CSF neuroinflammatory biomarkers are associated with amyloid-β42/40, tau pathology, and cognitive impairment across the Alzheimer's disease spectrum.

Neuroinflammation is increasingly implicated in Alzheimer's disease (AD), but how distinct CSF inflammatory biomarkers relate to AD pathology remains unclear. This study examined whether CSF biomarkers reflecting astrocytic activation (GFAP), microglial activation (TREM2), systemic inflammation (CRP), TNF-related signaling (TNFR2), and inflammatory proteolysis (ADAM17) were associated with CSF Aβ42/40, CSF p-tau181, and cognitive performance across the AD clinical spectrum. Data were obtained from 933 ADNI participants, including 312 cognitively normal (CN) individuals, 471 participants with mild cognitive impairment (MCI), and 150 participants with AD dementia. Analyses were corrected for multiple comparisons using the FDR method. The results showed that CSF neuroinflammatory biomarkers differed across diagnostic groups, with GFAP showing the strongest progressive increase from CN to MCI and AD dementia. Higher GFAP, TREM2, TNFR2, and ADAM17 levels were associated with lower CSF Aβ42/40, higher CSF p-tau181, and poorer cognitive performance, particularly in MCI, whereas CRP showed weaker and less consistent associations. In joint models including all inflammatory and core AD biomarkers, both higher GFAP and higher TNFR2 remained independently associated with worse cognitive function. Mediation analyses showed that lower CSF Aβ42/40 partly mediated the associations of higher GFAP and TREM2 with worse cognitive performance. Higher CSF p-tau181 mediated broader associations linking higher GFAP, TREM2, TNFR2, and ADAM17 levels to worse cognitive performance, with the strongest effects observed in MCI. Overall, higher CSF neuroinflammatory biomarkers may be linked to AD pathology and cognitive impairment; however, given the observational design, causality cannot be established, and longitudinal mechanistic studies are needed to validate these findings.