Cerebrospinal Fluid CCL25 as a Biomarker for Alzheimer's Disease: Associations with Pathology, Neurodegeneration, and Cognitive Decline

Neuroinflammation plays a crucial role in Alzheimer's disease (AD) pathogenesis. We investigated the relationship between cerebrospinal fluid (CSF) C-C chemokine ligand 25 (CCL25), an inflammatory regulator, and AD pathology and progression. We analyzed data on CSF CCL25, AD biomarkers (CSF β-amyloid [Aβ]42, phosphorylated tau [pTau]181, amyloid positron emission tomography [PET]), postmortem neuropathology, magnetic resonance imaging-based neurodegeneration, and cognitive function from 703 participants in the Alzheimer's Disease Neuroimaging Initiative cohort. We found that elevated CSF CCL25 levels were associated with cognitive impairment, abnormal Aβ and tau pathology, greater brain atrophy, and worse cognitive performance (all P < 0.05). Notably, CSF CCL25 exhibited nonlinear relationships with Aβ and tau pathology, reaching a plateau as AD pathology increased. CSF CCL25 showed acceptable diagnostic accuracy in distinguishing amyloid-positive/negative (A ±) and tau-positive/negative (T ±) participants (area under the curve [AUC] = 0.71-0.77) and autopsy-confirmed AD cases (AUC = 0.77), with optimal performance in differentiating A + T + from A-T- participants (AUC = 0.82-0.85 with age and sex adjustment). Longitudinally, higher baseline CSF CCL25 predicted accelerated amyloid accumulation, hippocampal atrophy, and cognitive decline. Mediation analyses revealed that CCL25 partially mediated associations between Aβ pathology and tau pathology (mediating effect: 54.5%), neurodegeneration (18.2%), and cognitive decline (7.4%). Among 37 CSF CCL and CXCL chemokines examined, 28 were associated with at least one AD-related outcome, with CCL25 demonstrating the strongest associations overall. These findings suggest that CSF CCL25 is involved in early AD pathological progression and may serve as an inflammatory biomarker for diagnosis and monitoring of disease progression in AD.