Flortaucipir (FTP) is a tau-PET tracer used to detect mature, phosphorylated tau pathology in neurodegenerative diseases. However, FTP exhibits uptake in frontotemporal lobar degeneration (FTLD), particularly in FTLD cases with phosphorylated TAR DNA-binding protein 43 (pTDP-43), raising concerns about its regional specificity. Transmembrane protein 106B (TMEM106B), a lysosomal protein, is genetically and pathologically linked to FTLD.
FTP retention in FTLD-TDP spatially overlaps with TMEM106B deposition, suggesting that TMEM106B may represent a candidate substrate contributing to regional off-target signal. Tissue samples were obtained from three cognitively normal controls, seven Alzheimer’s disease (AD) cases, and ten FTLD-TDP cases (five type A, five type C). Formalin-fixed, paraffin-embedded sections from hippocampal and limbic subregions, including the dentate gyrus, CA1-CA4, subiculum, entorhinal cortex, and choroid plexus, were analyzed.
A fluorescent FTP analog (T726) was used to assess tracer binding, and fluorescence immunohistochemistry was employed to detect TMEM106B protein and pTDP-43. Confocal microscopy enabled colocalization analysis. TMEM106B protein was observed in both AD and FTLD-TDP cases across all examined subregions.
In the AD cases, there were more extended and larger TMEM106B staining patterns compared to those with FTLD-TDP. Colocalization between T726 and TMEM106B was most prominent in the choroid plexus (a common hotspot for off-target binding) in controls, AD, and FTLD cases. Additional colocalization was observed across hippocampal regions, particularly in FTLD-TDP type C cases.
These results suggest that FTP off-target binding in FTLD-TDP may be partially attributable to the TMEM106B protein, particularly in the choroid plexus. Further investigations may enhance our understanding of disease mechanisms and refine FTP imaging interpretation in FTLD-TDP. Phosphorylated TAR DNA‑Binding Protein 43 Alzheimer’s disease neuropathologic change Cornu Ammonis hippocampal subfields (CA1, CA2, CA3, CA4) Progranulin (key protein regulator of lysosomal function) We thank all patients and families who helped make this research study possible.
We thank Avid Radiopharmaceuticals for providing the materials for this study. We also want to acknowledge Matt C. Baker and Professor Rosa Rademakers for providing the genetic data for this study.
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