Plasma neuroimmune pathway signatures are associated with clinical impairment and lower MRI-derived hippocampal volume across the Alzheimer's disease continuum.

METHODS: This retrospective observational study included 506 Alzheimer's Disease Neuroimaging Initiative participants: 53 cognitively normal individuals, 352 with mild cognitive impairment, and 101 with dementia. Plasma proteins from the quality-controlled Rules-Based Medicine multiplex dataset were standardized and grouped into five circulating protein scores: complement-acute-phase, endothelial-associated, extracellular matrix remodeling, myeloid, and interleukin. Outcomes included Mini-Mental State Examination, Clinical Dementia Rating Sum of Boxes, Functional Activities Questionnaire, normalized hippocampal volume, and normalized brain volume. Multivariable models were adjusted for age, sex, education, and APOE ε4 carrier status. RESULTS: In the primary cross-sectional pathway-level analyses, complement-acute-phase scores were higher in participants with dementia than in cognitively normal participants after FDR correction (β = 0.314, 95% CI 0.118 to 0.511; FDR q = 0.018). Higher complement-acute-phase scores were associated with lower MMSE (β = -0.859; FDR q < 0.001), higher CDR-SB (β = 0.622; FDR q < 0.001), and higher FAQ scores (β = 2.473; FDR q < 0.001). Higher endothelial-associated plasma protein scores were associated with lower normalized hippocampal volume (β = -1.47 × 10⁻4; FDR q = 0.028). CONCLUSIONS: Plasma neuroimmune signatures showed pathway-specific associations with Alzheimer's disease-related phenotypes, with complement-acute-phase score linked most consistently to clinical impairment and endothelial-associated circulating protein profile linked to hippocampal volume.