Inflammation profiles in Alzheimer’s disease relate to cognition and neurodegeneration

Structured Abstract Introduction Immune signalling alterations have been implicated in Alzheimer’s disease (AD) pathophysiology, but their heterogeneity across the disease continuum in real-world cohorts is poorly characterised, limiting the development of stratified immunomodulatory approaches. Methods In a diverse multicentre cohort (BioHermes) of 176 amyloid-positive individuals with AD/MCI and 173 age and sex-matched controls, principal component analysis was performed on Luminex-measured plasma cytokines to derive inflammatory signatures, and their direct/indirect associations with cognition and neurodegeneration. Results Two components were identified. Proinflammatory Component 2 was elevated in AD/MCI and in Black/African American participants and strongly associated with poorer cognition (independently of NfL, ptau217 and GFAP). Inflammatory Component 1 showed an indirect association with cognition, mediated by neurodegeneration (plasma NfL). Discussion Plasma inflammation profiles were associated with poorer cognition via direct and neurodegeneration-mediated pathways, supporting their potential use as stratification markers in AD therapeutics.