Activation of inflammatory processes has been observed within the brain as well as periphery of subjects with Alzheimer's disease (AD). Among several putative neuroinflammatory mechanisms, the tumor necrosis factor-alpha (TNF-alpha) signaling system plays a central role. TNF-alpha converting enzyme (TACE) does not only cleave pro-TNF-alpha but also TNF receptors, however, whether the TACE activity and soluble TNF receptors (sTNFRs) were changed in the plasma were not clear. The aim of this study was to determine whether the levels of TACE activity and sTNFRs are sufficiently altered in the plasma of AD patients to be helpful in AD diagnosis. We examined TACE levels in the plasma of 153 patients with AD, 98 patients with amnestic mild cognitive impairment (aMCI), 53 patients with vascular dementia (VaD), and 120 age-matched healthy control subjects, and found TACE activity and sTNFRs were significantly higher in patients with AD and aMCI compared with control subjects (TACE: P < 0.001, P < 0.01; sTNFR1: P < 0.001, P < 0.001; sTNFR2: P < 0.001, P < 0.01, respectively). The TACE activity and sTNFRs levels in VaD patients were significantly higher than the levels observed in AD patients (TACE activity: P < 0.001, sTNFR1: P < 0.01, sTNFR2: P < 0.01). In the plasma of AD patients, the levels of both TACE activity and sTNFRs positively correlated with the levels of A beta 40 and negatively correlated with the ratio of A beta 42/A beta 40. AD patients with at least one copy of the ApoE epsilon 4 allele showed higher TACE activity and sTNFR plasma levels compared with patients without the ApoE epsilon 4 allele. We then combined the data on plasma TACE activity, sTNFRs, and A beta with the presence of the APOE epsilon 4 allele and found that this biomarker panel exhibited a high sensitivity and specificity for discriminating AD patients from non-demented control subjects and VaD patients. (C) 2013 Elsevier Ireland Ltd. All rights reserved.