Plasma lipidome dysregulation in frontotemporal dementia reveals shared, genotype-specific, and severity-linked alterations

Abstract

Developing new treatment strategies for frontotemporal dementia (FTD) and other forms of neurodegeneration requires biomarkers to monitor disease progression. Dysregulated brain lipid metabolism, particularly sphingolipids enriched in the nervous system, is a key feature of neurodegeneration. However, plasma lipids have been investigated less for their potential as biomarkers than brain imaging and serum proteins. Here we examined the plasma lipidomes of a cohort of heterozygous carriers of gene variants associated with autosomal dominant familial FTD (including GRN, C9orf72, and MAPT loci), comparing them with aged-matched controls. In general, FTD subjects exhibited increases in plasma levels of specific species of gangliosides (GM3(d18:1_16:0), GM3(d18:1_18:0), and GM3(d18:1_24:1)) and ceramide (Cer(d18:1_23:0)) and selected polyunsaturated triacylglycerols (TG). Other species of ceramides (Cer(d18:0_22:0)), phosphatidylethanolamine (PE(18:0_24:0)), and sphingomyelin (SM(38:0)) were reduced in plasma of FTD subjects. Levels of glucosylsphingosine (GlcSph(d18:1)) were elevated specifically in GRN carriers, SM(34:1) was reduced in C9orf72 carriers, and TG(16:0_18:1_20:3)) were decreased in MAPT variant carriers. Notably, the ganglioside GM3(d18:1_16:0) was consistently elevated across all FTD genetic subtypes. Furthermore, the levels of these lipids correlated with disease severity in FTD patients. Our findings suggest that specific plasma lipid changes, notably several sphingolipids, may be useful biomarkers for FTD disease or progression.