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Clinical Associations of Cerebrospinal Fluid TMEM106B in Familial and Sporadic Frontotemporal Dementia
Molly Olzinski1, Joshua Downer1, Yann Cobigo1
1Edward and Pearl Fein Memory and Aging Center, Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco.
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.
Insights
Cerebrospinal fluid (CSF) TMEM106B levels correlate with frontotemporal lobar degeneration (FTLD) severity and brain volume, and are influenced by the TMEM106B rs1990622 genotype. These findings suggest CSF TMEM106B may aid in understanding FTLD mechanisms and developing diagnostic tools.
Area of Science:
- Neuroscience
- Genetics
- Biomarker Discovery
Background:
- TMEM106B is a known genetic susceptibility factor for frontotemporal lobar degeneration (FTLD).
- TMEM106B protein aggregates are observed in aging and neurodegenerative conditions.
- The association between TMEM106B protein levels and clinical FTLD features remains unclear.
Purpose of the Study:
- To investigate the clinical associations of cerebrospinal fluid (CSF) TMEM106B levels in patients with FTLD.
- To explore the relationship between CSF TMEM106B and disease severity, genetic factors, and neuroimaging findings.
Main Methods:
- A cross-sectional study involving two independent FTD cohorts (discovery and validation).
- CSF samples were analyzed for TMEM106B quantification using aptamer proteomics.
- Clinical, genetic, biomarker, and neuroimaging data were integrated.
Main Results:
- Lower CSF TMEM106B levels were associated with increased disease severity, reduced frontotemporal brain volumes, and faster clinical progression.
- TMEM106B levels were significantly influenced by the TMEM106B rs1990622 genotype.
- CSF TMEM106B associations with severity were independent of neurofilament light chain levels and did not differentiate FTLD subtypes or Alzheimer's disease.
Conclusions:
- CSF TMEM106B is detectable and reflects disease severity in sporadic and genetic FTLD and Alzheimer's disease.
- CSF TMEM106B levels are influenced by the rs1990622 genotype.
- CSF TMEM106B holds potential as a biomarker for understanding FTLD mechanisms and developing clinical tools for neurodegenerative diseases.
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