{"doi":"10.1002/alz.70631","title":"Plasma lipidome dysregulation in frontotemporal dementia reveals shared, genotype‐specific, and severity‐linked alterations","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.","journal":"Alzheimer s & Dementia","year":2025,"id":522023,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":5,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9489,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":457245,"name":"Peter A. Ljubenkov","orcid":"0000-0002-3348-9215","position":1,"is_corresponding":false},{"id":849809,"name":"Shubham Singh","orcid":"0000-0002-2428-7718","position":2,"is_corresponding":false},{"id":1393450,"name":"Abdi Hamed","orcid":null,"position":3,"is_corresponding":false},{"id":84817,"name":"Sebastian Boland","orcid":"0000-0002-6694-2039","position":4,"is_corresponding":false},{"id":253908,"name":"Adam L. Boxer","orcid":"0000-0002-1215-5064","position":5,"is_corresponding":false},{"id":50222,"name":"Tobias C. Walther","orcid":"0000-0003-1442-1327","position":6,"is_corresponding":false},{"id":263113,"name":"Robert V. Farese","orcid":"0000-0001-8103-2239","position":7,"is_corresponding":false},{"id":849807,"name":"Yohannes A. Ambaw","orcid":"0000-0002-1703-400X","position":0,"is_corresponding":true}],"reference_count":48,"raw_metadata":null,"created_at":"2026-07-19T02:49:49.198144Z","pmid":"40922380","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}