Plasma and CSF proteomic signatures related to Alzheimer’s, α-synuclein, or vascular pathologies and clinical decline

Older individuals frequently harbor multiple brain pathologies, including Alzheimer's disease (AD) related amyloid-β (Aβ) and tau alongside α-synucleinopathy and vascular pathology. Proteomic profiling offers a strategy to better understand common as well as unique features of these different brain pathologies. 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 Aβ- and tau-PET positivity), α-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) Aβ-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. We identified 84 CSF DAPs, with largely distinct protein signatures for each pathology (AD, n=66 DAPs; vascular pathology, n=55; α-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 Aβ pathology, and synaptic/neuronal injury markers (VSNL1, NRGN, NEFL) and metabolic enzymes (FABP3, MDH1) linked to tau pathology. Aβ-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 Aβ 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 α-synucleinopathy. Only a few proteins, including UCHL1, NPTX2, and NEFL, predicted cognitive decline and cortical atrophy after accounting for all brain pathologies. In plasma, although fewer DAPs were identified (n=20), findings included established AD biomarkers. Only plasma VCAM1 and NEFL were associated with α-synuclein and vascular pathology. 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.