{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,10,19]],"date-time":"2026-10-19T22:07:01Z","timestamp":1792447621147,"version":"4.5.0"},"posted":{"date-parts":[[2026,2,4]]},"group-title":"Neurology","reference-count":52,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,2,4]],"date-time":"2026-02-04T00:00:00Z","timestamp":1770163200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.medrxiv.org\/about\/FAQ#license"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,2,4]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>Older individuals frequently harbor multiple brain pathologies, including Alzheimer\u2019s disease (AD) related amyloid-\u03b2 (A\u03b2) and tau alongside \u03b1-synucleinopathy and vascular pathology. Proteomic profiling offers a strategy to better understand common as well as unique features of these different brain pathologies.<\/jats:p>\n                <jats:p>We analyzed cerebrospinal fluid (CSF) (n=1,658) and plasma (n=749) samples from participants in the BioFINDER cohorts using the automated NULISAseq CNS Disease panel of 125 proteins. Differentially abundant proteins (DAPs) related to AD pathology (based on A\u03b2\u2013 and tau-PET positivity), \u03b1-synuclein (based on synuclein amplification assay [SAA] positivity) and vascular pathology (based on white matter lesion [WML] load) were identified with linear models simultaneously including a binary measure for the three pathologies. In the BioFINDER-2 subcohorts, DAPs were further evaluated for associations with continuous baseline (n=1,137) and longitudinal (n=656) A\u03b2-PET, tau-PET, and WML measures in models accounting for all pathologies. Associations with AD-signature cortical atrophy (n=915) and cognitive decline by the MMSE (n=1054) were also examined.<\/jats:p>\n                <jats:p>We identified 84 CSF DAPs, with largely distinct protein signatures for each pathology (AD, n=66 DAPs; vascular pathology, n=55; \u03b1-synuclein pathology, n=16). 10 DAPs (e.g., FABP3, UCHL1, NPTXR, NPTX2) were altered across all three pathologies, reflecting general neurodegeneration. AD-associated DAPs included glial\/inflammatory markers (CHIT1, CX3CL1, CD63) linked to A\u03b2 pathology, and synaptic\/neuronal injury markers (VSNL1, NRGN, NEFL) and metabolic enzymes (FABP3, MDH1) linked to tau pathology. A\u03b2-associated proteomic differences were most evident in CU individuals, while tau-associated differences predominated in MCI. More proteins, particularly neurodegeneration and synaptic markers, were associated with tau change than with A\u03b2 change. Vascular pathology exhibited a distinct profile, enriched for inflammatory, angiogenic and extracellular matrix proteins (PGF, POSTN, TREM1, VCAM1). DDC was the main protein associated with \u03b1-synucleinopathy. Only a few proteins, including UCHL1, NPTX2, and NEFL, predicted cognitive decline and cortical atrophy after accounting for all brain pathologies.<\/jats:p>\n                <jats:p>In plasma, although fewer DAPs were identified (n=20), findings included established AD biomarkers. Only plasma VCAM1 and NEFL were associated with \u03b1-synuclein and vascular pathology.<\/jats:p>\n                <jats:p>NULISA identified stage-dependent, disease-specific CSF biomarker signatures with limited overlap, alongside shared neurodegenerative markers, supporting improved biological interpretation and more refined classification of neurodegenerative pathology.<\/jats:p>","DOI":"10.64898\/2026.02.04.26345534","type":"posted-content","created":{"date-parts":[[2026,2,5]],"date-time":"2026-02-05T01:55:19Z","timestamp":1770256519000},"source":"Crossref","is-referenced-by-count":3,"title":["Plasma and CSF proteomic signatures related to Alzheimer\u2019s, \u03b1-synuclein, or vascular pathologies and clinical decline"],"prefix":"10.64898","author":[{"given":"Anna Ordu\u00f1a","family":"Dolado","sequence":"first","affiliation":[{"name":"Clinical Memory Research Unit, Department of Clinical Sciences Malm\u00f6, Faculty of Medicine, Lund University, Lund, 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Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, M\u00f6lndal, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"K\u00fcbra","family":"Tan","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, M\u00f6lndal, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wiebke","family":"Traichel","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, M\u00f6lndal, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ines","family":"Hristovska","sequence":"additional","affiliation":[{"name":"Clinical Memory Research Unit, Department of Clinical Sciences Malm\u00f6, Faculty of Medicine, Lund University, Lund, 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