TNF- Levels Are Increased in Patients with Subjective Cognitive Impairment and Are Negatively Correlated with Amyloid-42

The role of tumor necrosis factor-alpha (TNF-alpha) in Alzheimer's disease (AD) has recently become a topic of debate. TNF-alpha levels increase in the blood of patients with AD, and amyloid beta (A beta) plaques contain TNF-alpha deposits. The therapeutic efficacy of blocking TNF-alpha in patients with AD remains controversial as it is mostly based on preclinical studies. Thus, whether and how TNF-alpha contributes to amyloidogenic processes in AD is still an open question to be addressed. We analyzed plasma TNF-alpha and A beta 42 levels in patients with subjective cognitive impairment (SCI), mild cognitive impairment (MCI), and AD, and in healthy volunteers (HLT). In addition, we performed correlation analysis to evaluate whether changes in plasma TNF-alpha levels correlate with cognitive decline, A beta 42 levels, age, and BMI, which are all factors considered to contribute to or predispose individuals to AD. We found that TNF-alpha and A beta 42 plasma levels were higher in patients with AD than in HLT individuals. High TNF-alpha levels were also observed in patients with SCI, in whom TNF-alpha and A beta 42 levels were negatively correlated. Notably, TNF-alpha did not affect the amyloidogenic pathway in human microglial cultures exposed to 48 h of incubation, although it did trigger neuroinflammatory processes. These results imply that high TNF-alpha levels are more likely to be a clinical condition linked to AD than are direct contributors. Nonetheless, elevated levels of TNF-alpha in early-stage patients, like those with SCI and MCI, may provide a distinguishing feature for identifying clinical profiles that are at risk of having a poorer outcome in AD and could benefit from tailored therapies.