Stage-dependent dynamics of neuroinflammation across the Alzheimer's continuum

Neuroinflammation is a core feature of Alzheimer's Disease (AD), but glial responses may evolve with disease progression. YKL-40 and GFAP reflect distinct astrocytic processes and may show differential relationships with pathology and cognition across the AD continuum. A total of 420 older adults underwent blood-based biomarker profiling (YKL-40, GFAP, pTau217, Aβ42/40, NfL) and neuropsychological assessment. Composite scores were derived for global cognition, memory, executive function, and processing speed. Linear regression interaction models investigated whether associations of glia markers with AD pathology or cognition differed with advancing disease, defined by plasma pTau217 status (negative < 0.4; positive > 0.6349 pg/mL) and clinical diagnosis (healthy controls [HC], subjective cognitive decline [SCD], mild cognitive impairment [MCI], AD). We observed stage-dependent relationships between YKL-40 and AD pathology. Higher YKL-40 was associated with greater pathology in cognitively unimpaired individuals (HC/SCD), but these associations progressively weakened in MCI and further in AD (pTau217: β_interaction = -0.230, p = 0.020; Aβ42/40: β_interaction = 0.003, p = 0.044). Similarly, the relationship between YKL-40 and pTau217 was dependent on AD likelihood (β_interaction = -0.218, p < 0.001); YKL-40 positively correlated with pTau217 in pTau-negative individuals (r = 0.208, p < 0.001), but negatively in pTau-positive individuals (r = -0.251, p = 0.025). In contrast, GFAP showed stable, monotonic positive relationships with all biomarkers across disease stages, with strengthening associations with poorer cognition, particularly memory and processing speed, at later stages. The findings suggest that astrocytic markers GFAP and YKL-40 exhibit distinct, stage-dependent relationships with AD pathology and cognition, underscoring key implications for biomarker interpretation and disease staging.