Citations 2
Clinical Associations of Cerebrospinal Fluid TMEM106B in Familial and Sporadic Frontotemporal Dementia
Olzinski, Molly, Downer, Joshua, Rajbanshi, Binita, Li, Jingyao, Loureiro, Joseph, Heuer, Hilary, Ljubenkov, Peter, Vandevrede, Lawren, Staffaroni, Adam, Lario‐Lago, Argentina, Leichter, Dana, Wolf, Amy, Wise, Amy, Sanderson-Cimino, Mark, Barragan, Eden, Spina, S, Grinberg, Lea T., Seeley, William W., Casaletto, Kaitlin B., Kramer, Joel, Ramos, Eilana, Geschwind, Daniel, Cook, Casey, Petrucelli, L, Forsberg, Leah K., Gendron, Tania, Boeve, Bradley F., Rademakers, Rosa, Rosen, Howard J., Saloner, Rowan, Boxer, Adam L., Rojas, Julio C., Abdullah, M. Samy, Apostolova, Liana, Appleby, Brian, Bayram, Ece, Hp, Botha, Bozoki, Andrea, Brushaber, Danielle, Clark, David, Considine, Ciaran M., Darby, R. Ryan, Day, Gregory S., Dickerson, Bradford C., Dickson, Dennis, Domoto-Reilly, Kimiko, Dwosh, Emily, Faber, Kelley M., Fields, Julie A. , Fong, Jamie C., Foroud, Tatiana, Galasko, Douglas R., Gavrilova, Ralitza, Ghoshal, Nupur , Goldman, Jill, Graff-Radford, Jonathan, Graff-Radford, Neill, Grant, Ian M., Cn, Hales, Honig, Lawrence S., Gd, Hsiung, Huey, Edward D, Irwin, David, Jones, David T., Kantarci, Kejal, Knopman, David, Kolander, Tyler , Kornak, J M, Kremers, W., Kwan, Justin , Lapid, Maria, Lee, Suzee, Litvan, Irene, Lucente, Diane, Mackenzie, Ian R., Masdeu, J C, Massimo, Lauren, McGinnis, Scott, McMillan, Corey T., Mendez, Mario F., Mester, Carly, Miyagawa, Toji , Molden, Joie, Onyike, Chiadi, Pantelyat, Alexander, Pascual, Belen, Paulson, Henry, Ramanan, Vijay, Rankin, Katherine P., Rascovsky, Katya, Rhoads, Kristoffer , Savica, Rodolfo, Snyder, Allison, Sullivan, A. Campbell, Syrjanen, Jeremy, Tartaglia, M, Taylor, Jack, Tipton, P E, WEINTRAUB, S, Wint, Dylan, Wong, Bonnie, Yokoyama, Jennifer, Paulson, Henry L. , Barmada, Sami J. , Paulson, Henry L , Barmada, Sami , Cobigo, Yann , Worringer, Kathleen A. , Heuer, Hilary W. , VandeVrede, Lawren , Staffaroni, Adam M. , Wolf, Amy , Wise, Amy B. , Sanderson‐Cimino, Mark , Barragan, Eden V. , Grinberg, Lea T. , Seeley, William W. , Casaletto, Kaitlin B. , Kramer, Joel, Ramos, Eliana Marisa , Geschwind, Daniel H. , Forsberg, Leah K. , Gendron, Tania F. , Boeve, Bradley F. , Perneel, Jolien , Rademakers, Rosa , Rosen, Howard J. , Saloner, Rowan , Boxer, Adam L. , Rojas, Julio C. , Appleby, Brian S. , Barmada, Sami, Bayram, Ece , Botha, Hugo, Bozoki, Andrea C , Brushaber, Danielle , Clark, David, Considine, Ciaran , Dickerson, Bradford Clark , Dickson, Dennis, Domoto‐Reilly, Kimiko , Dwosh, Emily , Foroud, Tatiana, Graff‐Radford, Jonathan , Graff-Radford, Neill, Hales, Chadwick M., Honig, Lawrence S. , Hsiung, Ging-Yuek R., Huey, Edward D. , Jones, David T., Kantarci, Kejal , Kornak, John , Kremers, Walter, Kwan, Justin, Léger, Gabriel C. , Litvan, Irene , Lucente, Diane , Mackenzie, Ian R. , Massimo, Lauren , McGinnis, Scott, McMillan, Corey T. , Mendez, Mario F. , Mester, Carly , Pascual, Belén , Ramanan, Vijay, Rankin, Katherine P. , Roberson, Erik D. , Savica, Rodolfo , Snyder, Allison , Sullivan, A. Campbell , Syrjanen, Jeremy A. , Taylor, Jack C. , Tipton, Philip W., Vandebergh, Marijne , Weıntraub, Sandra , Wint, Dylan
JAMA Neurology | June 22, 2026 | Volume: 83 | Issue: 8 | Pages: 778
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.
Trajectories of brain structure and function in young adult carriers of genetic frontotemporal dementia variants
So, Isis , Staffaroni, Adam M. , Coleman, Kristy , Bouzigues, Arabella , Ferry‐Bolder, Eve , Cullen, Eva , Russell, Lucy L. , Foster, Phoebe H. , Farley, Sophie , Thompson, Alexander, Ber, Isabelle Le , Körtvelyessy, Péter , Schroeter, M., Uzelac, Željko , Kruger, Johanna S. W. , Langheinrich, Tobias , Ducharme, Simon , Santana, Isabel J., Tartaglia, Carmela, Mendonca, Alexandre de, Morenoizco, Fermin, Brushaber, Danielle, Considine, Ciaran , Faber, Kelley, Fagan, Anne, Fields, Julie, Foroud, Tatiana, Forsberg, Leah K. , Geschwind, Daniel, Heuer, Hilary W. , Huang, Eric, Kantarci, Kejal, Kolander, Tyler , Lago, Argentina Lario , Lavigne, Shannon B., Mester, Carly , Molden, Joie, Petrucelli, Leonard , Rademakers, Rosa , Ramos, Eilana, Rankin, Katherine P., Rascovsky, Katya, Rhoads, Kristoffer , Weintraub, Sandra, Wong, Bonnie, Boxer, Adam L. , Rosen, Howard J. , Lee, Suzee E. , Lombardi, Jolina , Staffaroni, Adam M , Coleman, Kristy K L , Bouzigues, Arabella , Ferry-Bolder, Eve , Cullen, Eva , Russell, Lucy L , Foster, Phoebe H , Farley, Sophie , Convery, Rhian , Van Swieten, John C , Jiskoot, Lize C , Seelaar, Harro , Galimberti, Daniela , Vandenberghe, Rik , Laforce, Robert , Bruffaerts, Rose , Bertoux, Maxime , Lebouvier, Thibaud , Solje, Eino , Xiong, Chengjie , di Fede, Giuseppe , Le Ber, Isabelle , Migliaccio, Raffaella Lara , Körtvélyessy, Peter , Logroscino, Giancarlo , Otto, Markus , Uzelac, Zeljko , Illán-Gala, Ignacio , Krüger, Johanna , Nacmias, Benedetta , Gerhard, Alexander , Langheinrich, Tobias , Ducharme, Simon , Masellis, Mario , Rowe, James B , Graff, Caroline , Synofzik, Matthis , Borroni, Barbara , Sánchez-Valle, Raquel , Considine, Ciaran M , Forsberg, Leah K , Gendron, Tania F , Heuer, Hilary W , Huang, Eric , Kolander, Tyler , Mester, Carly , Petrucelli, Leonard , Rademakers, Rosa , Vandebergh, Marijne , Boeve, Brad , Boxer, Adam , Rosen, Howard J , Lee, Suzee E , Rohrer, Jonathan D , Finger, Elizabeth C. , Lombardi, Jolina , Swieten, John C. van , Jiskoot, Lize C. , Seelaar, Harro , Galimberti, Daniela , Vandenberghe, Rik , Laforce, Robert , Lebouvier, Thibaud , Xiong, Chengjie , Thompson, Alexander G. , Logroscino, Giancarlo , Otto, Markus , Illán‐Gala, Ignacio , Nacmias, Benedetta , Tartaglia, Carmela M., de Mendonça, Alexandre , Rowe, James B. , Graff, Caroline , Moreno, Fermín , Synofzik, Matthis , Borroni, Barbara , Sánchez‐Valle, Raquel , Brushaber, Danielle , Fagan, Anne M. , Gendron, Tania F. , Geschwind, Daniel, Kantarci, Kejal , Ramos, Eliana Marisa , Rankin, Katherine P. , Vandebergh, Marijne , Weıntraub, Sandra , Boeve, Bradley F. , Rohrer, Jonathan D.
No container title available | June 11, 2026 | Volume: No volume available | Issue: No issue available | Pages: No page available
ABSTRACT Background and Objectives Converging evidence hints at neurodevelopmental effects in genetic frontotemporal degeneration (FTD). In cross-sectional studies, for some genes, young adult FTD variant carriers show differences in brain volumes and cognition compared to familial non-carriers. However, longitudinal trajectories may more sensitively capture FTD-related neurodevelopmental vs. neurodegenerative changes than cross-sectional approaches. This study examined longitudinal trajectories of brain volumes, executive function, and plasma biomarkers in young adult carriers compared to familial non-carriers, as measures of neurodevelopmental and neurodegenerative outcomes of FTD-causing variants. Methods This longitudinal cohort study comprised participants, aged 18-30 years, from the FTD Prevention Initiative across Europe, Canada, and the USA. Genetic groups included C9orf72 (47%), MAPT (30%), and GRN (23%). Linear mixed-effects models were computed to assess longitudinal outcomes across age between groups, controlling for sex, scanner (for brain volumes), and education (for executive function); random effects accounted for between-subject variability nested within family membership. Results Variant carriers ( n =147) and familial non-carriers ( n =113) did not differ in age (mean±SD, 25.9±3.2 years), sex (53% female), or number of visits (2.1±1.7). Young adult C9orf72 repeat expansion carriers exhibited smaller thalamic volumes than non-carriers at the reference age of 26 years ( b =-982.8mm 3 , SE=317.0, p= 0.0046, f 2 =0.32), with relatively stable trajectories across ages 18-30 (i.e., no change over time). Trajectories of rostral anterior cingulate volumes differed in C9orf72 carriers and non-carriers across age, where carriers showed relatively stable trajectories and non-carriers showed age-appropriate declines ( b =64.4mm 3 , SE=29.9, p= 0.035, f 2 =0.07). For MAPT and GRN , there were little to no differences in total brain, cortical, or subcortical volumes between groups and over time. No longitudinal differences were observed between carriers and non-carriers in executive function, or plasma NfL or GFAP for any genetic group. Discussion C9orf72 repeat expansions were linked to smaller average thalamic volumes and stable trajectories between ages 18 to 30, supporting potential neurodevelopmental origins. The modest evidence supporting an absence of difference in neurodegenerative biomarkers and executive function suggests minimal early neurodegeneration and functional preservation in young adulthood.