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

INTRODUCTION: Immune signaling alterations have been implicated in Alzheimer's disease (AD) pathophysiology, but their heterogeneity across the disease continuum in real-world cohorts is poorly characterized, limiting the development of stratified immunomodulatory approaches. METHODS: In a diverse multicenter cohort (BioHermes) of 176 amyloid-positive individuals with AD/mild cognitive impairment (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 neurofilament light [NfL], phosphorylated tau 217 [p-tau217], and glial fibrillary acidic protein [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.