Alzheimer’s disease and neuroinflammation: will new drugs in clinical trials pave the way to a multi-target therapy?

Abstract

Despite extensive research, no disease-modifying therapeutic option, able to prevent, cure or halt the progression of Alzheimer’s disease [AD], is currently available. AD, a devastating neurodegenerative pathology leading to dementia and death, is characterized by two pathological hallmarks, the extracellular deposits of amyloid beta (Aβ) and the intraneuronal deposits of neurofibrillary tangles (NFTs) consisting of altered hyperphosphorylated tau protein. Both have been widely studied and pharmacologically targeted for many years, without significant therapeutic results. In 2022, positive data on two monoclonal antibodies targeting Aβ, donanemab and lecanemab, followed by the 2023 FDA accelerated approval of lecanemab and the publication of the final results of the phase III Clarity AD study, have strengthened the hypothesis of a causal role of Aβ in the pathogenesis of AD. However, the magnitude of the clinical effect elicited by the two drugs is limited, suggesting that additional pathological mechanisms may contribute to the disease. Cumulative studies have shown inflammation as one of the main contributors to the pathogenesis of AD, leading to the recognition of a specific role of neuroinflammation synergic with the Aβ and NFTs cascades. The present review provides an overview of the investigational drugs targeting neuroinflammation that are currently in clinical trials. Moreover, their mechanisms of action, their positioning in the pathological cascade of events that occur in the brain throughout AD disease and their potential benefit/limitation in the therapeutic strategy in AD are discussed and highlighted as well. In addition, the latest patent requests for inflammation-targeting therapeutics to be developed in AD will also be discussed.

Transcriptomic signatures of Aβ- and tau-induced neuronal dysfunction reveal inflammatory processes at the core of Alzheimer’s disease pathophysiology

“…Likewise, anti-inflammatory multiple sclerosis medication has shown promise in AD mouse models for reversing all Aβ, tau and microglia pathologies, and synaptic and cognitive dysfunction (Dionisio-Santos et al, 2021; Leßmann et al, 2023). It is worth noticing that, in clinical trials, drugs with anti-inflammatories properties have not slowed cognitive and/or functional decline (Howard et al, 2020; Melchiorri et al, 2023). One possible explanation is that the thus-far tested agents interfere with microglia’s supportive function instead of modulating its detrimental chronic activation effects (Howard et al, 2020; Melchiorri et al, 2023; Rivers-Auty et al, 2020; Shen et al, 2018).…”

“…It is worth noticing that, in clinical trials, drugs with anti-inflammatories properties have not slowed cognitive and/or functional decline (Howard et al, 2020; Melchiorri et al, 2023). One possible explanation is that the thus-far tested agents interfere with microglia’s supportive function instead of modulating its detrimental chronic activation effects (Howard et al, 2020; Melchiorri et al, 2023; Rivers-Auty et al, 2020; Shen et al, 2018). At least 18 investigational drugs targeting neuroinflammation currently undergo clinical assessment, including phase III trials (Melchiorri et al, 2023; Reading et al, 2021).…”

A small-molecule TLR4 antagonist reduced neuroinflammation in female E4FAD mice

“…Epidemiological and in vivo studies indicated that non-steroidal anti-inflammatory drugs (NSAIDs) lower AD risk and pathology (reviewed in [ 111 , 112 ]). However, NSAIDs have not been found efficacious in some AD clinical trials [ 20 ]. In addition, a recent re-analysis of the NSAID epidemiological data in an ADNI dataset revealed that although some NSAIDs are associated with decreased AD prevalence, they did not affect cognitive decline in AD patients [ 21 ].…”

“…Neuroinflammation is complex and involves multiple cell-types, receptors, signaling pathways, cytokines, and chemokines. One approach to identify the contribution of neuroinflammatory pathways to AD progression is to evaluate activity of FDA approved drugs with known anti-inflammatory activities such as NSAIDs [ 20 ]. Although some studies supported that NSAIDs may be efficacious as an AD therapeutic, including in APOE4 carriers, others have shown no beneficial effects [ 21 – 23 ].…”

Immunological dimensions of neuroinflammation and microglial activation: exploring innovative immunomodulatory approaches to mitigate neuroinflammatory progression

“…Meanwhile, p38α MAPK heightened pathogenic p-tau in neurons, contributing to neuronal damage. Currently, two experimental medications are undergoing clinical trials that inhibit p38 MAPKs: Neflamapimod (NCT03402659) and MW150 (NCT05194163) ( 353 ). Yet, information on Neflamapimod is already publicly available.…”