DOI: 10.1001/jamaneurol.2026.1927 ISSN: 2168-6149

Clinical Associations of Cerebrospinal Fluid TMEM106B in Familial and Sporadic Frontotemporal Dementia

Molly Olzinski, Joshua Downer, Yann Cobigo, Binita Rajbanshi, Jingyao Li, Joseph Loureiro, Kathleen A. Worringer, Hilary Heuer, Peter Ljubenkov, Lawren Vandevrede, Adam Staffaroni, Argentina Lario-Lago, Dana Leichter, Amy Wolf, Amy Wise, Mark Sanderson-Cimino, Eden Barragan, Salvatore Spina, Lea T. Grinberg, William W. Seeley, Kaitlin B. Casaletto, Joel Kramer, Eliana Marisa Ramos, Daniel Geschwind, Casey Cook, Leonard Petrucelli, Leah K. Forsberg, Tania Gendron, Bradley F. Boeve, Jolien Perneel, Rosa Rademakers, Howard J. Rosen, Rowan Saloner, Adam L. Boxer, Julio C. Rojas, , M. Samy Abdullah, Liana Apostolova, Brian Appleby, Sami Barmada, Ece Bayram, Hugo Botha, Andrea Bozoki, Danielle Brushaber, David Clark, Ciaran M. Considine, R. Ryan Darby, Gregory S. Day, Bradford C. Dickerson, Dennis Dickson, Kimiko Domoto-Reilly, Emily Dwosh, Kelley M. Faber, Julie A. Fields, Jamie C. Fong, Tatiana Foroud, Douglas R. Galasko, Ralitza Gavrilova, Nupur Ghoshal, Jill Goldman, Jonathan Graff-Radford, Neill Graff-Radford, Ian M. Grant, Chadwick M. Hales, Lawrence S. Honig, Ging-Yuek R. Hsiung, Edward D. Huey, David Irwin, David T. Jones, Kejal Kantarci, David Knopman, Tyler Kolander, John Kornak, Walter Kremers, Justin Kwan, Maria Lapid, Suzee Lee, Gabriel C. Léger, Irene Litvan, Diane Lucente, Ian R. Mackenzie, Joseph C. Masdeu, Lauren Massimo, Scott McGinnis, Corey T. McMillan, Mario F. Mendez, Carly Mester, Toji Miyagawa, Joie Molden, Chiadi Onyike, Alexander Pantelyat, Belen Pascual, Henry Paulson, Vijay Ramanan, Katherine P. Rankin, Katya Rascovsky, Kristoffer W. Rhoads, Erik D. Roberson, Rodolfo Savica, Allison Snyder, A. Campbell Sullivan, Jeremy Syrjanen, M. Carmela Tartaglia, Jack Taylor, Philip W. Tipton, Marijne Vandebergh, Sandra Weintraub, Dylan Wint, Bonnie Wong, Jennifer Yokoyama
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Importance

TMEM106B is a frontotemporal lobar degeneration (FTLD) genetic susceptibility factor, and TMEM106B protein aggregates are a feature of aging and neurodegeneration. Whether TMEM106B protein levels are associated with clinical features is unknown.

Objective

To investigate the clinical associations of cerebrospinal fluid (CSF) TMEM106B in FTLD.

Design, Setting, and Participants

This cross-sectional study was conducted in 2 independent frontotemporal dementia (FTD) cohorts (recruitment from April 2009 through July 2023, with analyses from January 2025 through April 2026), with a 2-year follow up. This multicenter clinical study integrated clinical, genetic, biomarker, and neuroimaging data. Individuals were recruited through the University of California, San Francisco (n = 3733), or ALLFTD (n = 2343). Participants with available CSF were included. A discovery cohort (n = 271) included participants with sporadic neuropathology-confirmed FTLD; presymptomatic or symptomatic carriers of pathogenic variants in C9orf72 , GRN , or MAPT ; or controls. An independent validation cohort (n = 383) included participants with clinically diagnosed sporadic FTD, Alzheimer disease (AD), and controls.

Exposures

CSF samples for TMEM106B quantification with aptamer proteomics (SomaScan version 3.0 [discovery cohort] and SomaScan version 4.1 [validation cohort]).

Main Outcomes and Measures

Parametric tests compared the primary outcome, CSF TMEM106B, by disease severity, TMEM106B rs1990622 genotype, sex, clinical syndrome, pathological diagnosis, and pathogenic variant and determined associations with brain volume.

Results

In the discovery (n = 271; 136 women [51%]; median [IQR] age, 59 [38-80] years) and validation (n = 383; 183 women [48%]; median [IQR] age, 64 [50-78] years) cohorts, lower CSF TMEM106B was associated with more severe disease (β, −0.15; 95% CI, −0.24 to −0.04; P  = .003), lower frontotemporal brain volumes (β, 0.42; 95% CI, 0.24-0.61; P  < .001), and faster clinical progression (β, −2.21; 95% CI, −3.70 to −0.72; P  = .001). Associations of TMEM106B with clinical disease severity were independent of those with neurofilament light chain. TMEM106B levels were influenced by TMEM106B rs1990622 genotype, where individuals with the protective G/G genotype had lower levels than the risk A/A genotype. CSF TMEM106B levels did not differentiate between FTLD subtypes or between FTLD and AD.

Conclusions and Relevance

Per the results of this cross-sectional study, TMEM106B is detectable in CSF and levels reflect disease severity in sporadic and genetic FTLD and AD, but levels are also influenced by the TMEM106B rs1990622 genotype. CSF TMEM106B could support further studies to understand the mechanisms of disease and develop clinical tools in FTLD and other neurodegenerative diseases.

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