Co-occurrence of multiple pathologies in a case of frontotemporal dementia with TBK1 mutation: first in vivo detection of alpha-synuclein and tau co-pathology

Topic: Brain proteins, microglia and lab models

Abstract We present the case of a 74-year-old woman with behavioral variant frontotemporal dementia (bvFTD) linked to a pathogenic TANK-binding kinase 1 (TBK1) mutation (c.1349_1352del; p.Ile450Lysfs*15). During clinical workup, the patient underwent comprehensive biomarker analysis, including tau positron emission tomography (PET) and cerebrospinal fluid (CSF) seed amplification assay (SAA) for α-synuclein (αSyn). While CSF biomarkers for Alzheimer’s disease were normal, the αSyn SAA was clearly positive, indicating misfolded αSyn aggregates. Tau PET revealed increased [18F]PI-2620 uptake in the basal ganglia. Genetic testing confirmed autosomal dominant TBK1-associated FTD. The patient’s condition deteriorated over the following year, with rapid cognitive decline and the emergence of cortical signs. Post-mortem neuropathological analysis confirmed multiple proteinopathies: FTLD-TDP43 (subtype A), Lewy body disease (limbic type, Braak stage 5), argyrophilic grain disease (AGD), aging-related tau astrogliopathy (ARTAG), and primary age-related tauopathy (PART). This is the first reported TBK1-FTD case with in vivo detection of αSyn pathology via SAA and in vivo monitoring of tau pathology. The case expands the clinical and neuropathological spectrum of TBK1-associated FTD. Our findings support a broader interpretation of TBK1-associated neurodegeneration and highlight the importance of multimodal diagnostic approaches that integrate molecular, genetic, imaging, and neuropathological tools. This case also underscores the utility of αSyn SAA and tau PET in detecting co-pathologies that may otherwise remain clinically silent and illustrates the need for further studies exploring the molecular cross-talk between TBK1, tau, and αSyn pathologies.

Key findings

• Tau PET revealed increased [18F]PI-2620 uptake in the basal ganglia.
• Our findings support a broader interpretation of TBK1-associated neurodegeneration and highlight the importance of multimodal diagnostic approaches that integrate molecular, genetic, imaging, and neuropathological tools.

Why it matters

In one patient with a TBK1 mutation, alpha-synuclein and tau pathology were both detected during life and multiple proteinopathies were confirmed after death. This single case report broadens the recognized spectrum of TBK1-related disease but does not provide a treatment or cure.

Study details

• Evidence strengthLow

Read the original

• DOI: 10.1186/s40478-025-02081-1
• PubMed: 40713844
• Original source →
• Free full text: Acta Neuropathologica Communications →

Full text: free to read — OpenAlex lists this copy as free to read: the link above (checked 6 Feb 1020).

@article{bernhardt2025-40713844,
  author  = {Bernhardt, Alexander Maximilian and Roeber, Sigrun and Ruf, Viktoria and Wlasich, Elisabeth and Weidinger, Endy and Longen, Sebastian and Trossbach, Svenja Verena and Gnörich, Johannes S. and others},
  title   = {{Co-occurrence of multiple pathologies in a case of frontotemporal dementia with TBK1 mutation: first in vivo detection of alpha-synuclein and tau co-pathology}},
  journal = {Acta Neuropathologica Communications},
  year    = {2025},
  doi     = {10.1186/s40478-025-02081-1},
  pmid    = {40713844},
  url     = {https://doi.org/10.1186/s40478-025-02081-1}
}

Studies this one cites

Referenced by this study and also in the alzhub library, so you can read them here.

• Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia Brain : a journal of neurology · 2011-08-02 · usefulness score 65/100 · Getting a diagnosis
• The Determinants of Quality of Life of Nursing Home Residents with Young-Onset Dementia and the Differences between Dementia Subtypes Dementia and Geriatric Cognitive Disorders · 2017-01-01 · usefulness score 56/100 · Caregiving

Related studies in Disease mechanisms

• Presence of reactive microglia and neuroinflammatory mediators in a case of frontotemporal dementia with P301S mutation Neuro-degenerative diseases · 2011-01-05 · usefulness score 41/100
• Frontotemporal dementia associated CHCHD10V57E mutation aggravates tau pathology via disrupting the CHCHD10-Rab7A-TBC1D15 complex Cell Death and Disease · 2026-06-19 · usefulness score 36/100
• Elevated tauopathy and alpha-synuclein pathology in postmortem Parkinson's disease brains with and without dementia Experimental neurology · 2010-06-28 · usefulness score 36/100
• A phenotypic screen for novel small molecules that correct tau‐mediated pathologies in human frontotemporal dementia neurons Alzheimer s & Dementia · 2025-09-01 · usefulness score 34/100
• The frontotemporal dementia mutation R406W blocks tau's interaction with the membrane in an annexin A2-dependent manner The Journal of cell biology · 2011-02-01 · usefulness score 40/100
• The L266V tau mutation is associated with frontotemporal dementia and Pick-like 3R and 4R tauopathy Acta neuropathologica · 2003-07-19 · usefulness score 40/100

Also tagged “phosphorylated”

732 studies in the library carry the topic tag “phosphorylated”; these are this study's neighbours in a fixed, alphabetical-by-hash tour of them, not the closest in content. All 732 tagged studies.

• A Phase II study targeting amyloid-beta with 3APS in mild-to-moderate Alzheimer disease Neurology · 2006-11-02 · usefulness score 64/100 · Tau biomarkers
• The interaction between dysfunction of vasculature and tauopathy in Alzheimer's disease and related dementias Alzheimer s & Dementia · 2025-02-01 · usefulness score 38/100 · Disease mechanisms
• Lack of tau proteins rescues neuronal cell death and decreases amyloidogenic processing of APP in APP/PS1 mice The American journal of pathology · 2012-09-28 · usefulness score 44/100 · Risk genes beyond APOE

Similar studies

• Tau and alpha-synuclein inclusions in a case of familial frontotemporal dementia and progressive aphasia 2005 · Down syndrome and Alzheimer's
• Frontotemporal dementia and corticobasal degeneration in a family with a P301S mutation in tau 1999 · Lewy body dementia
• Invited review: Frontotemporal dementia caused by microtubule-associated protein tau gene (MAPT) mutations: a chameleon for neuropathology and neuroimaging 2015 · Lewy body dementia
• Frontotemporal dementia and Parkinsonism linked to chromosome 17: a new group of tauopathies 1998 · Disease mechanisms
• Structural and functional connectivity in tau mutation carriers: from presymptomatic to symptomatic frontotemporal dementia 2025 · Lewy body dementia
• Frontotemporal dementia with the V337M <i>MAPT</i> mutation: Tau-PET and pathology correlations 2017 · Brain scans and imaging

More on Disease mechanisms

• A review that covers this ground Alpha-synuclein in Lewy body disease and Alzheimer's disease Brain pathology (Zurich, Switzerland) · 1999-10-01 · usefulness score 36/100
• Newest in this subject Aβ42 oligomers disrupt calcium homeostasis via Piezo1 and induce neurotoxicity in differentiated SH-SY5Y cells Research Square · 2026-10-29 · Preprint — not yet peer-reviewed · usefulness score 16/100
• Newest in this subject Neuronal Hyperactivity Induces Tau Phosphorylation Selectively in Excitatory Pyramidal Neurons Which Contributes to GluA2 Regulation bioRxiv · 2026-10-28 · Preprint — not yet peer-reviewed · usefulness score 16/100

See all studies in Disease mechanisms →