Linking TMEM106B pathology to flortaucipir signal in FTLD-TDP

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.