Proteome-wide Mendelian randomization identifies causal plasma proteins in frontotemporal dementia
1Department of Cardiology, West China School of Public Health and West China Fourth Hospital, Sichuan University, 18th, Section 3, Renmin Road South, Wuhou District, Chengdu, Sichuan, 610041, China.
Background:
Frontotemporal dementia (FTD) is a genetically and clinically heterogeneous neurodegenerative disorder with no disease-modifying treatments. Plasma proteomic signatures offer a promising avenue for uncovering disease mechanisms and developing targeted interventions.
Methods:
We conducted protein-wide Mendelian randomization meta-analysis to explore causal relationships between plasma proteins and FTD and four subtypes, utilizing comprehensive datasets of protein quantitative trait loci.
Results:
We identified four plasma proteins significantly associated with FTD, namely RGS7 and ASAP2 (increased risk), as well as TMCC3 and VPS29 (decreased risk). Subtype-specific analyses revealed distinct protein signatures, including S100A13 and TREM1 in behavioral variant FTD, ING4 and TEX29 in FTD overlapping with motor neuron disease, SPINT2 in progressive non-fluent aphasia, and UGDH in semantic dementia.
Conclusions:
This study implicates specific plasma proteins in FTD pathogenesis, with subtype-dependent effects. The identified proteins represent potential biomarkers for stratification and therapeutic targets.
