Therapeutic Potential of TNF-α Inhibition for Alzheimer's Disease Prevention

Background: Alzheimer's disease (AD) is increasingly prevalent and over 99% of drugs developed for AD have failed in clinical trials. A growing body of literature suggests that potent inhibitors of tumor necrosis factor-alpha (TNF-alpha) have potential to improve cognitive performance. Objective: In this review, we summarize the evidence regarding the potential for TNF-alpha inhibition to prevent AD and improve cognitive function in people at risk for dementia. Methods: We conducted a literature review in PubMed, screening all articles published before July 7, 2019 related to TNF blocking agents and curcumin (another TNF-alpha inhibitor) in the context of AD pathology. The keywords in the search included: AD, dementia, memory, cognition, TNF-alpha, TNF inhibitors, etanercept, infliximab, adalimumab, golimumab, and curcumin. Results: Three large epidemiology studies reported etanercept treated patients had 60 to 70% lower odds ratio (OR) of developing AD. Two small-randomized control trials (RCTs) demonstrated an improvement in cognitive performance for AD patients treated with etanercept. Studies using animal models of dementia also reported similar findings with TNF blocking agents (etanercept, infliximab, adalimumab, Theracurmin), which appeared to improve cognition. A small human RCT using Theracurmin, a well-absorbed form of curcumin that lowers TNF-alpha, showed enhanced cognitive performance and decreased brain levels of amyloid-beta plaque and tau tangles. Conclusion: TNF-alpha targeted therapy is a biologically plausible approach to the preservation of cognition, and warrants larger prospective RCTs to further investigate potential benefits in populations at risk of developing AD.