Recent research suggests that certain dietary patterns can influence essential pathophysiological characteristics of AD, such as neuroinflammation, oxidative stress, and amyloid-beta deposition (Stefaniak et al., 2022). Nutritional methods can help improve brain resilience by increasing synaptic plasticity, modulating insulin signaling, and lowering the burden of neurotoxic proteins.

AD has several subgroups depending on age of onset, genetic predisposition, and clinical characteristics. Understanding these categories is crucial for creating precise diagnoses and therapies.

Nutritional deficiencies are increasingly recognized as modifiable risk factors in AD, influencing neuronal health, vascular integrity, and cognitive function. Below, we summarize key micronutrients and biological cofactors implicated in AD pathogenesis (Bianchi, 2024).

Preclinical studies have demonstrated that these natural products modulate multiple AD-related pathways including reducing Aβ burden, inhibiting tau hyperphosphorylation, preserving mitochondrial function, and suppressing pro-inflammatory cytokines (Wang et al., 2022b). Systematic reviews and meta-analyses demonstrate that when combined with standard treatments, HM can improve cognitive performance, delay functional decline, and improve quality of life in Alzheimer’s patients.

Natural products offer multi-targeted effects, making them well-suited for addressing the multifactorial pathology of AD. Experimental studies have utilized diverse animal models including transgenic mice (APP/PS1, 5×FAD), senescence-accelerated mice (SAMP8), and even Drosophila melanogaster—to explore these mechanisms. The ability of herbal compounds to restore redox homeostasis, enhance synaptic signaling, and inhibit apoptotic pathways underscores their therapeutic versatility.

Network pharmacology is a systems-based approach that integrates bioinformatics, cheminformatics, and systems biology to investigate the complex interactions between drugs, targets, and diseases. Unlike traditional “one drug, one target” paradigms, network pharmacology enables identification of multiple molecular targets and pathways simultaneously (Li X. et al., 2023), making it ideal for dissecting the multifaceted nature of AD. It leverages large-scale databases such as TCMSP, STITCH, STRING, GeneCards, and OMIM to construct compound target pathway networks, helping researchers identify hub genes, key targets, and synergistic interactions. Network pharmacology enhances the precision of drug discovery by linking pharmacological targets to disease mechanisms through target prediction algorithms and functional enrichment analyses, such as Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway mapping (Singh et al., 2022).

In AD research, this approach uncovers how phytochemicals modulate core pathological pathways including Aβ aggregation, tau phosphorylation, oxidative stress, and neuroinflammation via shared molecular targets (Naseri et al., 2019). For instance, certain herbal compounds such as curcumin, resveratrol, and ginsenosides have been shown to interact with key nodes such as MAPK, AKT, BACE1, and TNF-α in AD networks.

Network pharmacology is particularly suitable for analyzing traditional herbal formulas, which contain multiple components acting on diverse biological targets. By deconstructing herbal formulas into their constituent compounds and targets, this approach provides mechanistic insights into how multi-component therapies achieve synergistic efficacy. In TKM and TCM, such analyses have clarified the roles of specific herbs in modulating neuroinflammatory and redox-related signaling pathways. Several recent studies employing this methodology have uncovered that traditional memory-enhancing formulas regulate PI3K/AKT, Nrf2, MAPK, and NF-κB pathways key nodes in the AD signaling network (Fão et al., 2019).

While powerful, this approach relies heavily on database accuracy, and functional validation through in vitro or in vivo experimentation remains essential. Emerging integration with omics platforms including spatial transcriptomics and metabolomics will enable higher-resolution modeling of drug–target–disease interactions in AD. As shown in Figure 2A, which illustrates the age distribution of study participants. The highest representation in the age groups of 60–69 and 70–79 reflects the heightened vulnerability of these age brackets to AD. This demographic analysis provides critical insights into the at-risk population, ensuring research efforts are appropriately targeted toward these groups. Key biomarkers, including Aβ42, total tau, phosphorylated tau (p181), and neurofilament light chain (NFL), are pivotal in diagnosing and tracking disease progression. As demonstrated in Figure 2B, elevated levels of tau and NFL indicate neurodegeneration, while reduced Aβ42 correlates with amyloid plaque pathology. These biomarkers underscore their indispensable role in early diagnosis, disease progression monitoring, and as targets for therapeutic intervention. The schematic in Figure 2C captures the sequential progression of hallmark AD features, such as amyloid plaques, tau tangles, neuronal loss, gliosis, synaptic degeneration, and cognitive decline. This temporal representation highlights critical windows for therapeutic intervention, emphasizing the importance of early detection and treatment to mitigate irreversible damage. Figure 2D reveals the intricate network of proteins and genes such as APOE, APP, beta-secretase 1(BACE1), and PSEN1 involved in amyloid metabolism and plaque formation. The interconnectedness of these molecular players underscores the challenge of targeting AD at the molecular level, requiring a multifaceted approach to disrupt these networks effectively. Similarly, Figure 2E focuses on TAO kinase 2 (TAOK2), a protein closely linked to tau phosphorylation and microtubule stability. This highlights its role as a potential therapeutic target in mitigating tau-associated neurodegeneration. The dense connectivity visualized in Figure 2F emphasizes the interplay between various signaling pathways and molecular mechanisms underlying AD. This holistic perspective is critical for the development of multi-targeted therapeutic strategies, as single-pathway interventions are unlikely to address the multifactorial nature of the disease. This analysis of AD through network pharmacology provides a promising roadmap for addressing the disease’s multifaceted pathology, paving the way for innovative, multi-targeted therapeutic solutions (Figure 2). To further enhance the interpretation of the combined PPI network (Figure 2F), we constructed an additional phytochemical-target-based PPI network (Figure 2G) using STRING analysis. The top 10 hub proteins ranked by node degree are summarized in (Figure 2H), highlighting critical intervention points in AD-related networks.

AD is driven by a complex interplay of genetic, molecular, and environmental factors, resulting in progressive neurodegeneration and cognitive impairment (Yuksel and Tacal, 2019). The key pathological hallmarks of AD include amyloid-beta (Aβ) plaque accumulation, neurofibrillary tangles of hyperphosphorylated tau, chronic neuroinflammation, oxidative stress, and mitochondrial dysfunction (Lv et al., 2020). In AD, tau becomes hyperphosphorylated and dissociates from microtubules, resulting in the formation of intracellular neurofibrillary tangles (Pavani and Tiwari, 2024). This disrupts axonal transport, destabilizes cytoskeletal architecture, and contributes to neuronal death (Duggal and Mehan, 2019). Recent findings suggest that pathological tau can spread trans-synaptically, accelerating neurodegeneration in a prion-like fashion (Meng et al., 2023). Microglial activation is a hallmark of AD, initially serving a protective role but becoming detrimental upon chronic stimulation (Li et al., 2021). Sustained microglial activation leads to the release of pro-inflammatory cytokines such as TNF-α, IL-1β, and IL-6, which exacerbate neuronal injury and amplify amyloid and tau pathology (Kaur et al., 2019). Oxidative stress, resulting from excessive reactive oxygen species (ROS) production and impaired antioxidant defense, plays a central role in AD progression (Yin, 2023). ROS cause lipid peroxidation, protein oxidation, and mitochondrial DNA damage, leading to neuronal apoptosis and synaptic dysfunction (Bhatia and Sharma, 2021). Other contributing factors include dysregulated calcium homeostasis (Buccellato et al., 2021). Mitochondria in AD show impaired electron transport chain activity, altered calcium buffering, and increased ROS generation (Simunkova et al., 2019). Mitochondrial dysfunction contributes to energy failure, triggers intrinsic apoptosis, and perpetuates oxidative stress, forming a self-reinforcing neurodegenerative cycle (Wang D. et al., 2021). Impaired mitophagy and fragmented mitochondrial morphology are emerging as novel contributors to neuronal vulnerability in AD (Cao et al., 2019). AD pathogenesis involves a number of interrelated pathways, including amyloid plaque development, tau protein hyperphosphorylation, oxidative stress, neuroinflammation, and metabolic failure (Figure 3). These degenerative processes all contribute to synapse loss, neuronal death, and cognitive decline, emphasizing the need for multi targeted treatment approaches.

Several natural compounds have been shown to modulate key signaling pathways implicated in the pathogenesis of AD. Curcumin inhibits the MAPK pathway by reducing ERK1/2 phosphorylation, thereby attenuating oxidative stress and neuronal apoptosis. Additionally, it suppresses NF-κB activation by preventing IκBα degradation and the nuclear translocation of the p65 subunit, resulting in reduced expression of pro-inflammatory cytokines. Resveratrol exerts anti-inflammatory and neuroprotective effects by activating SIRT1, which in turn suppresses NF-κB signaling. Epigallocatechin gallate (EGCG), a major polyphenol in green tea, mitigates amyloid-beta production by inhibiting β-secretase (BACE1) activity. Furthermore, EGCG enhances Nrf2-mediated antioxidant responses, thereby protecting against mitochondrial dysfunction. Collectively, these pathway-specific actions highlight the therapeutic promise of natural compounds as multi-targeted agents in AD treatment. A summary of these compounds, their associated molecular targets, and supporting references is provided in Table 1.

AD, as a multifaceted neurodegenerative disorder, involves a complex array of pathological processes, including amyloid-beta (Aβ) plaque formation, tau protein hyperphosphorylation, oxidative stress, mitochondrial dysfunction, and chronic neuroinflammation. Given the limitations of current single-target therapies, interest has grown in natural products as promising multi-target agents for modulating AD pathology (Zhang et al., 2024). Natural compounds sourced from plants, fungi, and marine organisms contain diverse bioactives capable of interacting with multiple molecular targets implicated in AD pathogenesis (Nahar et al., 2025). These compounds exhibit antioxidant activity, inhibit amyloid and tau aggregation, modulate neuroinflammation, protect mitochondrial function, and promote neuronal survival. This broad-spectrum activity makes natural products well-suited to address the multifactorial nature of AD (Chen et al., 2021). Curcumin (from Curcuma longa), a potent antioxidant and anti-inflammatory agent, curcumin disrupts Aβ aggregation, dissolves pre-formed amyloid fibrils, and protects neurons from oxidative damage (Yang et al., 2005; Doytchinova et al., 2020). Resveratrol (from grapes and red wine) enhances mitochondrial function, reduces oxidative stress, and activates neuroprotective proteins like SIRT1 (Zhou J. et al., 2021). It also facilitates Aβ clearance via autophagy (Kou and Chen, 2017). Huperzine A (from Huperzia serrata), an acetylcholinesterase (AChE) inhibitor that enhances memory by increasing acetylcholine (ACh) level shown to improve memory and inhibit glutamate-induced excitotoxicity (Qian and Ke, 2014; Lee et al., 2018). Ginkgo biloba terpenoids improve cerebral blood flow, reduce oxidative stress, inhibit Aβ aggregation, and regulate microglial activity to curb neuroinflammation (Xia et al., 2024). Ginsenosides (from Panax ginseng) exhibit neuroprotective effects by reducing oxidative stress, enhancing mitochondrial function, and preventing tau hyperphosphorylation (Shi et al., 2022; Zhang et al., 2023). EGCG (a catechin from green tea) prevents Aβ aggregation, reduces plaque toxicity, and enhances synaptic plasticity while providing strong antioxidant effects (Chen et al., 2020). In addition, marine-derived compounds such as fucoidans and bryostatin (Bălaşa et al., 2020), along with cannabinoids from cannabis, have shown potential for neuroprotection, inflammation reduction, and synaptic repair (Valeri and Mazzon, 2021). To help illustrate the therapeutic significance and developmental advancement of these natural chemicals, Table 2 highlights their molecular targets, experimental models used, clinical status, and potential future research avenues.

However, despite the widespread use of in vitro and in vivo models—such as transgenic animal models and brain organoids—to investigate the effects of natural compounds, these systems often fall short in capturing the full complexity of late-onset Alzheimer’s disease (LOAD). In particular, they frequently fail to account for age-associated changes, comorbidities, and human-specific pathological features (Vitek et al., 2020). These limitations may partially explain the discrepancy between promising preclinical results and the limited success observed in clinical trials. To bridge this translational gap, future research should incorporate advanced platforms, including patient-derived induced pluripotent stem cell (iPSC) models, aged brain organoids, and computational models of disease progression, to more accurately assess the therapeutic potential of natural products.

Moreover, although many natural compounds share neuroprotective mechanisms—such as antioxidant and anti-inflammatory effects—their actions are not necessarily redundant (Zhang et al., 2022). The pharmacological efficacy of each compound may vary significantly depending on factors such as bioavailability, target specificity, and downstream signaling pathways. Considering the clinical differences between early-onset Alzheimer’s disease (EOAD) and LOAD, future investigations should explore how these compounds interact with subtype-specific pathological processes. Advanced disease models, including genetically stratified organoids, patient-derived iPSC lines, and age-appropriate 3D brain cultures, may offer more refined platforms to dissect these differences and identify compound-subtype associations (Sirkis et al., 2022).

Additionally, growing evidence suggests that the therapeutic efficacy of natural products in AD may be modulated by genetic factors, particularly the apolipoprotein E (APOE) genotype (Frisoni et al., 2022). APOE4 carriers, who exhibit greater susceptibility to AD, display distinct oxidative stress and inflammatory profiles that may influence their responsiveness to phytochemicals (Sharifi-Rad et al., 2022). For instance, curcumin has been shown to reduce amyloid plaque burden more effectively in APOE3 than in APOE4 transgenic mouse models (Far et al., 2024). While genotype-specific responses remain incompletely understood, recent clinical trials have demonstrated that resveratrol exerts neuroprotective effects by mitigating neuroinflammation, enhancing mitochondrial function, and preserving blood-brain barrier integrity in patients with mild cognitive impairment (MCI) and early AD (Buglio et al., 2022). These findings underscore the importance of incorporating genetic stratification into precision medicine approaches that utilize natural compounds for AD treatment.

Natural products exert therapeutic effects in AD through multiple interrelated mechanisms. Several natural compounds reduce Aβ toxicity by inhibiting its aggregation, promoting its clearance via autophagy, and limiting synaptic dysfunction (Zeng et al., 2019). Antioxidant-rich compounds reduce ROS production, protecting neurons from oxidative stress-induced apoptosis (Simunkova et al., 2019). Many phytochemicals inhibit glial activation and attenuate neuroinflammatory signaling cascades (Deng et al. 2023). AChE inhibitors, such as huperzine A, increase ACh levels to support memory and cognitive function (Friedli and Inestrosa, 2021). Compounds like resveratrol improve mitochondrial bioenergetics, enhance ATP production, and reduce ROS generation (Moawad et al., 2024). However, clinical translation is hindered by low oral bioavailability, limited BBB permeability, and inconsistent pharmacokinetics. To overcome these limitations, researchers are exploring nanoformulations, targeted delivery platforms, and prodrug strategies. Integrating in silico modeling, cell-based assays, and animal studies allows for a comprehensive understanding of how natural compounds act in AD. Multimodal research is essential to bridge the translational gap and optimize therapeutic development pipelines. Their multi-target pharmacology presents a unique opportunity for breakthrough therapies in complex disorders such as AD.

In vitro models are instrumental in unraveling the complexities of AD, providing a controlled environment to investigate cellular and molecular mechanisms. They serve as efficient platforms to evaluate the effects of natural products in a reproducible and cost-effective way (Vignon A. et al., 2021). Traditional two-dimensional (2D) cell cultures have long been the cornerstone of AD research (Guido et al., 2023). However, 2D cultures oversimplify the cellular architecture and fail to capture the complex brain microenvironment (Acharya et al., 2024). Recent advancements, such as three-dimensional (3D) brain organoids derived from induced pluripotent stem cells (iPSCs), have significantly enhanced the physiological relevance of in vitro models (Zivko et al., 2024). These systems reproduce key hallmarks of AD pathology, including Aβ deposition, tau pathology, and glial activation. This advancement narrows the gap between reductionist models and physiological relevance, improving preclinical assessment of natural products (Lei et al., 2024). Several studies have demonstrated the efficacy of natural products in targeting AD-related mechanisms using in vitro models (Table 3).

In vivo studies are pivotal in bridging the gap between preclinical findings and clinical applications for AD. They offer a physiologically integrated setting to evaluate disease mechanisms and therapeutic efficacy of natural products. These models capture dynamic interactions between brain regions, immune cells, and systemic physiology features not replicable in vitro. Genetically engineered animal models, particularly mice, have revolutionized AD research. Humanized models expressing risk genes like APOE4 faithfully recapitulate genetic susceptibility and clinical phenotypes observed in human AD (Vitek et al., 2020). Advanced techniques like CRISPR gene-editing technology have further enhanced the precision of in vivo models, allowing the replication of specific mutations linked to AD (Bhardwaj et al., 2022). These innovations facilitate the study of epigenetic modifications, combinatorial gene interactions, and environmental triggers in AD (Zeiss, 2020). Non-human primates (NHPs), such as rhesus monkeys, naturally exhibit age related tau and amyloid β (Aβ) pathologies, providing models that closely mimic human disease progression (Li et al., 2019). Due to their high translational value, NHPs help unravel complex immune and neurodegenerative mechanisms relevant to therapeutic modulation (Fulop et al., 2021). Recent technological advances have enhanced the translational relevance of animal models. Techniques like PET and twophoton microscopy allow longitudinal monitoring of pathological progression in living animals. Biomarker studies, involving cerebrospinal fluid (CSF) and blood analyses, enhance the translational relevance of these models by paralleling findings observed in human AD patients (Bjorkli et al., 2020). Behavioral paradigms such as Morris water maze and Y-maze offer quantifiable endpoints (Okada et al., 2021), that correlate with histopathological and molecular findings (Shokhirev and Johnson, 2022). Environmental and lifestyle model (Decourt et al., 2022). such as chronic stress or exposure to metals like aluminum (Gom, 2024), worsen AD features via oxidative injury and proteinopathy enhancement (Althobaiti, 2024). Rodents remain widely used due to practical advantages such as short lifespans, established behavioral assays, and genetic modifiability. Popular rodent strains include APP/PS1, 3×Tg-AD, 5×FAD, SAMP8, BALB/c, ICR, and C57BL/6 mice, as well as Sprague Dawley and Wistar rats. They have been extensively used to evaluate the multi-target effects of natural compounds on amyloidogenesis, tauopathy, mitochondrial health, and glial reactivity (Dhapola et al., 2023).

BALB/c mice have emerged as a valuable model in AD research due to their TH2-biased immune responses and genetically stable background. This unique immune profile supports enhanced antibody production and modulates neuroinflammation, a critical factor in AD pathology (Table 5) (Cacabelos, 2020). BALB/c mice provide essential insights into both immunological and neurodegenerative mechanisms, contributing significantly to understanding and addressing AD-related challenges. One hallmark of AD is the activation of microglia, the brain’s resident immune cells, which can either clear amyloid-β (Aβ) plaques or exacerbate neuronal damage through chronic inflammation (Wang J. M. et al., 2017; Edler et al., 2021). BALB/c mice offer a unique platform for studying how TH2-mediated immune responses influence microglial activity, which can modulate neuronal health and disease outcomes (Mukhopadhyay et al., 2020). Although BALB/c mice do not naturally develop AD (Mancuso et al., 2019), their genetically stable background makes them an excellent model for isolating the effects of genetic modifications, environmental factors, or therapeutic interventions on AD pathology (Balietti et al., 2023). Through targeted genetic engineering, researchers can replicate key AD features, such as tau tangles and amyloid plaque deposition, allowing for precise investigation of the disease mechanisms. The TH2-skewed immune environment in BALB/c mice promotes the production of anti-inflammatory cytokines like IL-4 and IL-10 while reducing cytotoxic T-cell responses (Alvarez-Sanchez and Dunn, 2022; Kumar et al., 2023). This profile creates opportunities to study how anti-inflammatory pathwa ys interact with neuroinflammation, amyloid accumulation, and tau pathology in AD. Such investigations are critical for understanding the intricate balance of cytokine-mediated neuroinflammation and its influence on AD progression (Xavier et al., 2023). Behaviorally, BALB/c mice display elevated anxiety and reduced social interaction compared to other strains, traits that mirror emotional (Mehla et al., 2022) and behavioral changes often observed in Alzheimer’s patients, such as anxiety, impaired social interaction, and disinhibition (Mitrea et al., 2022). This makes BALB/c mice particularly effective for studying the emotional and behavioral dimensions of AD. By leveraging their immune characteristics, genetic stability, and behavioral traits, BALB/c mice provide a versatile and powerful tool for AD research. They enable a deeper understanding of the interplay between immune responses, neuroinflammation, and genetic modifications, paving the way for targeted and innovative therapeutic strategies.

The identification of mutations linked to familial AD has provided critical insights into the fundamental mechanisms underlying disease pathogenesis and progression. These discoveries have enabled the development of animal models, which play a pivotal role in unraveling molecular pathways and advancing therapeutic interventions for AD (Lloyd et al., 2020). The 5×FAD and SAMP8 mouse models are among the most widely used in AD research, offering valuable insights into disease mechanisms, progression, and potential therapeutic interventions. Both models replicate critical hallmarks of AD, including amyloid-β plaque deposition, neuroinflammation, oxidative stress, and cognitive decline, making them indispensable tools for preclinical studies.

Kunming mice, closely related to the C57BL strain, are highly valued in AD research for their resilience, adaptability, and high reproductive efficiency. Their genetic stability and robust physiological responses make them an excellent model for investigating AD pathophysiology, including amyloid beta (Aβ) aggregation, neuroinflammation, oxidative stress, and cholinergic dysfunction. These attributes position Kunming mice as a critical preclinical model for evaluating the therapeutic efficacy of natural compounds in mitigating AD-related pathology. In recent years, significant studies have employed Kunming mice to assess the potential of natural products in addressing hallmark features of AD, such as neuroinflammation, Aβ aggregation, and neuronal apoptosis. These findings underscore the therapeutic potential of natural compounds as promising alternatives or complementary treatments for AD. Addressing these gaps is crucial for enhancing reproducibility and understanding the comprehensive therapeutic potential of these compounds (Table 8).

C57BL/6 mice are the most extensively used models in AD research, owing to their exceptional genetic stability, robust breeding capabilities, and adaptability to laboratory conditions. These mice have proven invaluable in investigating the molecular mechanisms underlying AD pathology and assessing the efficacy of therapeutic interventions, particularly natural products. Their genetic background makes them highly suited for exploring core aspects of AD pathology, such as amyloid-beta (Aβ) aggregation, tau hyperphosphorylation, neuroinflammation, synaptic dysfunction, and cognitive decline. C57BL/6 mice have served as the foundation for numerous preclinical studies, enabling researchers to gain insights into the complex interplay of pathological processes in AD. Seven pivotal studies utilizing this model have demonstrated the multifaceted neuroprotective effects of natural products, as detailed below (Table 9).

Sprague Dawley rats, distinguished by their white fur and red eyes, are a cornerstone in AD research. Their rapid growth, high fertility, and low incidence of tumors, coupled with their sensitivity to hormonal changes, make them ideal for studying neurological, cardiovascular, and endocrinal disorders. In the realm of AD research, these rats have proven indispensable for unraveling molecular mechanisms of disease progression and evaluating the therapeutic potential of natural compounds. Over the years, studies using Sprague Dawley rats have elucidated therapeutic pathways targeting neuroinflammation, amyloid-beta (Aβ) aggregation, tau hyperphosphorylation, oxidative stress, and synaptic plasticity. This model has provided a robust platform for testing natural products and their ability to mitigate AD pathology (Table 10).

Wistar rats, an outbred albino strain distinguished by their white fur, red eyes, and characteristic physical features, are a cornerstone model in neuroscience and pharmacology. Known for their high activity levels, tumor resistance, and adaptability, these rats are invaluable for studying AD. Their robust physiological attributes make them ideal for exploring disease mechanisms and evaluating therapeutic interventions. In AD research, Wistar rats have been instrumental in understanding critical aspects of neuroinflammation, tau hyperphosphorylation, amyloid-beta (Aβ) aggregation, oxidative stress, and cholinergic dysfunction. Several studies have focused on natural product-based therapies, revealing promising mechanisms of action such as antioxidant activity, neuroprotection, and inflammation modulation. These findings contribute to developing novel therapeutic strategies targeting AD pathology (Table 11).

The Lewis rat, an albino strain widely used in immunological and transplantation studies, holds significant value in research focusing on inflammation-related pathologies. Known for its susceptibility to immune-mediated diseases and distinct immune response profile, the Lewis rat serves as a specialized model for investigating neuroinflammation and related neurodegenerative processes. Although its use in AD research is relatively limited, its unique immunological traits offer valuable insights into inflammatory mechanisms underlying AD pathology (Table 12).

Drosophila melanogaster, commonly known as the fruit fly, has emerged as a highly versatile and efficient model organism in AD research. Its genetic simplicity, short life cycle, ease of genetic manipulation, and high reproductive capacity provide researchers with a cost-effective platform for investigating complex neurodegenerative mechanisms. The fly’s nervous system shares significant functional and structural similarities with mammals, making it an ideal model for studying the molecular pathways underlying AD pathology. Furthermore, transgenic Drosophila models expressing human AD-associated genes, such as amyloid-beta (Aβ) and tau, have enabled precise exploration of disease progression and therapeutic interventions (Table 13).

The zebrafish (Danio rerio) has emerged as an indispensable model organism for studying neurodegenerative diseases, including AD (Shenoy et al., 2022). Its unique combination of genetic similarity to humans, transparent embryos, and neuroanatomical parallels makes it a powerful platform for investigating AD mechanisms and testing therapeutic compounds. The zebrafish genome contains orthologs for approximately 70% of human disease-related genes, including those implicated in AD, such as APP, PSEN1, and PSEN2. Additionally, their small size, rapid reproduction cycle, and compatibility with high-throughput screening techniques provide unmatched efficiency in large-scale drug discovery studies (Koehler D, 2018). Behavioral assays, including memory-based tasks and spatial navigation tests, are easily adapted to zebrafish models, enabling detailed assessments of cognitive function and neurobehavioral changes. These attributes, coupled with cost-effectiveness and ethical advantages, have cemented zebrafish as a pivotal tool in AD research. This review compiles insights from ten key studies investigating the therapeutic effects of natural compounds using zebrafish models (Table 14).

Clinical trials form the cornerstone of translational research, bridging the gap between preclinical findings and practical therapeutic applications. They offer critical, evidence-based insights into the safety, efficacy, and mechanisms of natural products in addressing AD. To date, 13 significant clinical studies have explored the therapeutic potential of natural compounds in alleviating cognitive decline, managing neuropsychiatric symptoms, and enhancing the quality of life for individuals with AD and age-related cognitive impairments (Table 15). These trials collectively underscore the multifaceted role of natural products in targeting hallmark pathological mechanisms, such as amyloid-beta (Aβ) plaque aggregation, oxidative stress, neuroinflammation, and neurotransmitter dysregulation.

Clinical trials highlight the therapeutic potential of natural products in AD patients, demonstrating improvements in memory, cognitive function, and neuropsychiatric symptoms. Diosgenin-rich yam extract (Dioscorea batatas) improves cognitive performance and semantic fluency in healthy adults (Tohda et al., 2017). Mentha spicata L. (Spearmint extract) enhances working memory, spatial accuracy, and mood in patients with AAMI (Herrlinger et al., 2018). Withania somnifera (Ashwagandha) significantly improves executive function, attention, and memory in individuals with MCI (Choudhary et al., 2017). GRAPE formula (P. ginseng, Rehmannia glutinosa, Acorus tatarinowii, Yuan Zhi, Epimedium brevicornu) demonstrates sustained cognitive improvements over 24 months (Shi et al. 2017). Huannao Yicong formula (HYF) and Jiannao Yizhi formula (JYF) reduce Aβ42 and tau protein levels, delivering comparable benefits to standard ChEIs (Yang et al., 2019; Wang et al., 2020). Yokukansan alleviates agitation, aggression, and hallucinations in severe AD patients (MMSE <20) (Furukawa et al., 2017). These clinical findings suggest that herbal formulations can complement or enhance conventional AD therapies, with lower side effects and improved safety profiles. However, larger randomized controlled trials (RCTs) with standardized methodologies are necessary for regulatory approval and clinical integration. The development of effective therapeutic strategies for AD necessitates addressing key research gaps and unresolved challenges in human studies involving herbal remedies. Despite promising results from preclinical investigations, clinical studies often face issues related to poor bioavailability, inconsistent dosing, and methodological variability. To improve efficacy and reproducibility, future research should focus on the standardization of herbal compounds, optimization of clinical trial design, and adoption of integrative approaches that combine herbal therapies with conventional pharmacological treatments. Moreover, advancing personalized medicine in AD will require the incorporation of pharmacogenomic profiling to assess individual responses to natural compounds. These efforts will facilitate the translation of herbal-based interventions into clinically effective and scientifically validated treatments for AD.

The development of pharmacological treatments for AD has been a significant focus of medical research, yet current FDA-approved drugs remain limited in their ability to modify the disease’s progression. Existing treatments primarily fall into two categories, ChEIs and NMDA receptor antagonists. ChEIs function by preventing ACh degradation within synaptic gaps, thereby enhancing neuronal communication and cognitive function. NMDA receptor antagonists, in contrast, work by reducing excitotoxicity, which can contribute to neuronal apoptosis and cognitive decline (Breijyeh and Karaman, 2020; Peng et al., 2023). Despite their benefits, these drugs provide only symptomatic relief and do not directly address the underlying mechanisms driving AD pathology, highlighting an urgent need for novel therapeutic strategies (Passeri et al., 2022). One major avenue of exploration has been monoclonal antibody therapies targeting amyloid beta (Aβ), such as donanemab and lecanemab. While these drugs show potential in reducing amyloid plaque burden, they come with risks such as amyloid-related imaging abnormalities with edema (ARIA-E), which can pose significant challenges to their widespread clinical use (Kurkinen, 2023; van Dyck et al., 2023; Høilund-Carlsen et al., 2024). Other FDA-approved drugs, including donepezil, galantamine, rivastigmine, and memantine, have demonstrated cognitive benefits but are frequently associated with gastrointestinal disturbances, dizziness, agitation, and, in some cases, severe hepatotoxicity, as observed with tacrine (Marucci et al., 2021; Peng et al., 2023; Varadharajan et al., 2023) (Table 16).

For years, the amyloid cascade hypothesis has been the dominant framework guiding AD research. However, the repeated failure of Aβ-targeted therapies in clinical trials highlights the limitations of focusing on a single pathological mechanism. The growing understanding of AD as a multifactorial disease necessitates an approach that simultaneously addresses tau pathology, neuroinflammation, oxidative stress, mitochondrial dysfunction, and synaptic loss (Chu et al., 2024). Emerging research suggests that combination therapies, multi-targeted drugs, and personalized interventions hold greater potential in modifying AD progression compared to single-target treatments.

Recent evidence underscores neuroinflammation as a central player in AD progression. Chronic inflammation, primarily driven by activated microglia and astrocytes, exacerbates neuronal damage, accelerates synaptic dysfunction, and contributes to cognitive decline. Targeting neuroinflammatory pathways is now recognized as a promising therapeutic strategy, with potential benefits including restoration of neuronal function, promotion of neuroregeneration, and mitigation of Aβ and tau toxicity (Guo et al., 2020). However, achieving successful neuroinflammatory modulation remains challenging, requiring a delicate balance between suppressing harmful inflammation while preserving protective immune responses.

Despite continuous research efforts, the efficacy of current FDA-approved drugs remains limited. ChEIs (e.g., donepezil, galantamine, rivastigmine) and NMDA receptor antagonists (e.g., memantine) primarily provide symptomatic relief, but they do not halt disease progression. Moreover, these drugs are often associated with side effects such as gastrointestinal distress, dizziness, and nausea, further limiting their long-term clinical utility (Alzheimer’sAssociation, 2022). Recent advances in monoclonal antibody therapies targeting Aβ plaques (e.g., donanemab, lecanemab) have shown potential, but they also pose significant risks, such as amyloid-related imaging abnormalities with edema (ARIA-E), highlighting the need for safer and more effective alternatives.

Beyond its medical impact, AD imposes a substantial socioeconomic burden, affecting patients, caregivers, and healthcare systems. In the United States alone, unpaid caregiving costs were estimated at $271 billion in 2021, underscoring the urgency of developing cost-effective treatments that not only alleviate symptoms but also slow disease progression (Alzheimer’sAssociation, 2022). Given the rising prevalence of AD, particularly in aging populations, innovative therapeutic approaches that integrate natural compounds, computational drug discovery, and precision medicine offer a sustainable and practical path forward.

Natural compounds have garnered significant attention for their multi-targeting properties, low toxicity, and long-standing use in traditional medicine. Preclinical and clinical studies have demonstrated that bioactive compounds such as polyphenols, alkaloids, terpenoids, saponins, and flavonoids exert beneficial effects on AD-related pathways by reducing oxidative stress, suppressing neuroinflammation, preventing Aβ aggregation, and modulating tau hyperphosphorylation (Liu et al., 2024). Notably, certain plant-derived metabolites activate neuroprotective signaling pathways, such as the MAPK/NF-κB system, (Md et al., 2021), and interact with estrogen receptor beta (ERβ), a known regulator of synaptic plasticity and neuroprotection (Cardona-Gómez et al., 2006). The ability of these compounds to modulate multiple aspects of AD pathology makes them valuable candidates for future therapeutic interventions.

Despite promising findings, translating the therapeutic potential of natural compounds into clinical practice presents several key challenges. Limited bioavailability and BBB penetration, reducing their central nervous system efficacy. Lack of standardization in formulation and dosing, leading to inconsistent study outcomes. Potential off-target effects and drug interactions, requiring more extensive toxicological profiling. Absence of large-scale clinical trials, delaying regulatory approvals and mainstream adoption (McGleenon et al., 1999). To address these barriers, advanced drug delivery systems (e.g., nanoformulations, liposomal carriers, prodrugs) are being explored to enhance bioavailability and targeted drug delivery to the brain. Additionally, network pharmacology and artificial intelligence (AI)-driven drug discovery are helping to optimize lead compounds and improve the efficiency of drug development pipelines. In addition, natural products are well recognized for their multi-target effects, a characteristic common to most herbal medicines. However, elucidating their precise molecular mechanisms of action remains a substantial challenge (Yang et al., 2023). This underscores the need for advanced research methodologies capable of addressing the complexity of translating preclinical findings into clinically validated treatments for AD using natural compounds (Ma et al., 2024b).

The rise of precision medicine, biomarker-driven diagnostics, and computational modeling is reshaping how AD is diagnosed and managed. Advances in fluid-based biomarkers (Aβ, tau, neurofilament light chain), functional neuroimaging (PET, MRI), and genetic profiling (APOE status, transcriptomics) are enabling earlier diagnosis and more personalized treatment strategies. The integration of natural compound research with these advanced diagnostic technologies represents a transformative shift, moving toward personalized and preventive therapeutic approaches rather than reactive symptomatic management.

Despite promising preclinical findings, translating the therapeutic potential of natural compounds into clinically effective treatments for AD remains a significant challenge. Natural products frequently encounter substantial obstacles, including low bioavailability, limited penetration across the BBB, and inconsistent clinical trial outcomes, as exemplified by studies involving curcumin. These limitations have contributed to the lack of conclusive clinical efficacy observed to date (Kurkinen, 2023). Additionally, clinical trials involving natural products often face methodological issues such as inconsistent formulations, inter-individual variability among participants, and a need for large-scale studies to robustly assess therapeutic outcomes. Beyond pharmacokinetic and methodological constraints, regulatory barriers further impede the clinical translation of natural compounds for AD therapy. Challenges include batch-to-batch variability, absence of standardized extraction protocols, and inconsistent concentrations of bioactive constituents, all of which complicate compliance with Good Manufacturing Practice (GMP) standards and hinder reproducibility in clinical trials. Furthermore, most herbal products are classified as dietary supplements rather than pharmaceutical agents, limiting their regulatory oversight and permissible therapeutic claims. Regulatory authorities such as the U.S. FDA require stringent evidence of efficacy, safety, and quality control for multi-component natural extracts—criteria that are often difficult to fulfill. To overcome these obstacles, the establishment of harmonized international regulatory frameworks, validated analytical methodologies, and rigorously designed large-scale trials is essential. Addressing these issues is critical for the integration of natural compounds into precision medicine approaches for AD and for advancing their recognition as credible therapeutic agents within evidence-based clinical practice.

While the majority of studies cited in this review report positive findings regarding the effects of natural compounds in AD models, the potential influence of publication bias must be acknowledged. Specifically, studies with favorable outcomes are more likely to be published than those reporting negative or null results, leading to a skewed perception of therapeutic efficacy. Although this review has emphasized the promising potential of natural compounds, it is important to recognize that inconclusive or unfavorable data—particularly from preclinical studies involving transgenic mouse and zebrafish models—also exist. In preparing this review, we selected the most robust and relevant preclinical data to illustrate the therapeutic promise of natural products. However, we acknowledge that studies with conflicting or non-replicable findings are equally important and should be included in comprehensive future analyses. A balanced perspective is essential for identifying compounds whose benefits may be overestimated or insufficiently validated. Incorporating studies with negative or null results will help mitigate publication bias and contribute to a more accurate, evidence-based understanding of the role of natural products in AD. To achieve this, we encourage the scientific community to prioritize transparency in data reporting and to support the publication of all findings—regardless of outcome—in order to foster rigorous and reproducible research in the field of natural compound-based AD therapeutics.