Bilirubin: a game-changer in alzheimer's therapy? Unveiling its neuroprotective and disease-modifying potential.

Alzheimer's disease (AD) is a neurological disease characterised by amyloid-beta (Aβ) plaques, neurofibrillary tangles (NFTS), oxidative stress, and neuroinflammation resulting in cognitive decline. Bilirubin is considered to be a by-product of heme metabolism and has emerged as a powerful endogenous antioxidant with significant neuroprotective activities. This article focuses on the multidirectional role of bilirubin in AD, underlining its capability to alleviate oxidative stress, reduce neuroinflammation, inhibit Aβ fibrillation and tau hyperphosphorylation, and maintain synaptic and mitochondrial function. The antioxidant activity of bilirubin, which involves the bilirubin-biliverdin redox cycle, scavenges ROS and promotes cellular defence mechanisms. In addition, bilirubin modulates inflammatory signalling pathways like NF-κB and TLR4 to downregulate pro-inflammatory cytokine release. It also induces Aβ clearance and prevents tau pathology by controlling kinase and phosphatase function, thus ensuring neuronal integrity. Despite its therapeutic promise, the role of bilirubin in AD is multifaceted, with reports from studies being conflicting regarding its levels in patients. While physiological levels have neuroprotective properties, higher levels are neurotoxic, and this emphasizes the requirement for accurate therapeutic dosing. The challenges of blood-brain barrier (BBB) permeability, heterogeneity in bilirubin metabolism, and the absence of large-scale clinical trials need to be overcome to apply preclinical observations to clinical applications. Future studies must aim at maximising bilirubin-based treatments, such as bilirubin analogues, HO-1 inducers, and nanocarrier systems, in addition to non-pharmacological methods such as dietary and lifestyle changes. Standardisation of bilirubin assessment and determining its potential as a diagnostic biomarker are also critical. Overall, bilirubin is a potential therapeutic target for AD, but additional research is necessary to optimize its potential while minimising risks.