Elevated oxidative stress and inflammatory levels are associated with plasma AD biomarkers in middle‐age

Abstract Background Neuroinflammation and oxidative stress (OS) are implicated in the pathophysiology of Alzheimer’s disease (AD). However, the extent to which inflammation is attributable to disease progression in the central nervous system in the pre‐ and clinical stages of dementia or emerges in the periphery and is a long‐term risk factor for the development of the pathological hallmarks of dementia is an unresolved question. Method Inflammatory (TNFa, TNF‐R1, TNF‐R2, IL1b, IL4, IL6, IL8, IL10), OS (NO, NEO, TAC), OS‐related DNA damage markers, and total tau, amyloid β1‐38 (Aβ38), amyloid β1‐40 (Aβ40), amyloid β1‐42 (Aβ42) levels were measured in plasma using highly sensitive immunoassays. Inflammatory and OS states were identified through principal component analysis. Associations between inflammatory/OS states and AD biomarkers were investigated in middle‐age (52‐56 years, n = 335, 52% female) and older‐age (72‐76 years, n = 351, 46% female) participants without dementia through linear regression analyses while controlling for relevant covariates. Result Four similar principal components reflecting different inflammatory states (PC1: unspecific increased inflammation; PC2: inflammation related to anti‐oxidant activity; PC3: increased OS activity with DNA damage; PC4: decreased OS and increased anti‐oxidant activity with DNA damage) were detected in the two age samples. In middle‐age, a component reflecting variation in OS (PC4) was most strongly associated with tau and to a lesser extent amyloid‐b levels. In older‐age, a similar component to that observed in middle‐age was only associated with tau, while another (PC1) component reflecting heightened inflammation independent of OS, was associated with all AD biomarkers. Conclusion In middle and older age community‐living individuals without dementia inflammation and OS states are already associated with plasma AD biomarkers. The fact that more consistent and robust associations with AD biomarkers involved OS, or OS‐related DNA damage suggests that oxidative stress may be a particularly strong contributor to early AD pathophysiology and requires more systematic investigation.