Alzheimer's disease (AD) is a debilitating progressively neurodegenerative disease. The best-characterized hallmark of AD, which is marked by behavioral alterations and cognitive deficits, is the aggregation of deposition of amyloid-beta (Aβ) and hyper-phosphorylated microtubule-associated protein Tau. Despite decades of experimental progress, the control rate of AD remains poor, and more precise deciphering is needed for potential therapeutic targets and signaling pathways involved. In recent years, phosphoinositide 3-kinase (PI3K) and Akt have been recognized for their role in the neuroprotective effect of various agents, and glycogen synthase kinase 3 (GSK3), a downstream enzyme, is also crucial in the tau phosphorylation and Aβ deposition. An overview of the function of PI3K/Akt pathway in the pathophysiology of AD is provided in this review, along with a discussion of recent developments in the pharmaceuticals and herbal remedies that target the PI3K/Akt signaling pathway. In conclusion, despite the challenges and hurdles, cumulative findings of novel targets and agents in the PI3K/Akt signaling axis are expected to hold promise for advancing AD prevention and treatment. Over the past decades, researchers have focused substantial attention on the PI3K/Akt signaling pathway, which is a key intracellular signaling pathway implicated in a range of essential cellular activities, and its physiological functions have progressively come to light. In neurons and various other cell types, PI3K and Akt are involved in key processes, p articularly crucial within the central The triple-transgenic (3xTg) and 5xFAD mouse models are typical for this stage, showing a range of AD features such as plaque formation and abnormal tau protein ( Götz et al., 2018 ). In the dementia stage, the therapeutic window for modulating PI3K and GSK3 may be more limited, with treatment primarily focused on supportive care. While some studies suggest potential benefits of targeting these pathways, the overall effectiveness may be reduced due to the advanced neuronal damage and extensive plaque and tangle formation ( Lauretti et al., 2020 ). During this stage, the selection should focus on mouse models that exhibit severe neurodegeneration and significant loss of cognitive function. In particular, abnormalities in autophagy lead to elevated γ -secretase activity, exacerbating Aβ buildup in the brain and causing amyloid processing of APP. The primary downstream target of PI3K-Akt signaling, mTOR, is responsible for the control of autophagy. As a serine/threonine kinase, mTOR controls transcription, protein synthesis, cell division, growth, and autophagy. In particular, mTOR can consolidate and sustain memory function by boosting both synaptic plasticity and protein synthesis in dendrites and synapses through the formation of two multiprotein complexes, mTORC1 and mTORC2 ( Querfurth and Lee, 2021 ). Given the function of the PI3K-Akt pathway in AD, several synthetic and natural modulators, ranging from chemicals to herbs, have been shown to alleviate the symptoms of this degenerative condition in various in vivo and in vitro models. Among these modulators, natural products can be classified into saponins, phenylpropanoids, flavonoids, non-flavonoid polyphenols, and others. Many of these compounds are derived from traditional Chinese medicine, offering increased safety and reduced toxicity in therapeutic applications, thus holding significant potential as future drug candidates. However, the reduction in circulating levels of risk molecules is still far from the improvement of clinical symptoms and more convincing evidence is required. Oxyphylla A is a recently identified compound extracted from Alpinia oxyphylla, a plant employed historically to treat brain-related disorders and also referred to as Yi Zhi in Chinese herbal medicine. Bian et al. demonstrated how oxyphylla A acts as a neuroprotective agent in N2a/APP cells and SAMP8 mice by lowering the expression levels of APP, Aβ 1-40 , and Aβ 1-42 and inhibiting oxidative stress through Nrf2 activation via the Akt/GSK3β pathway ( Bian et al., 2021 ). In addition, pharmacological and clinical studies suggest Chinese herbal medicine Fructus broussonetiae (FB) may be a possible medication for AD therapy. In the experiment to test the neuroprotective effects of FB on APP/PS1 mice, Li et al. demonstrated that FB exerted anti-AD effects both in vivo and in vitro , and the in vitro experiment revealed that cells treated with FB had elevated levels of both AKT and β-catenin signaling ( Li Y. H. et al., 2021 ). Research has indicated that asiatic acid (AA), a naturally occurring pentacyclic triterpene derived from Centella asiatica , may aid in lowering the concentration of Aβ in the AD brain. As a result, magnesium-L-threonate (MgT), a new magnesium compound, has been applied recently for its capacity to increase brain magnesium levels and reduce degenerative alterations associated with AD. Xiong et al. demonstrated that, in Aβ 25-35 -treated HT22 cells and APP/PS1 mouse hippocampus, MgT treatment exerts neuroprotective benefits against oxidative stress and hippocampal neuronal injury and activates the PI3K/Akt pathway as well ( Xiong et al., 2022 ). As stated earlier, GSK3β inhibitors are utilized in the treatment of AD because GSK3β is crucial to the pathogenesis of the disease. Lithium has a well-established ability to reduce AD pathogenesis by preventing tau phosphorylation due to its GSK3β inhibitory effects ( Haussmann et al., 2021 ). In terms of clinical efficacy, several recent meta-analyses showed that lithium can successfully enhance cognitive functions in AD patients. According to Shinji et al., there were no appreciable variations in CSF biomarkers between the GSK3β inhibitor and placebo therapy groups. That can be the result of the individual heterogeneity and an inadequate sample size of the group ( Matsunaga et al., 2015 ; Matsunaga et al., 2019 ).