Metabolic context modulates neuroinflammation: Type 2 diabetes mellitus moderates the association of interleukin-8 with amyloid pathology and cognitive decline in mild cognitive impairment

BackgroundInterleukin-8 (IL-8) exhibits dual roles in Alzheimer's disease (AD), yet how the metabolic milieu of type 2 diabetes mellitus (T2DM) influences its impact in mild cognitive impairment (MCI) remains unclear.ObjectiveThis study aimed to investigate how T2DM status moderates the longitudinal association between baseline plasma IL-8 levels and AD-related outcomes, including cognitive decline, amyloid-β (Aβ) deposition, and neurodegeneration.MethodsData from 373 MCI participants (Alzheimer's Disease Neuroimaging Initiative cohort) were analyzed. Moderation analyses examined the IL-8 × T2DM interaction on cognitive trajectories, amyloid-β (Aβ) accumulation, and regional atrophy, adjusting for key covariates.ResultsIn the T2DM group, higher baseline IL-8 was significantly associated with a slower longitudinal increase in Clinical Dementia Rating-Sum of Boxes (p = 0.005), indicating preserved clinical function. Furthermore, elevated IL-8 in the T2DM cohort correlated with lower hippocampal Aβ burden (p = 0.041) and attenuated atrophy rates in the parahippocampal cortex (p = 0.044). In contrast, no significant associations between IL-8 and any AD biomarkers or cognitive trajectories were observed in the non-T2DM group.ConclusionsThis research demonstrates that the role of IL-8 in MCI is "context-dependent," contingent upon the patient's metabolic state. The author suggests that under chronic metabolic stress, IL-8 may reflect an adaptive immune response that mitigates amyloid pathology and slows neurodegeneration. These results emphasize the necessity of integrating metabolic profiles into the interpretation of neuroinflammatory biomarkers to facilitate personalized therapeutic strategies for AD.