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Background: The activation of inflammatory cascades reactions has been consistently demonstrated in the pathophysiology of Alzheimer's disease (AD). Among several neuroinflammatory mechanisms, the tumor necrosis factor (TNF) signaling system has a central role in this process. The abnormal production of inflammatory factors may accompany the progression from mild cognitive impairment (MCI) to dementia. We aimed to examine serum levels of soluble TNF receptor (sTNFR1) in patients with MCI and AD as compared to cognitively unimpaired elderly subjects. We further aimed to investigate whether abnormal levels of these cytokines predict the progression from MCI to AD upon follow up. Materials and Methods: We utilized cross-sectional determination of serum levels of sTNFR1 (ELISA method) in a test group comprising 150 older adults (30 AD, 60 MCI, and 60 healthy controls), and longitudinal reassessment of clinical status after12 months. Results: At baseline, there were statistically significant differences in serum sTNFR1 between patients with MCI and AD and controls (p< 0.05). Also, patients with MCI who had more disorder in diagnostic functions and progressed to AD after one year, had significantly higher serum sTNFR1 levels as opposed to patients who retained the diagnosis of MCI upon follow up (p=0.03). Conclusion: The results showed that abnormal activation of TNF signaling system, represented by increased expression of sTNFR1, is associated with a higher risk of progression from MCI to AD. [ABSTRACT FROM AUTHOR]