Article Impact Level: HIGH Data Quality: STRONG Summary of Brain, awaf019. https://doi.org/10.1093/brain/awaf019 Dr. Saira S. Mirza et al.
Points
- The study found that the TMEM106B rs1990622 G allele is associated with slower disease progression in genetic frontotemporal dementia, particularly among GRN and C9orf72 mutation carriers.
- Presymptomatic carriers with the G allele showed less brain atrophy in several regions and exhibited lower baseline neurofilament light chain levels, indicating reduced neurodegeneration.
- Symptomatic carriers of the G allele demonstrated better preservation of cognitive and behavioral functions, slower brain atrophy, and decreased NfL levels over time.
- These results suggest the G allele exerts a protective effect by modifying key biomarkers and structural brain changes in individuals at risk for or affected by frontotemporal dementia.
- The study supports including TMEM106B genotype information in clinical trials and treatment strategies to tailor more effective precision medicine approaches for genetic FTD.
Summary
This study investigated the impact of the TMEM106B gene variant, specifically the rs1990622 G allele, on disease progression in individuals with genetic frontotemporal dementia (FTD). The research was embedded within the Genetic Frontotemporal Dementia Initiative (GENFI) and included 518 participants, divided into 209 non-carriers, 222 presymptomatic carriers (C9orf72 = 79; GRN = 101; MAPT = 42), and 87 symptomatic carriers (C9orf72 = 45; GRN = 29; MAPT = 13), followed for up to 7 years. The study used linear mixed-effects models to assess the effects of TMEM106B-rs1990622G allele dosage on grey matter volume, serum neurofilament light chain (NfL) levels, and cognitive/behavioral measures across clinical stages.
The results showed that the rs1990622 G allele had protective effects, particularly in GRN and C9orf72 mutation carriers. In presymptomatic carriers, greater G allele dosage was associated with less atrophy in the right occipital region and a slower atrophy rate in the putamen, caudate nucleus, and bilateral insular cortices. Furthermore, G allele carriers had lower NfL levels at baseline and better executive function and language abilities. In symptomatic carriers, the G allele was linked to reduced atrophy in the right frontal cortex and insula, lower NfL levels over time, and maintained cognitive and behavioral performance.
This study highlights the protective role of the TMEM106B rs1990622 G allele in genetic FTD, particularly for GRN and C9orf72 mutations. The authors suggest that the TMEM106B genotype should be considered in clinical trials, as it influences biomarkers, neuroimaging, and cognitive outcomes, thereby modifying the disease course. This finding underscores the need for incorporating genetic variants in precision medicine approaches to understand disease progression better and improve therapeutic strategies.
Link to the article: https://academic.oup.com/brain/advance-article/doi/10.1093/brain/awaf019/8115908
References Mirza, S. S., Pasternak, M., Paterson, A. D., Rogaeva, E., Tartaglia, M. C., Mitchell, S. B., Black, S. E., Freedman, M., Tang-Wai, D., Bouzigues, A., Russell, L. L., Foster, P. H., Ferry-Bolder, E., Bocchetta, M., Cash, D. M., Zetterberg, H., Sogorb-Esteve, A., Van Swieten, J., Jiskoot, L. C., … Lemos, J. (2025). Disease-modifying effects of TMEM106B in genetic frontotemporal dementia: A longitudinal GENFI study. Brain, awaf019. https://doi.org/10.1093/brain/awaf019
