Plasma inflammation profiles directly link to poorer cognition and indirectly to neurodegeneration in Alzheimer's disease.

Current therapeutic interventions for Alzheimer's disease (AD) primarily address symptoms, with limited impact on underlying neurodegenerative processes. Emerging evidence points to immune signaling alterations and inflammation as key drivers of AD pathophysiology. However, the heterogeneity of these inflammatory responses across the disease continuum in real-world cohorts remains poorly characterized, hindering the development of stratified immunomodulatory approaches. Understanding specific inflammatory signatures could unlock personalized treatment strategies, moving beyond a one-size-fits-all approach to target the early metabolic and inflammatory vulnerabilities that drive AD progression.

Researchers conducted a multicenter cohort study (BioHermes) involving 176 amyloid-positive individuals diagnosed with Alzheimer's disease (AD) or mild cognitive impairment (MCI), alongside 173 age and sex-matched controls. Plasma cytokine levels were measured using Luminex assays. Principal component analysis was then applied to these cytokine data to identify distinct inflammatory signatures. The study's primary objective was to assess the direct and indirect associations of these derived inflammatory profiles with cognitive function and established neurodegeneration biomarkers, including plasma neurofilament light (NfL), phosphorylated tau 217 (p-tau217), and glial fibrillary acidic protein (GFAP).

The principal component analysis identified two distinct inflammatory components. Proinflammatory Component 2 was significantly elevated in individuals with AD/MCI compared to controls, and also notably higher in Black/African American participants. This component demonstrated a strong, independent association with poorer cognitive performance, meaning its impact on cognition was not explained by the levels of NfL, p-tau217, or GFAP.