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.
Birditt et al. (Sat,) studied this question.
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