Glycosphingolipids in Dementia: Insights from Mass Spectrometry and Systems Biology Approaches

This review synthesizes the current evidence on glycolipid dysregulation in dementia, with a focus on the data generated by mass spectrometry (MS) and systems biology approaches. Glycolipids, key regulators of neuronal function and integrity, have emerged as important players in neurodegenerative processes. In this context, we ex-amine here their altered expression reported in major forms of dementia, including Alzheimer’s disease, frontotemporal dementia, dementia with Lewy body, Parkinson's disease dementia, Huntington’s disease, and mixed dementia. By comparing these conditions, we identified molecular signatures that appear broadly conserved, suggesting common pathways of neuronal vulnerability, while also outlining disease-specific changes that may cause the observed clinical diversity. A special consideration is given to methodological advances, particularly the development and application of high performance MS in glyolipidomics and integrative analytical workflows, which have significantly expanded our understanding of lipid-mediated mechanisms in the diseased brain. Situating these findings within the context of dementia research, we further discuss here how glycolipid biology intersects with protein aggregation, neuroinflammation, and synaptic dysfunction. The results assessed here highlight the major role of MS-based platforms in discovery of glycolipids associated to dementia pathogenesis and at the same time of species with potential biomarker role and/or as novel targets for therapeutic intervention. This review, thus, provides an integrative perspective on glycolipid research by modern MS and allied techniques, emphasizing its potential to influence future strategies for diagnosis and treatment of dementia.