Objective: To determine whether TMEM106B fibrils contribute to AV-1451 retention in the choroid plexus (CP) and to elucidate the structural basis of their binding.

Background: Prominent [¹⁸F]AV-1451 uptake in the CP is frequently observed in tau positron emission tomography (PET) imaging and may influence interpretation of adjacent medial temporal structures^1,2. TMEM106B amyloid fibrils have recently been identified as a major component of Biondi bodies in the CP and represent a potential binding substrate for tau PET tracers^3,4, which is consistent with our previous study showing that the tau PET tracer PBB3 binds to TMEM106B fibrils⁵.

Method: Eighteen Alzheimer’s disease (AD) participants from ADNI4 who underwent both [¹⁸F]AV-1451 and [¹⁸F]AV-45 PET were analyzed. CP standardized uptake value ratios (SUVRs) were quantified using tracer-appropriate reference regions. Postmortem human CP tissue was examined by immunofluorescence. Brain-derived TMEM106B fibrils were extracted and then incubated with AV-1451 or AV-45 for structural characterization using cryo-electron microscopy (cryo-EM).

Results: Nine of eighteen participants (50%) demonstrated visually positive CP uptake on [¹⁸F]AV-1451 PET, whereas all participants were CP-negative on [¹⁸F]AV-45 PET. The mean CP SUVR for [¹⁸F]AV-1451 was 1.27±0.33, reflecting robust tracer retention within the CP. In contrast, [¹⁸F]AV-45 demonstrated a mean CP SUVR of 0.68±0.12, consistent with low background-level uptake (Table 1, Figure 1). Immunofluorescence analysis of postmortem CP tissue revealed robust co-localization of AV-1451 signal with TMEM106B fibrils, whereas AV-45 showed no specific binding (Figure 2). Cryo-EM analysis uncovered three defined AV-1451 binding sites along the TMEM106B fibril surface, one of which was characterized by a stacked ligand configuration, providing structural evidence for direct molecular engagement (Figure 3). In contrast, incubation with AV-45 yielded no comparable binding density (data not shown).

Conclusion: TMEM106B amyloid fibrils in the CP represent a structural substrate for [¹⁸F]AV-1451 retention. These findings provide molecular and structural insight into the CP signal observed in tau PET imaging, informing the interpretation of tracer uptake patterns in neurodegenerative diseases. Furthermore, they establish a structural basis for the development of TMEM106B fibril-specific tracers.

Table 1

Figure 1

Figure 2

Figure 3

References: 1 Leuzy, A. et al. Tau PET imaging in neurodegenerative tauopathies-still a challenge. Mol Psychiatry 24, 1112-1134 (2019). https://doi.org/10.1038/s41380-018-0342-8
2 Ikonomovic, M. D., Abrahamson, E. E., Price, J. C., Mathis, C. A. & Klunk, W. E. [F‐18]AV‐1451 positron emission tomography retention in choroid plexus: More than “off‐target” binding. Annals of Neurology 80, 307-308 (2016). https://doi.org/10.1002/ana.24706
3 Ghetti, B. et al. TMEM106B amyloid filaments in the Biondi bodies of ependymal cells. Acta Neuropathol 148, 60 (2024). https://doi.org/10.1007/s00401-024-02807-w
4 Yokoyama, Y. et al. Transmembrane protein 106B amyloid is a potential off-target molecule of tau PET tracers in the choroid plexus. Nuclear Medicine and Biology 142-143 (2025). https://doi.org/10.1016/j.nucmedbio.2024.108986
5 Zhao, Q. et al. A Tau PET tracer PBB3 binds to TMEM106B amyloid fibril in brain. Cell Discov 10, 50 (2024). https://doi.org/10.1038/s41421-024-00674-z

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MDS Abstracts - https://www.mdsabstracts.org/abstract/tmem106b-amyloid-fibrils-in-the-choroid-plexus-mediate-18fav-1451-retention-cohort-level-imaging-and-cryo-em-evidence/