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

Abstract

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-α (TNF-α) have potential to improve cognitive performance.

Objective: In this review, we summarize the evidence regarding the potential for TNF-α 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-α inhibitor) in the context of AD pathology. The keywords in the search included: AD, dementia, memory, cognition, TNF-α, 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-α, showed enhanced cognitive performance and decreased brain levels of amyloid-β plaque and tau tangles.

Conclusion: TNF-α 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.

Keywords: Alzheimer’s disease; TNF-α; dementia; inflammation; mild cognitive impairment; tissue necrosis factor-alpha.

Fig. 1

Adjusted odds ratio (AOR) for a diagnosis code of dementia associated with a diagnosis for an inflammatory disease compared to the non-inflammatory group disease [15]. AS, ankylosing spondylitis; Crohn’s, Crohn’s disease; IBD, inflammatory bowel disease; PA, psoriatic arthritis; RA, rheumatoid arthritis; UC, ulcerative colitis.

Fig. 2

Etanercept was associated with OR of 0.30, 0.34 and 0.36 in the 3 large epidemiological studies focusing its effect on the incidence of AD [15–17].

Fig. 3

For the primary verbal memory outcome measure (Buschke SRT, Consistent Long-Term Recall), the Theracurmin group showed significant improvement from baseline after 18 months of treatment (p = 0.002); the placebo group did not show significant change (p = 0.8), and between group differences were significant (p = 0.05) [22].