Among various cytokines involved in the immune response, tumor necrosis factor (TNF) is considered to play a significant upstream role in dementia pathology on a molecular level. Its pleiotropic effects vary from physiological neuroprotective and repair activities to pathological neuronal loss occurring in neurodegenerative and autoimmune conditions which are dependent on TNF form and activated receptor [23]. TNF receptor type 1 (TNFR1) is commonly expressed and can be bound by both transmembrane and soluble TNF forms, while TNF receptor type 2 (TNFR2), expressed by myeloid and endothelial cells but also by CNS-residing glia and neurons, is mainly bound by transmembrane TNF [24]. Protective versus deleterious outcomes of receptor activation depend on various factors including TNF concentration, activation of other signaling pathways or cell susceptibility resulting from cell type and age-related priming [25,26]. TNF signaling activates intracellular pathways with transcription factors such as NFκB (nuclear factor kappa-light-chain-enhancer of activated B cells) leading to pro-inflammatory cytokine production and, in conditions of prolonged signaling, aggravation of inflammation [27,28].

Exposure to TNF in an in vitro AD model has been shown to result in aggregation of extracellular proteins which are considered characteristic traits of AD and LBD pathology [29]. Interestingly, exposure to TNF does not need to be sustained in order to maintain increased secretion and aggregation of amyloid-β or α-synuclein in such models. This mechanism may demonstrate profound effects of TNF signaling on pro-inflammatory activation and cytokine production of astrocytes and microglia, leading to prolonged neuroinflammation [30]. This phenomenon has been reflected in a cohort study by Lindbergh et al., in which TNF plasma concentration of participants were assessed annually. Increased systemic TNF resulted in reduction in grey matter volumes in further assessments in a curvilinear correlation, with initially-increased TNF correlating with following loss of volume [31]. Additionally, within-person increases in TNF correlated with lower scores obtained in neuropsychological evaluation with the use of Mini Mental State Examination.

Since TNF signaling exerts a triggering effect in the development of cognitive decline [29,31], the question arises, whether interventions focused on reduction in TNF concentrations or inhibition of its signaling pathway may play a role in dementia prevention or treatment. There are several methods of reducing an inflammatory state in the human organism, including dietary and pharmacological interventions.

Diet has been implicated in pathology of numerous neurodegenerative diseases, including dementia. A well-balanced diet provides all nutritional ingredients necessary for maintaining healthy and functional neurons [117]. On the other hand, it is believed that diet largely impacts inflammatory activation and immune response, which in turn influences regional inflammatory response in the brain. Various studies, including large cohorts, have associated inflammatory dietary patterns with faster cognitive decline and subsequent cognitive impairment [118,119,120]. The correlation between inflammatory diet and cognition is especially apparent in regard to several cognitive functions, such as episodic memory, semantic-based memory, executive functions and working memory [121].

The Western diet which comprises highly-processed food rich in fructose and saturated fat is known to increase TNF concentration in animal models [122]. Mice immunized against Klebsiella pneumoniae were shown to have lower levels of inflammasome-related inflammation, providing yet another link between gut microbiota and inflammation. This phenomenon was mediated by the presence of apolipoprotein E and was not observed in ApoE −/− animals [122]. Although individually tailored diets are not yet within reach and require further exploration, some conclusions regarding the influence of particular diets on neurodegenerative processes can be made based on existing studies [123]. For example, use of Dietary Inflammatory index (DII), which takes into account individual’s dietary composition and characteristics, allows us to indicate the general influence of one’s diet on systemic cytokine levels and inflammatory activation [124]. Higher scores of DII were shown to strongly correlate with worse cognitive performance [125]. It stands to reason, that the influence of environmental factors such as diet in preserving cognition cannot be underestimated. On the other hand, it seems that the inflammatory potential of the consumed food may be related not only to the specific products but also to the gut microbiota composition resulting from the daily diet. A summary of findings associated with specific diets can be found in Table 1 [126,127,128,129,130,131,132,133,134,135].

TNF antagonists offer yet another interesting approach to reducing inflammatory activation in humans. These agents are commonly used in autoimmune diseases, such as rheumatoid arthritis, psoriasis or inflammatory bowel diseases [147]. Their effects in controlling excessive immune response are mediated by binding TNF but the exact mechanisms and affinity to soluble and transmembrane TNF vary, hence their clinical use can also differ [26,148,149]. Moreover, some other mechanisms of action have been described, such as lymphotoxin-α blocking by etanercept. Additionally, infliximab has been proven to reduce expression of GM-CSF (granulocyte-macrophage colony stimulating factor) [150,151], while infliximab and adalimumab are able to induce production of immunosuppressive IL-10 by macrophages in vitro [152]. Psoriasis patients treated with etanercept had decreased expression of IL-1 and IL-8 genes which correlated with reduction in total pro-inflammatory immune response [153]. Importantly, although molecular weight and properties do not allow for free entry of TNF antagonists into the CNS, evidence indicates that these drugs may have protective influence against brain aging.

It seems that both BBB-nonpenetrating and modified, BBB-penetrating, etanercept reduce tauopathy, microgliosis and therefore, neuronal loss in a mouse model of AD. Additionally, they increase PSD95 protein levels indicating synaptic health. This phenomenon may be related to the peripheral effects of the drug and underlines the importance of tackling chronic inflammatory activation in order to maintain physiological neuronal function [154]. Similar observations had been made previously, in a study by Chang et al. [155]. Administration of BBB-penetrating TNF-inhibitor, cTfRMAb-TNFR, resulted in a significant decrease in neuroinflammatory markers, amyloid burden and BBB disruption in an AD mouse model. These results were comparable to those obtained with the use of etanercept in regard to amyloid burden and BBB integrity but not for neuroinflammation portrayed with ICAM-1 concentration. The cognitive performance of tested mice was highest in a group treated with cTfRMAb-TNFR highlighting the crucial role of neuroinflammation in cognitive decline [155]. Use of BBB-penetrating agents remains especially interesting in regard to FTD pathology, in which cytokine production seems to take place mainly in the brain [7].

An experiment conducted in an animal model of metabolic syndrome proved that intraperitoneal administration of infliximab improved lipid profiles in rats—i.e., decreased triglycerides and increased HDL. Additionally, the study group had lower adiponectin concentrations compared to the control, impacting low-grade inflammation. Noteworthy, not all metabolic aspects were normalized and cognitive tests were not included in the study protocol [156]. It may be hypothesized that an up-stream role of TNF in obesity-induced pathology, limits the potential protective effects of TNF inhibition in conditions of already present metabolic syndrome. On the other hand, intracerebroventricular administration of infliximab in a transgenic mouse model of AD resulted in a significant decrease in brain TNF levels, reduction in amyloid burden and tau pathology [157]. Another study conducted in a rat model of VaD, revealed a therapeutic effect of adalimumab administration in treating cognitive deficits resulting from cerebral hypoperfusion. This finding was associated with a reduction in neuronal loss and of microglial activation mediated by NFκB suppression [158].

A systematic literature review of TNF antagonist effects on AD revealed beneficial influence of TNF inhibition on cognition [27]. Most commonly studied agents, etanercept, infliximab and adalimumab, used in rheumatoid arthritis coincided with up to 60–70% reduction in AD incidence in large epidemiological analyzes of rheumatoid arthritis patients, whereas other methods of treatment did not affect AD incidence [159]. Similar results were obtained in patients with psoriasis who were treated with etanercept, infliximab or adalimumab [160]. Rheumatoid arthritis and psoriasis, among other autoimmune diseases, are known risk factors of AD due to the occurrence of persistent inflammatory activation which may constitute a confounding factor for generalized conclusions [161,162,163]. However, these observations warrant further research in other populations in order to establish a protective role of TNF inhibition on development and progression of various types of dementia. Updates on current clinical trials can be found in Table 2.