Cerebrospinal fluid protein elevations in Alzheimer's disease are dissociated from immune cell composition

Elevated cerebrospinal fluid (CSF) inflammatory proteins have been reported in Alzheimer's disease (AD), yet whether they reflect peripheral immune cell infiltration or central nervous system (CNS)-intrinsic pathological processes remains unclear. We tested whether AD exhibits a distinct CSF protein signature and how it relates to CSF immune cell composition.

We conducted a cross-sectional study of 64 participants: 22 with biomarker-confirmed AD (bioAD), 22 non-AD biomarker-negative cognitive controls (NAD-CC), and 20 other neurological disease controls (OND). CSF proteins were quantified using the Olink Target 96 Inflammation panel, and immune cell populations were characterized by multiparameter spectral flow cytometry. Cell-protein associations were assessed using hierarchical generalized linear models adjusted for age and sex.

BioAD showed widespread inflammatory and trophic protein elevation versus NAD-CC, with 21 proteins significantly increased (false discovery rate [FDR] q < 0.05), whereas NAD-CC was largely indistinguishable from OND. MMP-10 showed the largest effect (geometric mean ratio [GMR] = 2.10, 95% confidence interval [CI]: 1.53-2.88, p < 0.001). CSF immune cell populations did not differ significantly between groups; only discrete T-cell alterations were detected: reduced regulatory T cells in bioAD relative to NAD-CC (odds ratio [OR] = 0.69, 95% CI: 0.54-0.88, p = 0.023), but not relative to OND and minor memory subset shifts. CD8+ effector memory T cells and TNFSF14 showed the only detected AD-specific association: in bioAD, a 10-fold increase in CD8+ EM2 cells corresponded to 70% higher TNFSF14 (GMR = 1.70, 95% CI: 1.39-2.09, p < 0.0001).

In this feasibility-sized, cross-sectional cohort, CSF inflammatory proteins in AD appeared dissociated from immune-cell composition, potentially reflecting CNS-intrinsic processes and/or altered CSF barrier dynamics. The identified signature, including MMP-10, is hypothesis-generating and may complement conventional biomarkers for diagnosis and treatment monitoring, pending longitudinal validation.