Multi-Target-Directed Ligands (MTDLs) as Potential Therapeutic Candidates Targeting Multiple Pathogenic Factor of...

Alzheimer's disease (AD) is the most common cause of dementia and a chronic neurodegenerative disorder in older adults. AD is not driven by a single factor but by the interaction of multiple pathological processes, including amyloid-β (Aβ) accumulation, tau hyperphosphorylation, and chronic neuroinflammation. Aβ aggregates into plaques that disrupt neuronal signaling, while hyperphosphorylated tau forms neurofibrillary tangles, leading to neuronal loss. These processes act synergistically to amplify toxicity. Persistent activation of microglia and astrocytes further promotes neuroinflammation, worsening Aβ and tau pathology.

Single-target therapies directed at Aβ or tau have shown limited clinical success and failed to alter disease progression, underscoring the complexity of AD.

In response, multi-target-directed ligands (MTDLs) have emerged as a promising strategy. By simultaneously modulating several disease pathways, MTDLs can inhibit Aβ aggregation, reduce tau phosphorylation, and exert antioxidant and anti-inflammatory effects. This review summarizes recent progress on MTDLs, highlighting their mechanisms of action, representative drug candidates, and outcomes from preclinical and clinical studies.

Multi-target strategies have the potential to achieve more effective and disease-modifying outcomes than conventional approaches. A critical evaluation of their opportunities and challenges may guide future therapeutic development and the advancement of precision medicine for Alzheimer's disease.