Proteomic analysis in Alzheimer's disease and other dementias: a focus on sex-specific differences

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dc.contributor.authorComas-Albertí, Aina
dc.contributor.authorLladó, Albert
dc.contributor.authorEsteller-Gauxax, Diana
dc.contributor.authorBorrego-Écija, Sergi
dc.contributor.authorFalgàs, Neus
dc.contributor.authorDakterzada, Farida
dc.contributor.authorPérez-Millan, Agnès
dc.contributor.authorPuey, Roger
dc.contributor.authorCollet-Romà, Tània
dc.contributor.authorGuillén, Núria
dc.contributor.authorMassons, Miquel
dc.contributor.authorTort-Merino, Adrià
dc.contributor.authorAugé, Josep Maria
dc.contributor.authorFernandez-Villullas, Guadalupe
dc.contributor.authorBosch, Bea
dc.contributor.authorRuiz-García, Raquel
dc.contributor.authorNaranjo, Laura
dc.contributor.authorBalasa, Mircea
dc.contributor.authorPiñol Ripoll, Gerard
dc.contributor.authorAntonell, Anna
dc.contributor.authorSánchez-Valle, Raquel
dc.date.accessioned2026-06-26T06:43:42Z
dc.date.available2026-06-26T06:43:42Z
dc.date.issued2026
dc.description.abstractBackground: Fluid protein studies in cerebrospinal fluid (CSF) and plasma have provided important insights into neurodegenerative dementias; however, there is a limited investigation of sex-related differences and cross-biofluid relationships. In Alzheimer's disease (AD), Lewy body dementia (LBD), and frontotemporal dementia (FTD), large-scale, sex-stratified analyses of paired CSF and plasma samples remain scarce. Using the multiplex and ultrasensitive capabilities of NULISAseq™ technology, this study aims to characterize sex- and disease-specific proteomic alterations associated with Central Nervous System (CNS) pathology to explore underlying mechanisms. Methods: CSF and plasma samples from 359 individuals with AD, LBD, FTD, and cognitively healthy controls were analyzed using the NULISAseq™ CNS Disease Panel 120. Differential protein expression analyses were conducted across diagnoses and stratified by sex, adjusting for relevant covariates. Spearman's correlation analyses were performed to assess concordance between CSF and plasma protein levels. All statistical analyses were conducted in R v4.4.3. Results: Differential protein expression analyses across diagnoses revealed two potential transdiagnostic biomarkers: ICAM1 in CSF and ANXA5 in plasma, showing consistent increases across AD, LBD, and FTD. Sex-stratified analyses in CSF showed modest changes, including higher CCL26, ANXA5, and IL10 in females with AD, and higher IL9, PRDX6, and CX3CL1 in males with AD. In LBD, females exhibited upregulation of ACHE, SFRP1, POSTN in both CSF and plasma. NPTX1 was identified as a potential CSF biomarker for FTD, showing downregulation particularly in males. In contrast, analyses stratified by sex in plasma displayed a larger number of proteins across all dementias, with females showing a higher number of upregulated inflammation-related proteins predominantly involved in cytokine signaling. Overall cross-fluid correlations were restricted to a small subset of proteins, indicating compartment-specific regulation. Conclusions: This study represents a large-scale, sex-stratified proteomic analysis of CSF and plasma across major neurodegenerative dementias using NULISAseq™ technology. The findings highlight sex-dependent biomarker patterns, particularly in plasma, and underscore the importance of incorporating sex as a biological variable in dementia research. Future studies should validate candidate proteins in independent cohorts, investigate their functional and mechanistic roles, and assess their utility for biomarker development and sex-tailored therapeutic strategies.
dc.identifier.doihttps://doi.org/10.1186/S13195-026-02068-7
dc.identifier.issn1758-9193
dc.identifier.urihttps://hdl.handle.net/10459.1/470671
dc.language.isoen
dc.publisherBioMed Central
dc.relation.isformatofReproducció del document publicat a: https://doi.org/10.1186/S13195-026-02068-7
dc.relation.ispartofAlzheimer's Research and Therapy, 2026, vol. 18, núm. 1
dc.rightscc-by-nc-nd (c)The Authors, 2026
dc.rightsAttribution-NonCommercial-NoDerivatives 4.0 International*
dc.rights.accessRightsinfo:eu-repo/semantics/openAccess
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/*
dc.subjectAlzheimer’s disease
dc.subjectBiomarkers
dc.subjectCerebrospinal fluid
dc.subjectFrontotemporal dementia
dc.subjectInflammation
dc.subjectLewy body dementia
dc.subjectNeurodegeneration
dc.subjectPlasma
dc.subjectProteomics
dc.subjectSex
dc.titleProteomic analysis in Alzheimer's disease and other dementias: a focus on sex-specific differences
dc.typeinfo:eu-repo/semantics/article
dc.type.versioninfo:eu-repo/semantics/publishedVersion
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