Current progress in pathway-targeted therapeutics for Alzheimer's disease: mechanistic insights and windows of opportunity.

Alzheimer’s disease (AD) remains a complex neurodegenerative condition characterized by progressive cognitive decline driven by amyloid-beta (Aβ) plaques, tau neurofibrillary tangles, and neuroinflammation. With extensive research, disease-modifying anti-amyloid monoclonal antibodies have now received U.S. FDA approval for early symptomatic disease; however, benefits remain modest and are accompanied by substantial monitoring and implementation constraints.. This review critically evaluates the current landscape of inhibitor-based therapeutics for AD, encompassing both clinical and preclinical developments, and identifies windows of opportunity for future research. This review synthesizes current progress in inhibitor-based strategies, ranging from cholinesterase inhibitors and NMDA receptor antagonists to amyloid-targeting antibodies, tau-based interventions, and novel anti-inflammatory mechanisms. While agents like Lecanemab show modest cognitive decline reduction, safety and efficacy challenges persist, and small-molecule inhibitors have largely failed. Promising preclinical candidates including multi-target ligands, allosteric modulators, and HDAC6 inhibitors, demonstrate robust effects in animal models, although translation remains elusive. Advances in biomarkers (plasma p-tau217, tau PET) and genetic risk profiling (APOE ε4) are enabling precision approaches, complemented by adaptive designs and AI-driven trial optimization. Integrating multi-target pharmacology with biomarker-guided strategies offers a promising path toward effective, accessible AD therapeutics.