Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and inability to perform daily activities. Recent research has implicated tumor necrosis factor-alpha (TNF-α) in the pathogenesis of AD. Elevated levels of TNF-α have been detected in the blood of patients with AD, and TNF-α has been observed in amyloid beta (Aβ) plaques. Despite the promising results from preclinical studies, the efficacy of TNF-α blockade as a therapeutic strategy for AD remains controversial. However, it remains unclear whether and how TNF-α influences the amyloidogenic processes in AD. In this study, we analyzed plasma TNF-α and Aβ42 levels in patients with subjective cognitive impairment (SCI), mild cognitive impairment (MCI), AD, and in healthy volunteers (HLT). Correlation analysis was used to assess whether changes in plasma TNF-α levels correlated with cognitive decline, Aβ42 levels, age, and BMI. We found that TNF-α and Aβ42 plasma levels were higher in patients with AD than in those with HLT. High TNF-α levels were also observed in patients with SCI in whom TNF-α and Aβ42 levels were negatively correlated. Notably, in human microglial cultures incubated for 48h incubation period, TNF-α did not alter the amyloidogenic pathway while inducing neuroinflammatory processes. These findings suggest that elevated TNF-α levels may be more indicative of a clinical condition related to AD than a direct contributor. Nevertheless, high TNF-α levels in early stage patients could serve as a distinguishing characteristic for identifying patients at a high risk of developing AD and those who may benefit from personalized treatments.