Cerebrospinal Fluid Over Plasma Links Analytes to Cognitive Decline in Older Adults at Risk for Alzheimer's Disease

ABSTRACT Objective To identify inflammatory analytes in cerebrospinal fluid (CSF) and plasma associated with cognitive decline in cognitively normal (CN) older adults at risk for Alzheimer's disease (AD). Methods In a longitudinal study of 118 CN older adults (65–80 years, 54% APOE ε4, 26% preclinical AD), 1331 CSF and 1501 plasma analytes were quantified at baseline and 2‐year follow‐up using SomaLogic, with key inflammatory findings validated on the Luminex platform. Linear models (Limma), adjusted for age, sex, APOEε4 , and amyloid‐positive status, identified pathology‐associated analytes. Co‐expression network and multivariable modeling defined hub analytes and enriched pathways. To assess robustness, a targeted panel of 94 inflammation‐related analytes was analyzed using best subsets regression to derive parsimonious models based on adjusted R 2 improvement (≥ 0.01) and ≥ 5 observations per predictor. Subgroup analyses by amyloid and APOE ε4 status were performed, and a two‐stage elastic‐net approach additionally validated analyte selection. Results CSF proteomics revealed stronger APOEε4 and amyloid‐associated analyte signatures than plasma. Forty‐four CSF analytes were co‐regulated by APOEε4 and amyloid‐positive status, forming central network hubs (e.g., EFNB2, NPTN, UNC5D) enriched in axon guidance, synaptic signaling, and extracellular matrix pathways. In contrast, inflammatory analytes including eotaxin‐1 and IL‐17 pathway‐related molecules were associated with longitudinal cognitive decline, with stronger effects observed in females. Eotaxin‐1 demonstrated the most consistent predictive performance across analytic methods, subsets, and assay platforms, whereas network hub analytes were not predictive of cognitive outcomes. Interpretation CSF reflects strong APOEε4 /amyloid related proteomic network alterations linked to cognitive decline, while plasma provides weaker but complementary signals. CSF inflammatory signaling, particularly eotaxin‐1, may serve as a correlate of longitudinal cognitive decline in cognitively normal older adults at risk for AD.