Efficacy of Standardized Ginkgo biloba Extract in Cognitive Enhancement for Alzheimer’s patients

Anushka Deore¹*, Smita Kothmire², Akshay Khade³, Suvarna Bhalerao³

¹Department of Pharmacognosy, MET’S Institute of Pharmacy, Adgaon, Nashik, Maharashtra, 422003, India.

²Department of Pharmaceutics, MET’S Institute of Pharmacy, Adgaon, Nashik, Maharashtra, 422003, India.

³Department of Pharmacology, MET’S Institute of Pharmacy, Adgaon, Nashik, Maharashtra, 422003, India.

*Corresponding Author E-mail: anushkadeore07@gmail.com

ABSTRACT:

The purpose of this review article is to comprehensively evaluate the efficacy of standardised Ginkgo biloba extract (EGb 761) in enhancing cognition in Alzheimer's disease (AD) individuals. Ginkgo biloba, derived from the leaves of the Ginkgo tree, has a long-standing history of use for its neuroprotective and cognitive-enhancing properties. As the global prevalence of AD continues to rise and effective treatments remain limited, there is increasing interest in alternative and adjunctive therapies such as Ginkgo biloba. Research from preclinical studies and clinical trials suggests that Ginkgo biloba may exert its neuroprotective effects through multiple mechanisms, including antioxidant activity, reduction of neuroinflammation, and improved cerebral blood flow. Randomized controlled trials (RCTs) and observational studies indicate modest benefits in cognitive performance and a potential slowdown in disease progression, particularly in patients with mild-to-moderate AD. However, the results are inconsistent, largely due to variations in study design, dosages, and formulations. Meta-analyses highlight the necessity for standardized protocols to determine consistent efficacy. Ginkgo biloba shows promise as an adjunctive therapy for cognitive impairment in AD, offering a favourable safety profile and good tolerability. Nonetheless, there is a need for larger, multicentre, long-term studies to establish optimal dosages, treatment durations, and which patient subgroups are most likely to benefit. Gaining insight into its molecular mechanisms and exploring personalized treatment approaches could effectively bridge the gap between traditional herbal medicine and modern neurotherapeutics.

KEYWORDS: Alzheimer's Disease, Cognitive Enhancement, Ginkgo biloba, EGb 761, Neuroprotection.

1. INTRODUCTION:

1.1 Background on Alzheimer’s Disease (AD):

Alzheimer’s Disease (AD) is a chronic and progressive neurodegenerative condition, representing the most prevalent cause of dementia, responsible for 60–80% of cases globally. The worldwide prevalence of AD is on the rise, with over 55million individuals affected as of 2023, a figure anticipated to double every twenty years due to ageing populations.¹ Alzheimer's disease (AD) causes a gradual decline in mental abilities, memory impairment, and a diminished capacity to perform everyday activities. Alongside these core challenges, individuals frequently encounter emotional and psychiatric symptoms, including depression, apathy, and agitation, affecting both themselves and their families.^2-4 Pathophysiological hallmarks of neurodegenerative diseases, particularly Alzheimer’s disease, encompass several key features. These include the buildup of neurofibrillary knots formed from hyperphosphorylated tau protein, which impair neuronal stability and function, and amyloid-beta plaques, which interfere with cellular communication. These include the buildup of neurofibrillary knots formed from hyperphosphorylated tau protein, which impair neuronal stability and function, and amyloid-beta plaques, which interfere with cellular communication. Additionally, synaptic dysfunction plays a crucial role in cognitive decline, while neuroinflammation contributes to the progression of the disease by exacerbating neuronal damage and impairing repair mechanisms. Understanding these processes is essential for developing targeted therapeutic strategies.⁵

Alzheimer’s Disease (AD) doesn't just affect those who have it; it also has a major impact on their caregivers and families. Taking care of someone with AD can be emotionally draining, physically exhausting, and financially challenging. Many caregivers experience high levels of stress and burnout from their responsibilities. Additionally, the financial toll of AD is expected to surpass $1 trillion worldwide by the year 2030.⁶

1.2 Treatment Landscape:

Current treatment options for Alzheimer's disease primarily focus on symptom management, as disease-modifying therapies are not widely available.

Pharmacological Treatments: Cholinesterase inhibitors, such as donepezil and rivastigmine, are commonly prescribed to improve cognitive function and delay disease progression by enhancing cholinergic neurotransmission. Memantine, an NMDA receptor antagonist, is used to mitigate excitotoxicity and slow cognitive decline in moderate to severe AD cases.⁷ Although these treatments effectively manage symptoms, they do not tackle the underlying disease processes.⁸

Non-pharmacological approaches: Making changes to our daily habits, exercising regularly, and engaging in activities that challenge our brains can help keep our minds sharp and lower the chance of developing certain diseases. Some people suggest taking dietary supplements, like omega-3 fatty acids and vitamin E, to support brain health, but it's important to note that there is still not enough strong evidence to say for sure how effective these supplements are.^9-11

1.3 Introduction to Ginkgo biloba:

Ginkgo biloba, derived from the leaves of the ancient Ginkgo tree, has been a fundamental component of traditional Chinese medicine for centuries. Renowned for its antioxidant, anti-inflammatory, and vascular properties, Ginkgo biloba has a long history of being used to address various health issues, including circulatory disorders and memory-related complaints.^12,13

Recent studies have concentrated on the potential of Ginkgo biloba in addressing neurodegenerative diseases, particularly Alzheimer’s Disease. This focus stems from its capacity to combat oxidative stress, enhance cerebral blood flow, and modulate neurotransmitter systems. Standardized extracts of Ginkgo biloba, such as EGb 761, are formulated to optimize therapeutic benefits, featuring specific ratios of flavonoids (24%) and terpenoids (6%).^14,15

1.4 Importance of Standardization:

The standardisation of Ginkgo biloba extracts is critical for ensuring consistency in the concentration of bioactive compounds, which is essential for the reproducibility of clinical research findings. In contrast, non-standardized formulations demonstrate considerable variability in both potency and efficacy, often resulting in conflicting outcomes across studies. This variability underscores the necessity for standardized preparations to facilitate reliable scientific inquiry into the therapeutic applications of Ginkgo biloba.¹⁶ EGb 761, the most extensively researched extract of Ginkgo biloba, is esteemed for its rigorous manufacturing standards and comprehensive assessment in clinical trials. Consequently, it is regarded as the gold standard for the exploration of Ginkgo biloba's therapeutic potential.¹⁷

2. Mechanism of Action of Ginkgo biloba Extract:

2.1 Bioactive Compounds:

Standardized extracts of Ginkgo biloba, notably EGb 761, exhibit their therapeutic efficacy through the presence of two principal classes of bioactive compounds: flavonoids and terpenoids. These compounds are integral to the pharmacological profile of Ginkgo biloba, contributing to its potential health benefits as documented in various scientific studies. Flavonoids are known for their antioxidant properties, while terpenoids possess a range of biological activities, collectively enhancing the extract's therapeutic potential.^18-21

Figure 1: Primary bioactive compounds of Ginkgo biloba and its effects.

Flavonoids: Flavonoids, including quercetin, kaempferol, and isorhamnetin, demonstrate significant antioxidant properties by effectively neutralizing reactive oxygen species (ROS) that are implicated in neuronal damage associated with Alzheimer’s Disease (AD). These compounds play a crucial role in mitigating oxidative stress, which is increasingly recognized as a contributing factor in the pathophysiology of AD.²² Flavonoids mitigate oxidative stress, thereby safeguarding neuronal integrity against toxicity induced by amyloid-beta(Aβ) and lipid peroxidation. These processes are critically implicated in the pathophysiology of Alzheimer's disease (AD).²³

Terpenoids: Terpenoids, specifically ginkgolides (including ginkgolides A, B, and C) and bilobalide, have been demonstrated to enhance microcirculation through the inhibition of platelet-activating factor (PAF) and the promotion of vasodilation. These pharmacological effects are instrumental in improving cerebral perfusion, which is essential for the preservation of neuronal health in areas of the brain that are adversely affected by Alzheimer's disease (AD). Their mechanism of action suggests a potential therapeutic avenue for mitigating the cognitive decline associated with neurodegenerative conditions.²⁴ Bilobalide exhibits neuroprotective properties, particularly by attenuating excitotoxicity through the modulation of glutamate receptor activity. This modulation plays a crucial role in safeguarding neuronal health and function.^25,26

2.2 Neurological Effects:

Influence on Neurotransmission and Synaptic Plasticity: Ginkgo biloba has been shown to influence cholinergic neurotransmission through the upregulation of choline acetyltransferase activity, leading to an enhancement in the availability of acetylcholine, a neurotransmitter essential for memory and learning processes.^27,28 Furthermore, Ginkgo biloba modulates synaptic plasticity by increasing levels of brain-derived neurotrophic factor (BDNF), which plays a critical role in facilitating synaptic repair and promoting the growth of damaged neuronal networks.²⁹

Reduction of Inflammation: Neuroinflammation, primarily driven by microglial activation and pro-inflammatory cytokines such as TNF-α and IL-1β, is a key factor in the progression of Alzheimer's disease (AD). Ginkgo biloba has been found to suppress these inflammatory mediators, thereby alleviating neuronal damage.³⁰ In animal studies, EGb 761 has demonstrated the ability to downregulate cyclooxygenase-2 (COX-2), which further reduces inflammatory cascades.³¹

Improvement in Cerebral Blood Flow: Alzheimer's disease is frequently associated with cerebral hypoperfusion, which can significantly exacerbate cognitive decline in affected individuals. The standardized extract EGb 761 has been shown to enhance nitric oxide bioavailability, thereby promoting endothelial-dependent vasodilation and subsequently improving cerebral blood flow. This augmentation of cerebral perfusion is crucial as it facilitates the delivery of oxygen and essential nutrients to the brain, potentially mitigating ischemic damage in regions particularly vulnerable to degeneration.^32-34

2.3 Evidence for Efficacy:

Amyloid-Beta Toxicity Mitigation: Preclinical investigations have demonstrated that EGb 761 exerts an inhibitory effect on the aggregation of amyloid-beta (Aβ) while concurrently facilitating its clearance through the upregulation of autophagy-related pathways.^35,36 This dual action effectively mitigates plaque burden and contributes to the preservation of neuronal function in experimental models of Alzheimer's disease (AD).

Mitochondrial Protection: Oxidative stress-induced dysfunction of mitochondrial pathways is a recognized characteristic of Alzheimer’s Disease (AD). The extract EGb 761 has been shown to enhance the stability of mitochondrial membranes and promote ATP synthesis, thereby safeguarding cellular energy metabolism.³⁷

Neurogenesis Promotion: In addition to its neuroprotective properties, EGb 761 has been shown to stimulate neurogenesis within the hippocampus, a critical brain region involved in the formation of memory and one of the first areas to be adversely affected in Alzheimer's disease (AD).^38,39

2.4 Standardization and Potency:

Standardized extracts of Ginkgo biloba, such as EGb 761, provide a reliable therapeutic efficacy by ensuring the maintenance of consistent concentrations of active compounds, specifically 24% flavonoids and 6% terpenoids. This standardization is critical for achieving uniformity in therapeutic outcomes and enhancing the reproducibility of clinical results associated with Ginkgo biloba supplementation.

Reproducibility: Non-standardized formulations are characterized by considerable variability in their composition, which consequently results in inconsistent outcomes in both preclinical and clinical research. In contrast, EGb 761 addresses this challenge by implementing rigorous quality control protocols, thereby ensuring reproducibility and reliability across various clinical trials.⁴⁰

Efficacy in Research: The rigorous standardization of EGb 761 has significantly contributed to its adoption in a multitude of randomized controlled trials (RCTs), thereby establishing it as the definitive benchmark for assessing the efficacy of Ginkgo biloba in the context of cognitive enhancement.⁴¹

Potency Across Populations: The consistent formulation of EGb 761 renders it appropriate for a wide range of patient populations, effectively minimizing variability associated with genetic or environmental factors that could impact bioavailability.⁴⁰

Figure 2: Neuroprotective Mechanism of Gingko Biloba extract (GBE)

3. Review of Clinical Trials and Studies:

3.1 Randomized Controlled Trials (RCTs):

Randomized Controlled Trials (RCTs) represent the pinnacle of methodological rigour in assessing the efficacy of Ginkgo biloba in the context of Alzheimer’s Disease (AD). Numerous key studies have systematically investigated its cognitive benefits, taking into account diverse patient populations, varying dosages, and different treatment durations. These investigations contribute to a nuanced understanding of Ginkgo biloba's potential role in cognitive enhancement within AD patient cohorts.

a. Key Findings:

One pivotal randomized controlled trial (RCT) assessed the efficacy of EGb 761 (240 mg/day) in 410 patients with mild-to-moderate Alzheimer's disease over six months. The study found significant improvements in cognitive performance and activities of daily living (ADL) compared to placebo, as evaluated using the Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) and the Clinical Global Impression of Change (CGIC).⁴²

A separate study involving 400 elderly participants diagnosed with mild cognitive impairment (MCI) discovered that a daily dosage of Ginkgo biloba (240 mg) notably slowed the progression to dementia over four years, especially among individuals with early memory complaints. However, the effect size was moderate, prompting inquiries regarding its clinical significance.⁴³

b. Methodologies and Outcomes:

Trials have varied widely in design, including differences in:

Dosage (120–600 mg/day of EGb 761).

Cognitive assessment tools (e.g., ADAS-Cog, Mini-Mental State Examination [MMSE]).

Patient demographics (e.g., age, baseline cognitive status).

A systematic RCT evaluating the effects of Ginkgo biloba on elderly participants without dementia found no significant benefit in preventing cognitive decline, indicating that its efficacy may be limited to those already exhibiting cognitive symptoms.⁴⁴

c. Clinical Significance:

Recent investigations into the efficacy of Ginkgo biloba, particularly in randomized controlled trials (RCTs), suggest that its benefits are generally modest and may be influenced by several factors, including baseline cognitive function, disease severity, and the duration of treatment. Notably, the formulation EGb 761 has demonstrated the most significant promise in individuals diagnosed with mild-to-moderate Alzheimer’s disease (AD), often serving as an adjunctive therapy to enhance clinical outcomes. Such findings underscore the complex interplay between treatment variables and patient characteristics in the management of cognitive decline.^44,45

3.2 Observational Studies:

a. Key Findings:

Observational studies have consistently indicated that long-term users of Ginkgo biloba experience a slower cognitive decline. For instance, a cohort study involving 1,000 elderly individuals revealed that daily use of EGb 761 over two years was linked to improved memory performance and lower rates of conversion to dementia compared to non-users. Another large-scale study observed that patients using Ginkgo biloba experienced fewer cognitive deficits over five years than those receiving no treatment.⁴⁶

b. Limitations:

· Potential Biases: Observational data may exhibit selection bias, as healthier individuals are often more inclined to utilize Ginkgo biloba.^47,48

· Confounding Factors: Variability in concurrent therapies, lifestyle choices, and adherence complicates the ability to attribute benefits solely to Ginkgo biloba.^49,50

· Non-standardized Extracts: Numerous studies fail to specify the formulation or standardization of Ginkgo biloba used, which results in inconsistent findings.^51,52

3.3 Meta-analyses and Systematic Reviews:

Meta-analyses offer a thorough assessment of the efficacy of Ginkgo biloba by synthesising findings from various clinical trials.

a. Key Findings:

A meta-analysis of 21 trials involving more than 2,500 participants revealed that standardized Ginkgo biloba extract significantly enhanced ADAS-Cog scores in comparison to a placebo, with more pronounced benefits noted in cases of mild-to-moderate Alzheimer's disease (AD).⁵³ Additionally, another review concluded that although Ginkgo biloba offers potential cognitive benefits, the variability in study designs hampers the strength of its conclusions.⁵⁴

b. Strengths:

Meta-analyses play a crucial role in synthesising a wide range of research findings from various studies, thereby providing a comprehensive overview of the effectiveness of interventions or treatments across different populations and contexts. By systematically combining data from multiple studies, meta-analyses can highlight overarching trends, identify variations in efficacy among different demographic groups, and reveal how external factors, such as study design and setting, may influence outcomes. This approach enhances our understanding of how and why certain interventions work effectively in some situations while being less effective in others, offering valuable insights for practitioners and policymakers in their decision-making processes.

c. Limitations:

· Heterogeneity: Variations in dosage, study duration, and cognitive assessment tools across trials reduce the reliability of aggregated results.

· Publication Bias: Positive findings may be overrepresented in published literature, skewing meta-analytical outcomes.

3.4 Comparison with Other Therapies:

a. Efficacy Relative to Standard Treatments:

· Cholinesterase Inhibitors: Donepezil, a commonly prescribed cholinesterase inhibitor, has been found to produce greater cognitive improvements compared to Ginkgo biloba; however, it is also associated with a higher incidence of gastrointestinal side effects.⁵⁵

· Memantine: Memantine is effective for moderate-to-severe Alzheimer's disease, whereas Ginkgo biloba seems to offer more benefits during the early stages of the condition. Some studies suggest that combining memantine with Ginkgo biloba may enhance therapeutic outcomes.^53,56

b. Practical Considerations: The tolerability and safety profile of Ginkgo biloba appear more favourable compared to standard pharmacological treatments, making it a potentially attractive option, especially for individuals hesitant about conventional medications.¹⁶

c. Adjunctive Role: The multifaceted mechanisms of Ginkgo biloba, including its antioxidative properties and enhancement of cerebral blood flow, provide a complementary approach to pharmacological interventions, positioning it as a promising adjunctive therapy for cognitive disorders. Evidence from a randomized controlled trial demonstrated that the combination of donepezil and EGb 761 resulted in significantly improved cognitive outcomes compared to the administration of donepezil alone over six months.⁵⁷

d. Safety Profile: In contrast to conventional pharmacological therapies, Ginkgo biloba is characterized by a reduced incidence of adverse effects, thereby presenting a viable option for sustained use, particularly among patients who possess contraindications to cholinesterase inhibitors or memantine.⁵⁸

Table 2: Comparison of Ginkgo biloba with Standard Alzheimer’s Therapies

Therapy	Mechanism of Action	Cognitive Benefits	Adverse Effects
Donepezil	Acetylcholinesterase inhibitors; increases acetylcholine availability by preventing its breakdown.	Improves memory, attention, and daily functioning in mild-to-moderate AD. Limited benefits in advanced stages.	Nausea, vomiting, diarrhoea, loss of appetite, insomnia, muscle cramps, bradycardia, fatigue.
Memantine	NMDA receptor antagonist; blocks excessive glutamate activity, reducing excitotoxicity that damages neurons.	Slows the progression of cognitive decline in moderate-to-severe AD; and enhances memory and learning.	Dizziness, headache, constipation, somnolence, agitation, and hypertension.
EGb 761 (Ginkgo biloba)	Combines antioxidant activity, reduced neuroinflammation, improved cerebral blood flow, and modulation of neurotransmitters.	Modest improvements in memory, attention, and daily functioning in mild-to-moderate AD; slows progression.	Headache, dizziness, mild gastrointestinal disturbances, and increased bleeding risk in predisposed patients.
Combination Therapy	Combines mechanisms of Donepezil or Memantine with EGb 761, enhancing antioxidant, cholinergic, and anti-inflammatory effects.	Synergistic improvement in cognitive function and daily living activities over monotherapy.	Combined side effects of each therapy; require monitoring for bleeding risks with Ginkgo biloba.

4. Safety and Side Effects:

4.1 Adverse Effects:

Standardized Ginkgo biloba extracts, particularly EGb 761, are generally well-tolerated in clinical settings. However, some adverse effects have been reported, including:

a. Common Side Effects:

· Headaches and Dizziness: Mild headaches and transient dizziness are among the most frequently reported side effects.⁵⁹

· Gastrointestinal Disturbances: Nausea, abdominal discomfort, and diarrhoea occur in a minority of users, often resolving without intervention.⁵⁹

b. Rare Side Effects:

· Allergic Reactions: Rare hypersensitivity reactions, such as skin rash, have been observed.

· Bleeding Complications: Due to its mild antiplatelet activity, Ginkgo biloba may increase bleeding risk, particularly in predisposed individuals.^60,61

4.2 Contraindications:

a. Bleeding Disorders: Patients with coagulopathies or a history of bleeding disorders should avoid Ginkgo biloba due to its potential to prolong bleeding times.⁶²

b. Concurrent Use of Anticoagulants: The use of Ginkgo biloba with anticoagulant or antiplatelet medications (e.g., warfarin, aspirin) may increase bleeding risks. Patients on such medications should consult healthcare providers before initiating Ginkgo biloba.⁶³

c. Surgical Procedures: Discontinuation of Ginkgo biloba at least two weeks before surgery is recommended to reduce intraoperative bleeding risks.⁶⁴

d. Pregnancy and Lactation: Limited data exist regarding its safety during pregnancy and lactation. Use is generally discouraged in these populations.⁶⁵

4.3 Long-term Use:

Studies assessing the safety of prolonged Ginkgo biloba use indicate a favourable profile. A four-year longitudinal trial reported no significant toxicological effects in elderly participants consuming EGb 761 (240 mg/day). However, continuous monitoring is advised in individuals with comorbidities or those taking concurrent medications.

a. Cumulative Antiplatelet Effects: Long-term use may slightly increase cumulative bleeding risk, particularly in patients with additional risk factors.⁶⁶

b. Safety in Vulnerable Populations: Ginkgo biloba showed tolerability in elderly people with mild dementia or Alzheimer's disease, though caution is needed in weak populations.⁶⁷

5. Limitations of Current Research:

5.1 Study Design Issues:

a. Small Sample Sizes: Numerous studies assessing the efficacy of Ginkgo biloba in the context of Alzheimer’s Disease have involved participant numbers below 300, which constrains both statistical power and the generalizability of the findings. To enhance the robustness of the evidence and to substantiate clinical recommendations, it is imperative to conduct research with larger cohorts.^68,69

b. Short Study Durations: Cognitive decline in Alzheimer's disease is characterized as a progressive phenomenon; however, numerous clinical trials are typically conducted over a limited timeframe of 6 to 12 months. This abbreviated duration may inadequately reflect the long-term advantages or potential risks linked to the utilization of Ginkgo biloba.^70-72

c. Variability in Methodologies: Numerous clinical trials have utilized a variety of cognitive assessment instruments, such as the Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) and the Mini-Mental State Examination (MMSE), which complicates the ability to conduct meaningful comparisons and meta-analyses. Furthermore, disparities in dosage regimens, ranging from 120 to 600 mg per day, along with variations in treatment protocols, contribute to the heterogeneity observed in reported outcomes.⁷³

5.2 Inconsistent Results:

a. Discrepancies Across Studies: Recent studies investigating the efficacy of Ginkgo biloba have yielded mixed outcomes regarding its cognitive benefits. While certain trials report marked improvements in cognitive function attributable to the supplement, others demonstrate no significant difference when compared to placebo. These discrepancies may be attributed to variations in patient demographics, baseline cognitive status of participants, and the methodological rigour employed across different studies. Such factors play a crucial role in interpreting the overall efficacy of Ginkgo biloba in cognitive enhancement.⁶⁷

b. Potential Factors Leading to Mixed Findings: Heterogeneous Populations: Differences in age, disease severity, and comorbidities across studies may influence outcomes.

Dose-Response Variability: Inconsistent dosages and formulations lead to variability in therapeutic effects.

5.3 Standardization Challenges:

a. Variability in Extracts: Not all research employs standardized extracts, such as EGb 761. The utilization of non-standardized formulations leads to variable concentrations of bioactive compounds, which can significantly impact both the efficacy and reproducibility of study outcomes.⁷⁴

b. Quality Control Issues: Over-the-counter Ginkgo biloba supplements, especially those not subjected to rigorous quality control standards, may contain subtherapeutic dosages or hazardous contaminants. Such deficiencies potentially compromise the integrity and validity of related research findings.⁷⁵

6. Future Directions and Research Needs:

6.1 Gaps in Knowledge

a. Optimal Dosages and Treatment Durations: Current studies employ a range of dosages for Ginkgo biloba extract, varying from 120 to 600 mg per day, which makes it difficult to establish an optimal therapeutic range. The long-term effects of these different dosages remain uncertain, especially in terms of safety and sustained efficacy. Furthermore, the treatment durations in most trials are restricted to 6 to 12 months, which may not be adequate to fully capture the potential long-term benefits of Alzheimer's Disease (AD).⁷⁶

b. Role of Patient Subgroups: The efficacy of Ginkgo biloba appears to be contingent upon various patient characteristics, including age, the stage of cognitive decline, and the presence of comorbidities. Conducting subgroup analyses may facilitate the identification of specific populations that are most likely to derive benefit from this intervention, particularly individuals with moderate to severe cognitive impairment or those in the initial phases of Alzheimer's disorder. (AD).⁷⁷

6.2 Potential Mechanisms:

Further research is needed to explore the molecular pathways underlying Ginkgo biloba’s neuroprotective effects:

a. Amyloid-Beta (Aβ) and Tau Modulation: Research examining the effects of Ginkgo biloba on hippocampal neurogenesis and synaptic repair processes could provide valuable insights into its potential role in cognitive enhancement.⁷⁸

b. Neurogenesis and Synaptic Plasticity: Investigations into the impact of Ginkgo biloba on hippocampal neurogenesis and synaptic repair mechanisms may elucidate its potential role in the enhancement of cognitive function.⁷⁹

6.3 Larger Trials:

a. Multicentre Studies: Future clinical trials should be designed to include larger, multicentre cohorts that encompass a diverse demographic spectrum. By integrating participants from various ethnicities and socioeconomic backgrounds, these studies could effectively address existing disparities in Alzheimer’s disease research and enhance the generalizability of the findings, ensuring that the results apply to a wider population.⁸⁰

b. Long-Term Follow-Up: Extended follow-up periods, lasting three years or more, are essential for a comprehensive assessment of Ginkgo biloba's effects on disease progression, functional independence, and overall quality of life. Such investigations must evaluate the sustained efficacy and safety of Ginkgo biloba across various stages of Alzheimer's disease.⁶⁷

6.4 Personalized Treatment:

a. Precision Medicine Approaches: Advances in biomarker research and genetic profiling could lead to personalized recommendations for Ginkgo biloba use. For instance, individuals with specific genetic risk factors, such as APOE ε4 carriers, might react differently to treatment.⁸¹

b. Integration with Digital Tools: Wearable devices and cognitive monitoring applications can enable real-time data collection, allowing for dynamic treatment adjustments and adherence monitoring.^82,83

7. CONCLUSION:

The efficacy of standardized Ginkgo biloba extract (EGb 761) in enhancing cognitive function among patients with Alzheimer’s Disease is supported by both preclinical evidence and clinical trials, particularly in cases classified as mild to moderate. Its neuroprotective effects are linked to antioxidant activity, anti-inflammatory properties, and improved cerebral blood flow. However, the findings are still inconsistent due to variability in study design, patient populations, and dosages.

Ginkgo biloba appears to be a promising adjunctive therapy for Alzheimer's Disease, especially for those patients who may not tolerate standard pharmacological treatments. Its favourable safety profile, along with its multimodal mechanisms of action, makes it a valuable complementary option. Clinicians should utilize standardized extracts like EGb 761 and take into account patient-specific factors, such as comorbid conditions and concurrent medications.

Future research should concentrate on long-term, multicentre trials employing standardized protocols to verify the efficacy of Ginkgo biloba. A personalized approach, utilizing biomarkers and genetic insights, could enhance its therapeutic application. Furthermore, expanding our comprehension of the molecular mechanisms involved and targeting specific patient subgroups could strengthen its role in the management of Alzheimer’s Disease, ultimately bridging the divide between traditional medicine and modern neurotherapeutics.

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Received on 09.04.2025      Revised on 15.05.2025

Accepted on 06.06.2025   Published on 24.07.2025

Available online from July 28, 2025

Res. J. Pharmacognosy and Phytochem. 2025; 17(3):219-228.

DOI: 10.52711/0975-4385.2025.00036

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