The PI3K/AKT and Nrf2 signaling systems are essential for neurogenesis, synaptic plasticity, and cellular survival, and their dysregulation has been linked to the progression of Alzheimer's disease (AD). Due to its complex pathophysiology, currently approved therapeutic agents only provide symptomatic relief and are often associated with serious side effects. Researchers have increasingly focused on natural bioactive compounds as potential therapies, with flavonoids emerging as promising candidates due to their diverse neuroprotective properties. These polyphenolic compounds exhibit notable anti-inflammatory, anti-apoptotic, and antioxidant effects, making them attractive therapeutic agents against AD. A key mechanism by which flavonoids exert neuroprotection is through modulation of the PI3K/AKT and Nrf2 signaling pathways. By enhancing neuronal resilience, reducing oxidative stress, inhibiting apoptosis, and regulating autophagy, flavonoids can mitigate neurodegenerative processes associated with AD. Additionally, they attenuate Aβ accumulation and tau hyperphosphorylation, both of which contribute to neuronal dysfunction, via PI3K/AKT activation and Nrf2 pathway regulation. In preclinical AD models, numerous flavonoids-including epicatechin, kaempferol, quercetin, and luteolin- have demonstrated neuroprotective effects through regulation of the PI3K/AKT and Nrf2 pathways. Despite these encouraging findings, further research is needed to determine optimal dosages, strategies for enhancing bioavailability, and the long-term effects of flavonoid-based therapies in AD. Future studies should focus on translating preclinical evidence into clinical trials, which could improve patient outcomes and quality of life. A deeper understanding of the molecular mechanisms underlying flavonoid activity, particularly their interaction with PI3K/AKT and Nrf2 pathways, may pave the way for novel neuroprotective therapies.
