Peripheral hematological inflammatory signatures in the amyloid-defined Alzheimer's disease continuum: associations with disease stage, cognitive function, and astroglial activation

Peripheral immune-inflammatory dysregulation has been implicated in Alzheimer's disease (AD) and cognitive decline. However, whether routinely available hematological inflammatory indices are associated with biological and clinical stages across the AD continuum and provide incremental information beyond established risk factors remains unclear. We aimed to investigate the associations of neutrophil-to-lymphocyte ratio (NLR), systemic immune-inflammation index (SII), and hemoglobin-to-red blood cell distribution width ratio (HRR) with AD continuum stage, cognition, and AD biomarkers.

This cross-sectional study included 267 participants who underwent comprehensive cognitive assessment, peripheral blood testing, and amyloid-β positron emission tomography (Aβ-PET) imaging. Participants were categorized into three groups according to cognitive status and available amyloid biomarker profiles: cognitively unimpaired (CU-Aβ^-), amyloid-positive mild cognitive impairment (MCI-Aβ⁺), and amyloid-positive Alzheimer's disease dementia (AD-Aβ⁺). Hematological inflammatory indices, including neutrophil-to-lymphocyte ratio (NLR), systemic immune-inflammation index (SII), and hemoglobin-to-red cell distribution width ratio (HRR), were calculated from routine blood parameters. A composite inflammatory index (Inflam_PC1) was derived using principal component analysis. Ordinal logistic regression models were used to examine the associations between inflammatory indices and AD continuum stage after adjustment for demographic, vascular, metabolic, and genetic factors.

Inflammatory profiles differed across the AD continuum, with increased NLR and SII and decreased HRR levels in more advanced stages. Higher NLR (OR = 1.54, 95% CI: 1.25-1.91, P < 0.001) and SII (OR = 1.29 per 100-unit increase, 95% CI: 1.15-1.45, P < 0.001) were independently associated with advanced AD continuum stages, whereas HRR was not. The composite inflammatory signature showed the strongest association (OR = 1.63 per SD increase, 95% CI: 1.30-2.03, P < 0.001) and provided incremental statistical improvement beyond conventional risk factors. Higher inflammatory burden was associated with poorer cognitive and functional performance and correlated with plasma glial fibrillary acidic protein (GFAP) level.

Peripheral hematological inflammatory signatures were associated with Alzheimer's disease continuum. Higher NLR and SII levels and a composite inflammatory signature were independently associated with more advanced disease stages, cognitive impairment, and functional decline. The association between inflammatory signatures and plasma GFAP, but not amyloid or tau biomarkers, suggests a relationship between peripheral inflammatory profiles and glial-related biomarker alterations that requires further longitudinal investigation.