Association between the TNFα‐308 A/G polymorphism and the onset‐age of Alzheimer disease

Abstract

Local inflammatory processes associated with amyloid plaques would contribute to the progression of late-onset Alzheimer disease (LOAD). Tumor necrosis factors alpha (TNF(alpha)) and beta (LT(alpha)) are inflammatory cytokines involved in the local immune response occurring in the central nervous system of LOAD patients. Genetic variation at these genes could contribute to the risk of developing AD or influence the age at the onset of the disease. We genotyped 315 LOAD patients and 400 healthy controls for DNA-polymorphisms in the genes encoding TNF(alpha) (-308 G/A, -238G/A) and LT(alpha) (Asn26Thr). Carriers of -308A showed a mean age at onset 3 years younger than noncarriers of this allele (P = 0.019). Our data suggest an effect of the TNF(alpha)-308 polymorphism on the age at onset of late AD. This represents additional evidence of the importance of genetic variation at the proinflammatory components in the origin and progression of this common neurodegenerative disease.

Perispinal etanercept: a new therapeutic paradigm in neurology

“…• Genetic evidence correlating specific polymorphisms in TNF promoter genes causing increased TNF production with increased AD risk, in multiple studies from several academic centers, supported by a recent meta-ana lysis [73,74,[79][80][81][82];…”

“…Recent data from transgenic murine AD models suggest that elevation of proinflammatory cytokines, including TNF, IL-1b, IL-6 and S100B, may precede the appearance of amyloid-b plaques [72]. Although the relative importance and inter-relationship of inflammatory pathways in AD is still being elaborated, a decade of accumulating scientific evidence suggests that excess TNF constitutes another target (in addition to amyloid and tau) that is a central mediator of AD pathogenesis (TaBle 2) [3-5,57, 70,[73][74][75][76][77][78]. This previously reviewed evidence includes:…”

“…TNF promoter polymorphisms causing increased TNF production are associated with increased AD risk [73,74,[79][80][81][82] Epidemiologic Both acute and chronic systemic inflammation, associated with increases in serum TNF, are associated with an increase in cognitive decline in AD [70] Higher spontaneous production of TNF by peripheral blood mononuclear cells found to be a marker of future risk of AD in older individuals [75] Production of TNF in whole blood stimulated by LPS in middle age is a risk factor for AD [77] Clinical Increased rate of disease progression from MCI to AD associated with increased CSF TNF [4,6] Increased CSF TNF associated with both AD and vascular dementia [3] Increased CSF TNF associated with frontotemporal dementia…”

“…Decreased age of AD-onset associated with increased TNF [74,81] Improvements in cognition following initiation of weekly perispinal etanercept injections in AD ranging from mild to severe [61,62,84,85] Basic science…”

Sistemas neuromodulatórios: implicações fisiopatológicas

“…Estes genes parecem estar relacionados, basicamente, à formação de agregados, estresse oxidativo e resposta inflamatória. Por exemplo, podemos citar, para a formação de agregados, a proteína precursora de beta amilóide (APP) (Goate et al, 1991), preselinina (PS1 e PS2) (Combarros et al, 1999), apolipoproteína E (APOE) (Poirier et al, 1993), cistatina C (Palsdottir et al, 1989), ubiquitina 1 (Xue & Jia, 2006), alfa2-macroglobulina (Blacker et al, 1998); para estresse oxidativo, a óxido nítrico sintase (NOS2, NOS3) (Singleton et al, 2001); e para resposta inflamatória, IL-1 alfa (Nicoll et al, 2000), IL-1 beta, IL-6 (Ravaglia et al, 2006) e TNF alfa (Alvarez et al, 2002).…”