Action of anti-TNF-α drugs on the progression of Alzheimer's disease: A case report

Abstract

The aim of this study was to describe a clinical case of a patient with Alzheimer's disease (AD) in use of an anti-TNF-α agent for rheumatoid arthritis (RA). The patient reported is an 81-year-old Caucasian man and retired teacher, diagnosed with RA in 2008 and AD in 2011. Treatment with donepezil was started in 2011 and the use of etanercept introduced in 2012. He was previously treated with adalimumab in 2010 for 18 months. In 2013, the subject was engaged in a clinical trial to assess a complementary non-pharmacological approach for AD, presenting significant cognitive improvement during the follow-up period. We propose the hypothesis of a synergistic effect of anti-TNF-α medication used for the treatment of RA as the cause of the improvement in cognitive response observed. These findings could suggest a possible use of this drug class in the therapeutic management of AD.

Novel small molecules inhibit proteotoxicity and inflammation: Mechanistic and therapeutic implications for Alzheimer’s Disease, healthspan and lifespan- Aging as a consequence of glycolysis

“…Many lines of evidence strongly implicate microglial inflammation in the pathophysiology of AD [31, 33, 42, 45, 80-83]. Of particular interest, several reports have concluded that inhibitors of TNF-alpha would plausibly be protective in AD [29, 30, 32, 38–40, 84, 85]. However, these inhibitors are generally biologicals (antibodies and protein binders of TNF-alpha) so have limited capacity to cross the blood-brain barrier, suggesting that small molecule inhibitors of TNF-alpha secretion could be far more effective.…”

“…As described above, microglial gene expression and in particular microglial secretion of inflammatory cytokines such as TNF-a, are increasingly implicated in driving the pathophysiology of AD [34][35][36][37][38][39][40][41][42][43][44][45][80][81][82] and stroke [83][84][85][86]. A different cytokine, IL-6, has also been implicated in driving the neuropathology of both AD and stroke [87], suggesting that dementia in both conditions might be driven by a general increase in inflammatory cytokines.…”

“…More specifically, ApoE4 promotes the secretion of microglial TNFa which in turn reduces neuronal viability, compared to other ApoE alleles [81]. This observation is particularly pertinent since ApoE is the major genetic risk factor for AD, and many studies have demonstrated that increased TNF-a is a major contributor to the pathophysiology of both AD [34][35][36][37][38][39][40][41][42][43][44][45][80][81][82] and stroke [83][84][85][86]. A different cytokine, IL-6, has also been implicated in driving the neuropathology of both AD and stroke [87], suggesting that dementia in both conditions might be driven by a general increase in inflammatory cytokines.…”

“…This activity is plausibly at least somewhat independent of Abeta [27], although Abeta1-42 peptide does produce microglial release of TNFa and IL-6 [28]. Of particular significance, numerous studies have demonstrated that inhibiting TNFa ameliorates impairments in rodent models of AD [29] [30, 31] and even, according to case reports, in humans [32] [27, 29-50]. Particularly compelling, chemical ablation of microglia improves outcome in the 3XTg mouse model of AD [51], strongly implying that microglial hyperactivity (likely including increased secretion of TNF-α) plays a major role in driving the pathophysiology of AD.…”

The Link between Oxidative Stress, Mitochondrial Dysfunction and Neuroinflammation in the Pathophysiology of Alzheimer’s Disease: Therapeutic Implications and Future Perspectives

“…Another molecule is etanercept, a combination of the Fc portion of human IgG1 with the extracellular domain of TNFR2. Significant cognitive improvement was reported in an AD patient who also suffered of rheumatoid arthritis and was treated with etanercept [ 223 ]. Small, open-label studies with perispinal injections of etanercept also reported cognitive improvement in AD patients [ 224 ].…”