Cognitive impairment (CI), characterized by memory decline, executive dysfunction, and impaired daily living abilities, encompasses a spectrum of neurodegenerative disorders, including mild cognitive impairment and dementia (1). With the accelerating aging of the global population, the prevalence of CI has risen dramatically. According to the World Health Organization, approximately 55 million people worldwide currently live with dementia, a figure projected to reach 139 million by 2050 (2). China, experiencing one of the fastest aging rates, accounts for over 25% of global cases, with more than 15 million affected individuals, imposing a severe burden on public health and socioeconomic systems (3). CI not only drastically diminishes patients’ quality of life but also incurs exorbitant healthcare costs (1). In 2019, global dementia-related expenditures reached 1.3 trillion and are expected to surge to1.3 trillion and are expected to surge to 2.8 trillion by 2030 (4). Furthermore, the long-term caregiving burden on families and associated psychosocial issues underscore the urgency of addressing this condition.

Current treatments for CI primarily focus on symptom management, with key pharmacological interventions including cholinesterase inhibitors (e.g., donepezil, rivastigmine) and N-methyl-D-aspartate receptor antagonists (e.g., memantine) (1). Although these drugs may temporarily alleviate certain symptoms, their efficacy is limited: cholinesterase inhibitors are effective in only 30–50% of patients, with benefits lasting an average of 6–12 months, while memantine, though modulating glutamatergic neurotransmission, offers marginal cognitive improvement in moderate-to-severe cases (5, 6). Additionally, these drugs often induce adverse effects such as gastrointestinal disturbances (e.g., nausea, diarrhea), cardiovascular complications (e.g., bradycardia), and neuropsychiatric symptoms (e.g., hallucinations), leading to poor patient adherence (5, 6). Crucially, existing therapies only slow disease progression without reversing neurodegeneration (5). Recent advances in monoclonal antibodies targeting β-amyloid (e.g., aducanumab) have shown promise, but their clinical benefits remain controversial, and they carry significant risks, such as cerebral edema (7). Thus, there is an urgent need to explore safer and more effective alternatives.

Given these limitations, herbal medicine has gained increasing attention due to its holistic approach—characterized by multi-component, multi-target, and systemic regulatory mechanisms (8–10). Herbal medicine formulations (e.g., Danggui-Shaoyao-San, Kaixin-San) and bioactive compounds (e.g., ginkgo biloba extract, ginsenosides) have demonstrated neuroprotective, anti-inflammatory, antioxidant, and synaptogenic effects in preclinical and clinical studies (11–13). For instance, Huanglian-Jiedu-Tang may mitigate neuroinflammation by suppressing the Nuclear Factor kappa-B (NF-κB) pathway, while gastrodin enhances synaptic plasticity via BDNF/Tropomyosin receptor kinase B (TrkB) signaling (14, 15). Compared to western drugs, herbal medicine offers distinct advantages (16–18): (1) synergistic multi-target effects that address both symptoms and pathogenesis; (2) fewer side effects, supporting long-term use; and (3) personalized treatment strategies aligned with the heterogeneous nature of CI. Advances in network pharmacology and metabolomics have further elucidated the scientific basis of herbal medicine formulations, facilitating their global acceptance.

This study aims to systematically evaluate the pharmacological mechanisms and clinical evidence supporting herbal medicine in CI treatment, emphasizing its comparative advantages over Western medicine. It also addresses challenges in herbal medicine development, such as compositional complexity and quality control standardization. The scientific significance lies in providing a theoretical foundation for integrated Western and herbal medicine approaches, while the societal impact involves promoting cost-effective, low-toxicity natural therapeutics to alleviate the healthcare burden of aging populations. By integrating evidence-based medicine with herbal medicine’s holistic principles, this research may pave the way for novel CI intervention strategies.

Herbal medicine exerts neuroprotective effects through multi-target regulation of neuroinflammation and oxidative stress (Figure 1). Current research demonstrates that baicalin from Huanglian Jiedu Decoction significantly inhibits NF-κB signaling pathway activation, reducing the release of pro-inflammatory cytokines including tumor necrosis factor-α and interleukin (IL)-6 (44, 45). Simultaneously, ginsenoside Rg1 modulates the assembly and activation of NLRP3 inflammasomes, decreasing caspase-1-mediated IL-1β maturation and secretion (46). Regarding antioxidant effects, tanshinone IIA activates the Nrf2/HO-1 pathway, enhancing the activity of superoxide dismutase and glutathione peroxidase to effectively scavenge oxygen free radicals (47). This dual regulatory mechanism provides a stable microenvironment for neuronal cells and delays neurodegenerative progression.

Herbal medicine exhibits regulatory effects on multiple neurotransmitter systems (Figure 1). Huperzine A, as a natural acetylcholinesterase inhibitor, significantly increases synaptic acetylcholine concentration and improves cholinergic neurotransmission deficits (48). Furthermore, jujuboside A modulates 5-HT1A receptor activity to alleviate cognitive dysfunction associated with depression (49). This synergistic regulation of multiple neurotransmitter systems demonstrates more comprehensive therapeutic effects compared to single-target Western medications.

In AD pathology regulation, flavonoids inhibit β-secretase (β-site amyloid precursor protein cleaving enzyme, BACE1) activity to reduce Aβ generation while promoting insulin-degrading enzyme expression to accelerate Aβ clearance (50). GSK-3β and CDK5 activity to decrease tau protein hyperphosphorylation (51). Notably, certain herbal medicine components like curcumin enhance microglial phagocytosis of Aβ, achieving bidirectional regulation of pathological proteins (Figure 1).

Herbal medicine facilitates neural repair through neurotrophic factor signaling networks (Figure 1). Icariin significantly upregulates hippocampal BDNF expression and activates the TrkB/CREB signaling pathway, increasing synaptic protein expression including synaptophysin and PSD-95 (52, 53). Ginsenoside Rb1 enhances dendritic spine density through miR-134-mediated mechanisms to improve synaptic plasticity (54). These effects extend beyond symptomatic relief to promote neural network reconstruction and functional compensation.

Herbal medicine demonstrates unique advantages in regulating cerebrovascular function and energy metabolism (Figure 1). Ligustrazine inhibits angiotensin-converting enzyme to improve vascular endothelial function and increase cerebral blood flow (55). Puerarin upregulates GLUT1/3 expression to enhance glucose transport efficiency and optimize neuronal energy supply (56, 57). Panax notoginseng saponins regulate the AMPK/PGC-1α pathway to promote mitochondrial biogenesis and improve energy metabolism efficiency (58). This multi-level regulation provides essential material foundations for cognitive function recovery.

In summary, through these multi-target, multi-pathway synergistic effects, herbal medicine constitutes a systematic therapeutic network for cognitive impairment. However, current research still faces challenges including complex compositions and narrow effective concentration ranges. Future studies should incorporate novel technologies like organoid culture and single-cell sequencing to elucidate herbal medicine’s comprehensive regulatory mechanisms, providing theoretical foundations for developing new neuroprotective agents. Meanwhile, establishing biomarker-based efficacy evaluation systems will facilitate the internationalization of herbal medicine in cognitive disorder treatment.

Network pharmacology has transformed the study of traditional herbal medicine by enabling systematic mapping of complex herb-compound-target-disease interactions (59). By integrating cheminformatics and bioinformatics, computational algorithms construct multi-scale networks that reveal the polypharmacological nature of herbal medicine formulations (60). For example, network analysis of Ginkgo biloba has identified a variety of bioactive compounds interacting with cognitive impairment-related targets, including APP, AKT1, and PTGS2, highlighting its multi-target mechanisms (61). Machine learning techniques, such as deep neural networks, further enhance predictive accuracy by analyzing structure–activity relationships across extensive phytochemical libraries (62). These approaches not only validate traditional uses but also uncover novel therapeutic targets for cognitive disorders.

Multi-omics technologies provide a comprehensive framework for deciphering herbal medicine’s holistic effects on cognitive function. Transcriptomic profiling of hippocampal tissue after herbal medicine treatment reveals differential expression of neuroplasticity-related genes (e.g., BDNF), while high-resolution mass spectrometry-based proteomics detects modulation of synaptic proteins (e.g., synaptophysin) and pathological markers (e.g., phosphorylated tau) (63). Metabolomic analyses, particularly of cerebrospinal fluid, capture dynamic changes in neurotransmitters (e.g., acetylcholine, glutamate) and energy metabolites (e.g., lactate), offering functional insights into herbal medicine efficacy (64). Integrated multi-omics studies have identified critical regulatory nodes, such as the CREB-miR-132-BDNF axis, which mediates herbal medicine-induced synaptic enhancement and neuroprotection.

Computational molecular docking, combined with advanced structural biology techniques, elucidates atomic-level interactions between herbal medicine compounds and their molecular targets (65). For instance, ginsenoside Rg1 has been shown to stabilize TrkB receptor activation by binding to the BDNF dimerization interface (66). Virtual screening of herbal medicine libraries against BACE1 identified salvianolic acid B as a potent inhibitor, with X-ray crystallography revealing its unique binding mode distinct from synthetic drugs (67). These structural insights facilitate the rational optimization of herbal medicine-derived lead compounds while preserving their inherent multi-target properties, bridging traditional knowledge with modern drug discovery.

Multimodal imaging enables real-time, non-invasive assessment of herbal medicine effects on brain structure and function (68). Ultra-high-field 7 T magnetic Resonance Imaging quantifies hippocampal volume preservation and white matter integrity in AD models treated with herbal medicine (69). Two-photon microscopy, using amyloid-specific probes, dynamically visualizes plaque clearance rates, while novel Positron Emission Tomography tracers track tau pathology modulation (70). Optoacoustic imaging further reveals rapid cerebrovascular improvements, such as enhanced cortical perfusion within 30 min post-herbal medicine administration (71). These technologies provide spatially and temporally resolved evidence of herbal medicine’s neuroprotective and restorative effects.

The synergy of network pharmacology, multi-omics, structural biology, and advanced imaging is forging a new paradigm in herbal medicine research. Network analyses, validated by multi-omics datasets, are decoding the systems-level mechanisms of complex herbal medicine formulations (72). High-content screening platforms now enable multiplexed assessment of cellular responses in herbal medicine-treated neuronal models (73). Emerging tools like spatial transcriptomics promise to map region-specific gene expression changes induced by herbal medicine interventions (74). However, challenges persist in standardizing herbal medicine preparations for reproducible omics studies and developing human-relevant organoid models for mechanistic validation. Addressing these gaps will accelerate the translation of herbal medicine research into clinically viable therapies for cognitive impairment.

Despite the demonstrated potential of herbal medicine in cognitive disorder treatment, significant challenges remain. First, the inherent complexity of herbal medicine compositions presents difficulties in active ingredient identification, quality control, and standardization (75). A single herbal extract may contain hundreds of compounds, while multi-herb formulations introduce additional complexities due to potential synergistic or antagonistic interactions. Second, mechanistic studies often lack depth, with most research limited to phenotypic observations or single-pathway validation rather than comprehensive analyses of multi-target regulatory networks (76). For instance, while flavonoids have been shown to inhibit Aβ aggregation, their integrated effects on synaptic plasticity, neuroinflammation, and blood–brain barrier function remain incompletely characterized. Furthermore, clinical studies frequently suffer from methodological limitations, including small sample sizes, non-standardized treatment protocols, and insufficient long-term follow-up, resulting in lower levels of evidence-based validation. These factors collectively hinder global recognition and clinical translation of herbal medicine research.

Future investigations should leverage cutting-edge technologies to address current limitations. At the basic research level, computational approaches such as virtual screening and target prediction can accelerate the discovery of bioactive compounds, while organ-on-chip platforms and single-cell sequencing may elucidate spatial heterogeneity in neuroprotective mechanisms. For example, network pharmacology approaches exploring the “herbal medicine-gut microbiota-brain axis” may reveal novel pathways through which herbal formulations modulate cognitive function. In clinical translation, precision medicine strategies should be prioritized, utilizing biomarker stratification to enable personalized treatment regimens. Additionally, advanced drug delivery systems (e.g., exosome-based carriers) may enhance blood–brain barrier penetration and target specificity. Standardization and internationalization efforts are equally critical, requiring establishment of quality control systems based on chromatographic fingerprinting and adherence to international consensus guidelines for multicenter randomized controlled trials.

The integration of herbal medicine formulations with modern targeted therapies represents a promising paradigm for cognitive disorder treatment. On one hand, structural optimization of active ingredients (e.g., ginsenoside Rg3-EE derivatives) could yield compounds with both polypharmacological profiles and improved bioavailability. On the other hand, exploring combination therapies with monoclonal antibodies (e.g., aducanumab) or gene therapies (e.g., BACE1-targeting siRNA) may produce synergistic effects while mitigating drug resistance. For instance, combined use of huperzine A with donepezil has demonstrated prolonged cognitive enhancement in clinical observations. Critical infrastructure development includes humanized AD mouse models, cerebrospinal fluid biobanks, and real-world data analytics systems to facilitate bidirectional bench-to-bedside translation. Ultimately, the convergence of herbal medicine’s holistic regulation with Western medicine’s targeted interventions may pioneer next-generation therapeutic strategies for cognitive disorders.

In summary, herbal medicine research for cognitive disorders is transitioning from empirical practice to mechanism-driven science. Overcoming current limitations will require multidisciplinary innovation, with future advancements potentially contributing not only to herbal medicine modernization but also to global neurodegenerative disease therapeutics.