Concurrent tau pathologies in frontotemporal lobar degeneration with TDP‐43 pathology
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Abstract
Aims: Accumulating evidence suggests that patients with frontotemporal lobar degeneration (FTLD) can have pathologic accumulation of multiple proteins, including tau and TDP‐43. This study aimed to determine the frequency and characteristics of concurrent tau pathology in FTLD with TDP‐43 pathology (FTLD‐TDP). Methods: The study included 146 autopsy‐confirmed cases of FTLD‐TDP and 55 cases of FTLD‐TDP with motor neuron disease (FTLD‐MND). Sections from the basal forebrain were screened for tau pathology with phosphorylated‐tau immunohistochemistry. For cases with tau pathology on the screening section, additional brain sections were studied to establish a diagnosis. Genetic analysis of C9orf72 , GRN and MAPT was performed on select cases. Results: We found 72 cases (36%) with primary age‐related tauopathy (PART), 85 (42%) with ageing‐related tau astrogliopathy (ARTAG), 45 (22%) with argyrophilic grain disease (AGD) and 2 cases (1%) with corticobasal degeneration (CBD). Patients with ARTAG or AGD were significantly older than those without these comorbidities. One of the patients with FTLD‐TDP and CBD had C9orf72 mutation and relatively mild tau pathology, consistent with incidental CBD. Conclusion: The coexistence of TDP‐43 and tau pathologies was relatively common, particularly PART and ARTAG. Although rare, patients with FTLD can have multiple neurodegenerative proteinopathies. The absence of TDP‐43‐positive astrocytic plaques may suggest that CBD and FTLD‐TDP were independent disease processes in the two patients with both tau and TDP‐43 pathologies. It remains to be determined if mixed cases represent a unique disease process or two concurrent disease processes in an individual.
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Mutations in GRN are associated with abnormal tau protein phosphorylation.
“gene mutations in the premature ageing proteins PSEN1, PSEN2 [138,139], and GRN [140,141] have been shown to be associated with abnormal tau protein phosphorylation”
From Role of Tau Protein in Neurodegenerative Diseases and Development of Its Targeted Drugs: A Literature Review (2024) · cites this paper as [140]
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Self-citationKoga, S., Metrick, M. A., Golbe, L. I., Santambrogio, A., Kim, M., Soto‐Beasley, A. I., Walton, R. L., Baker, M., De Castro, C. F., Deture, M. A., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26593406
Self-citationRole of Alpha-Synuclein in Frontotemporal Dementia: Narrative Review
Bougea, A. M. (2026) · Cells · doi:10.3390/cells15050470
Kai, T., Tominaga, K., Matsunaga, A., Shimizu, H., Iwama, K., & Ishizawa, K. (2026) · Reports — Medical Cases Images and Videos · doi:10.3390/reports9030209
Gatto, R. G., Uruk, G., Youssef, H., Reichard, R. R., Lowe, V. J., Whitwell, J. L., & Josephs, K. A. (2026) · The Lancet Medical Imaging & Theranostics · doi:10.1016/j.lanmit.2026.100013
- Authors
- Koga, S., Zhou, X., Murakami, A., Fernandez De Castro, C., Baker, M. C., Rademakers, R., & Dickson, D. W.
- Affiliations
- Mayo Clinic (US)
- Department of Neuroscience Mayo Clinic Jacksonville Florida USA
- University of Antwerp (BE)
- Corresponding author
- Dickson, Dennis W.
- Venue
- Neuropathology and Applied Neurobiology
- Publisher
- Wiley
- Published
- 2021-12-10
- Volume
- 48
- Issue
- 2
- Pages
- e12778-e12778
- ISSN
- 0305-1846 (ISSN-L)
- 1365-2990
- PMC
- PMC9300011
- OpenAlex
- W3217136548
- Cited by
- 30
- References
- 50
- Citations by year
- 2026: 4 · 2025: 5 · 2024: 13 · 2023: 3 · 2022: 5
- FWCI
- 2.50
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Neuropathology and Applied Neurobiology (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- CurePSP
- National Institute of Neurological Disorders and Stroke
- Rainwater Charitable Foundation
- Topics
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- frontotemporal lobar degeneration, FTLD-TDP, TDP-43 pathology, tau pathology, primary age-related tauopathy, argyrophilic grain disease, corticobasal degeneration, motor neuron disease, C9orf72 mutation, MAPT, gene regulatory networks, basal forebrain
- MeSH terms
- Aged, Aged, 80 and over, Brain, DNA-Binding Proteins, Female, Humans, Male, Middle Aged, Neurons, tau Proteins, Tauopathies, Frontotemporal Lobar Degeneration
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