TARGETING THE DOPAMINERGIC SYSTEM IN ALZHEIMERS DISEASE: FROM PATHOPHYSIOLOGY TO THERAPEUTIC POTENTIAL OF BROMOCRIPTINE: A COMPREHENSIVE LITERATURE REVIEW

Salman Abdullah M. Alharthi*, Mohammed Alsieni, Mai Abdul Alim Abdul Sattar Ahmad

Background: Alzheimer's disease (AD) affects over 40 million individuals worldwide, with current therapeutic approaches showing limited efficacy. While the cholinergic hypothesis has dominated AD drug development, emerging evidence suggests that dopaminergic system dysfunction may play a crucial role in AD pathophysiology. Bromocriptine, a selective dopamine D2 receptor agonist, has demonstrated neuroprotective properties and potential therapeutic benefits in preclinical AD models. Aim: This comprehensive review critically evaluates the current understanding of dopaminergic dysfunction in AD and systematically assesses the therapeutic potential of bromocriptine as a novel treatment approach, analyzing mechanistic pathways, preclinical evidence, and clinical implications. Methods: A systematic literature search was conducted across PubMed, Embase, Web of Science, and Cochrane databases from inception to September 2025. Search terms included combinations of "Alzheimer's disease," "dopamine," "bromocriptine," "D2 receptor," and "neurodegeneration." Studies were selected based on their relevance to AD pathophysiology, dopaminergic mechanisms, and the therapeutic effects of bromocriptine. Results: The review synthesizes evidence from 93 studies demonstrating that dopaminergic dysfunction occurs early in AD progression, with D2 receptor availability in the hippocampus correlating strongly with memory performance. Bromocriptine uniquely modulates amyloid-β processing through D2 receptor activation, reduces neuroinflammation via PP2A/JNK pathways, and provides neuroprotection against glutamate excitotoxicity. Unlike other dopamine agonists, bromocriptine specifically targets amyloidogenic pathways while maintaining cognitive enhancement properties. Conclusions: Bromocriptine represents a promising therapeutic candidate for AD treatment through its multi-target approach addressing dopaminergic deficits, amyloid pathology, and neuroinflammation. However, clinical translation requires carefully designed trials considering dosing optimization, patient stratification, and safety profiles in elderly populations. The evidence supports bromocriptine as a potential disease-modifying therapy that could complement existing cholinesterase inhibitors.