Novel inflammatory markers predict early tau pathology and synaptic damage in an elderly asymptomatic population at risk of Alzheimer's disease

Neuroinflammation is recognized as a central driver of Alzheimer’s disease (AD) pathology, yet the specific immune mediators that shape disease progression remain poorly defined. To identify optimal biomarkers for early intervention, we measured a broad panel of inflammation-associated proteins using OLINK proximity extension assays in cerebrospinal fluid (CSF) from the longitudinal PREVENT-AD cohort of cognitively unimpaired individuals at high risk of AD, and from participants across the clinical spectrum of AD in the ADNI cohort. Proteins were tested against amyloid/tau (AT) staging, synaptic markers, MRI-derived brain volumes, and clinical progression. Distinct immune proteins segregated with amyloid, tau, or combined pathology. CNTN5 and CD200 were reduced in amyloid-only stages, whereas EPHB6 and NTRK2 tracked selectively with tau, and ADAM23 and SIRT2 were altered with combined AT pathology. Several of these proteins correlated with CSF synaptic markers (GAP43, SNAP25, SYT1, neurogranin), indicating potential roles in early synaptic vulnerability. Replication in ADNI confirmed robust associations of ADAM23, CNTN5, EPHB6, and NTRK2 with CSF P(181)-tau levels across diagnostic groups. In survival analyzes, higher baseline levels of these immune proteins were associated with a reduced probability of progression from normal cognition or mild cognitive impairment to AD dementia, and they attenuated the deleterious associated of elevated P-tau with outcome While chronic inflammation has classically been viewed as deleterious in AD, our results suggest that certain immune mediators are associated with slower progression and may reflect compensatory, stage-associated responses, particularly in relation to tau-driven synaptic neuropathology. These findings argue for a more nuanced understanding of neuroinflammation in AD and highlight specific proteins as potential biomarkers and therapeutic targets.