD cases, 1.3% of ALS cases, and 3.6% of combined FTD-ALS cases, with functional assays confirming transcript loss via nonsense-mediated decay (PMID:28008748).

Functional studies demonstrate that TBK1 haploinsufficiency alters K63-linked ubiquitination profiles in brain tissue and patient fibroblasts, reduces phosphorylation of autophagy and interferon regulatory substrates, and impairs TBK1–IRF3 complex formation, consistent with a loss-of-function mechanism in FTD models (PMID:34800171; PMID:36113750).

Clinically, TBK1-related FTD manifests as a right temporal variant with progressive behavioral change, apathy, and memory impairment, often with TDP-43 type A pathology at autopsy. The overlap with ALS and other neurodegenerative syndromes underscores the importance of including TBK1 in genetic panels for FTD and FTD-ALS.

Key Take-home: TBK1 LoF variants are a definitive cause of autosomal dominant FTD; genetic testing for TBK1 should be considered in FTD patients, especially those with temporal-predominant atrophy or combined motor neuron features.

References

• Alzheimer's & dementia (Amsterdam, Netherlands) • 2017 • The clinical, neuroanatomical, and neuropathologic phenotype of TBK1-associated frontotemporal dementia: A longitudinal case report. PMID:28229125
• Neurology • 2015 • Loss of TBK1 is a frequent cause of frontotemporal dementia in a Belgian cohort. PMID:26581300
• Human mutation • 2017 • TBK1 Mutation Spectrum in an Extended European Patient Cohort with Frontotemporal Dementia and Amyotrophic Lateral Sclerosis. PMID:28008748
• Journal of neurology • 2022 • TBK1 haploinsufficiency results in changes in the K63-ubiquitination profiles in brain and fibroblasts from affected and presymptomatic mutation carriers. PMID:34800171
• Neurobiology of disease • 2022 • Functional and structural consequences of TBK1 missense variants in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. PMID:36113750

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