CSF TMEM106B Emerges as a Potential Biomarker for Frontotemporal Lobar Degeneration: JAMA
USA: Researchers have demonstrated in a new study published in JAMA Neurology that TMEM106B can be detected in cerebrospinal fluid (CSF), with its levels reflecting both disease severity and the influence of the TMEM106B rs1990622 genetic variant.
The findings support a role for TMEM106B in the pathophysiology of both sporadic and familial frontotemporal lobar degeneration (FTLD), with a weaker association observed in Alzheimer's disease. Although CSF TMEM106B is not currently used in clinical practice, it shows promise as a biomarker and potential therapeutic target. Further research is needed to clarify its role in FTLD mechanisms and to evaluate its utility in improving diagnosis and treatment development.
The study, published in JAMA Neurology, was led by Molly Olzinski and colleagues from the Edward and Pearl Fein Memory and Aging Center, Department of Neurology, University of California, San Francisco.
TMEM106B is a genetic risk factor for frontotemporal lobar degeneration (FTLD), and its protein aggregates have been implicated in aging and neurodegenerative diseases. However, the clinical significance of CSF TMEM106B levels remains uncertain.
To address this, researchers analyzed data from two independent frontotemporal dementia cohorts recruited through the University of California, San Francisco, and the ALLFTD consortium between 2009 and 2023. The study integrated clinical, genetic, neuroimaging, and biomarker data.
The analysis included a discovery cohort of 271 participants and a validation cohort of 383 participants, encompassing individuals with sporadic FTLD, carriers of C9orf72, GRN, or MAPT pathogenic variants, patients with Alzheimer's disease, and healthy controls. CSF TMEM106B levels were quantified using aptamer-based proteomic testing.
The study revealed the following findings:
- Lower CSF TMEM106B levels were associated with greater disease severity in FTLD.
- Reduced CSF TMEM106B levels correlated with smaller frontotemporal brain volumes.
- Lower TMEM106B concentrations were linked to faster clinical progression.
- The association between TMEM106B and disease severity remained significant independent of neurofilament light chain levels.
- CSF TMEM106B levels were influenced by the TMEM106B rs1990622 genotype.
- Individuals with the protective rs1990622 G/G genotype had lower TMEM106B levels than those with the risk-associated A/A genotype.
- The genotype-related differences in TMEM106B levels were observed across FTLD subtypes and pathogenic genetic variants.
- CSF TMEM106B levels did not distinguish between FTLD subtypes.
- CSF TMEM106B levels also did not differentiate FTLD from Alzheimer's disease.
- Despite limited diagnostic utility, CSF TMEM106B levels were associated with disease burden and progression, highlighting a potential role in neurodegenerative disease mechanisms.
The study was limited by relatively small sample sizes, limited racial and ethnic diversity, potential selection bias, and its cross-sectional design, which precluded assessment of long-term changes in TMEM106B levels. Differences in analytical platforms between cohorts may have also affected the findings.
Despite these limitations, the researchers concluded that CSF TMEM106B reflects both disease severity and genetic influences in FTLD. They noted that further research could improve understanding of disease mechanisms and support the development of future diagnostic and therapeutic approaches for FTLD and other neurodegenerative disorders.
Reference:
Olzinski M, Downer J, Cobigo Y, et al. Clinical Associations of Cerebrospinal Fluid TMEM106B in Familial and Sporadic Frontotemporal Dementia. JAMA Neurol. Published online June 22, 2026. doi:10.1001/jamaneurol.2026.1927
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