Drug repurposing in Alzheimer's disease: Emerging therapeutic strategies and promising candidates.

Alzheimer's disease is a progressive neurodegenerative disorder, and the most common cause of dementia, which causes 60-70 % of cases worldwide, and its prevalence is increasing by more than 55 million people globally, with an expected increase of 139 million cases by 2050. AD is characterized by Amyloid-β plaque deposition, tau hyperphosphorylation, synaptic dysfunction, neuroinflammation, and oxidative stress, which makes the pathophysiology multifactorial and complex in terms of the development of therapeutic treatment. Existing approved therapies, such as cholinesterase enzyme inhibitors and NMDA receptors antagonists, are merely symptomatic, whereas novel anti-amyloid monoclonal antibodies approved recently have low clinical efficacy with safety and cost issues. The low success rates of clinical trials highlight the necessity of alternative approaches. Drug repurposing of drugs has proved to be a promising solution, which uses drugs with know safety profiles to speed up the discovery of therapeutic solutions. These repurposed agents are used targeting diverse pathologic pathways, including amyloid aggregation, tau pathology, neuroinflammation, and synaptic dysfunction, with antidiabetic agents (metformin, GLP-1 receptor agonists) and anti-hypertensives (candesartan), anti-inflammatory ones (NSAIDs, pioglitazone), and neuroprotective ones (minocycline, sildenafil). Notably, mitochondrial dysfunction is becoming a significant early and essential cause of AD development, and mitochondria-targeted therapeutics like SS-31, Mdivi-1, MitoQ, DDQ, and SkQ1 are currently considered promising disease-modifying options. The development of artificial intelligence, multi-omics, and precision medicine also improves drug repurposing plans. Overall possibility to integrate multi-target repurposed therapies with novel technologies is a promising prospect to overcome the available shortcomings and improve clinical outcomes in AD.