Abstract
INTRODUCTION: Biomarkers are essential for monitoring the progression of frontotemporal dementia (FTD). Although dysregulated brain lipid metabolism, particularly sphingolipids enriched in the nervous system, is a key feature of neurodegeneration, plasma lipids remain underexplored as biomarkers compared to imaging and serum proteins. METHODS: We examined plasma lipidomes using liquid chromatography-tandem mass spectrometry (LC-MS/MS) from individuals carrying pathogenic variants linked to autosomal dominant FTD (GRN, C9orf72, MAPT) and non-carriers. RESULTS: FTD subjects exhibited increased plasma levels of gangliosides (GM3(d18:1_16:0), GM3(d18:1_24:1)), ceramide Cer(d18:1_23:0), and select polyunsaturated triacylglycerols. In contrast, phosphatidylethanolamine (PE(18:0_24:0) and sphingomyelin (SM(38:0) were reduced. Subtype-specific changes included elevated glucosylsphingosine (GlcSph(d18:1) in GRN carriers, reduced SM(34:1) in C9orf72, and decreased TG(16:0_18:1_20:3) in MAPT carriers. GM3(d18:1_16:0) was consistently elevated across all subtypes. Furthermore, the levels of these lipids correlated with disease severity. DISCUSSION: Our findings suggest that specific plasma lipid changes, notably several sphingolipids, may be useful biomarkers for FTD disease or progression. HIGHLIGHTS: Plasma lipidomics reveals both shared and mutation-specific lipid alterations in frontotemporal dementia (FTD). Glucosylsphingosine is specifically elevated in FTD caused by GRN mutations and correlates with disease severity. The ganglioside GM3(d18:1_16:0) is consistently elevated across GRN, MAPT, and C9orf72 variants and correlates with disease severity. Plasma sphingolipids emerge as promising biomarkers for FTD diagnosis, subtype differentiation, and disease monitoring.