Herbal Strategies in The Management of Alzheimer’s Disease: Insights into Pathophysiology and Future Direction

Alzheimer’s disease (AD) is the leading cause of dementia and the most prevalent neurodegenerative disorder, particularly in developed nations.^[5] Anatomically, it is characterized by pronounced cerebral atrophy, especially in regions such as the hippocampus and entorhinal cortex, which leads to progressive memory loss and impaired daily functioning.^[2] AD is defined as a chronic, progressive neurological disorder, primarily affecting older adults. Its hallmark pathological features include the presence of extracellular amyloid plaques composed of amyloid-beta (Aβ) peptides and intracellular neurofibrillary tangles formed by hyper phosphorylated tau proteins. ^[3] These abnormalities contribute to synaptic dysfunction, neuronal death, and cognitive deterioration. Amyloid accumulation can occur in brain tissue and blood vessels, resulting in cerebral amyloid angiopathy. Neurofibrillary tangles, comprising paired helical filaments, are associated with neuronal degeneration and synaptic loss. ^[3] Currently, treatment options include acetyl cholinesterase inhibitors such as rivastigmine, glutamine, and donepezil, as well as NMDA receptor antagonists like meantime. ^[6] Traditionally, AD has been seen as a condition involving progressive loss of neurons and synapses across specific brain regions, leading to varying clinical presentations. Diagnostic assessments often include evaluating the distribution and severity of characteristic lesions through neuroimaging, which allows for early detection—even in asymptomatic stages. While imaging plays a pivotal role in diagnosis, definitive confirmation still relies on neuropathological evaluation via autopsy or biopsy.^[3] Cortical atrophy in AD is typically diffuse and symmetrical across the cerebral hemispheres, often accompanied by ventricular enlargement (hydrocephalus ex vacuo) and subcortical white matter changes. The disease progression involves a gradual decline in cognitive functions such as memory, learning, and reasoning, with the risk significantly increasing in individuals over 65 years of age. Although early-onset AD (before age 65) accounts for only 1–6% of cases, around 60% of these are familial, with some inherited in an autosomal dominant manner. ^[5] Mortality in AD patients is often due to complications such as malnutrition, infections, or pneumonia. The disease typically progresses through four stages: mild cognitive impairment (MCI), mild AD, moderate AD, and severe AD. MCI involves subtle cognitive decline without major interference in daily life, while later stages are marked by substantial cognitive and functional impairments requiring complete caregiver support.^[6] AD currently ranks among the top causes of mortality worldwide and contributes to the majority of dementia cases. Symptoms may include memory loss, confusion, impaired judgment, hallucinations, irritability, and behavioral changes. Advanced cases may also present with seizures, rigidity, incontinence, and monism. Effective disease management requires early recognition and accurate diagnosis through primary care, enabling both pharmacologic intervention and psychosocial support to improve patient outcomes and quality of life. ^[7]

1. Global economic of AD

The global prevalence of Alzheimer’s disease (AD) is projected to rise significantly, with an increase from 26.6 million cases in 2006 to approximately 106.8 million by 2050. ^[5] In 2010, the global financial burden of dementia—including AD—was estimated at around USD 604 billion, which accounted for nearly 1% of the total global Gross Domestic Product (GDP). ^[8] A breakdown of the global cost distribution reveals stark disparities: low-income countries contributed less than 1% of the total financial burden despite representing 14% of dementia cases. Middle-income countries were responsible for 10% of the overall costs, though they accounted for 40% of the disease prevalence. High-income countries, on the other hand, incurred 89% of the global costs but only comprised 46% of the dementia cases. Remarkably, about 70% of the worldwide expenditure originated from just two regions—Western Europe and North America. These economic discrepancies are largely attributed to differences in per capita care costs. For instance, the average cost per patient was USD 868 in low-income countries, USD 3,109 in lower-middle-income countries, USD 6,827 in upper-middle-income regions, and USD 32,865 in high-income nations.^[8] In wealthier regions, informal caregiving (such as unpaid care provided by family members) and formal social care collectively account for 85% of the total costs, with direct medical expenses contributing only 15%. Conversely, in lower-income countries, informal care dominates the cost structure due to limited access to institutional healthcare services. However, shifting demographics and urbanization trends in many low- and middle-income countries (LMICs) are expected to challenge the traditional caregiving model, as fewer family members may be available to support elderly relatives in the coming decades. This was highlighted in the 2012 WHO report, “Dementia: A Public Health Priority,” which emphasized the need for urgent policy planning and resource allocation to manage the growing economic impact of dementia globally.^[8]

2. Pathophysiology of AD

Alzheimer’s disease (AD) is marked by progressive degeneration and death of neurons, predominantly affecting areas like the hippocampus, amygdala, entorhinal cortex, and association regions of the frontal, temporal, and parietal lobes. ^[3] Subcortical structures such as the cholinergic basal forebrain, noradrenergic locus coeruleus, and serotonergic dorsal raphe nuclei are also involved. ^[3] The accumulation of neurofibrillary tangles (NFTs) begins in the transentorhinal region and subsequently spreads to the entorhinal cortex, hippocampal CA1 area, and eventually the neocortical association areas. The severity of dementia correlates more closely with tangle density than with amyloid plaque numbers. Tau protein aggregation is strongly associated with both cognitive decline and brain atrophy, especially in the hippocampus. In AD, the loss of neurons and shrinkage in the temporofrontal cortex is accompanied by chronic inflammation, amyloid plaque formation, and the accumulation of abnormal protein aggregates. These pathological changes trigger increased infiltration of immune cells like macrophages and monocytes and activate microglial cells within the brain’s parenchyma, contributing to neuro-inflammation and disease progression. ^[9] The pathophysiological mechanisms underlying AD are complex and multifactorial, involving interactions among protein misfielding, oxidative stress, mitochondrial dysfunction, and neuroinflammation. ^[9] These abnormalities ultimately disrupt synaptic transmission and lead to widespread neuronal loss, driving the clinical symptoms observed in AD patients. A visual summary of the pathological mechanisms involved in AD is illustrated in Figure 1.

Figure 1 Hypothesis for pathophysiology of Alzheimer's disease.

3.1Amyloid-β and Tau Protein Hypothesis

One of the central pathological features of Alzheimer’s disease is the accumulation of amyloid-beta (Aβ) plaques, which form extracellular and contribute to the development of senile plaques (SP). Aβ peptides are typically produced through the enzymatic cleavage of amyloid precursor protein (APP) by β-secret’s and γ-secretes. Under normal conditions, these peptides remain soluble, but in AD, an imbalance between their production and clearance leads to the formation of toxic oligomers, protofibrils, and insoluble plaques. ^[10] The exact trigger for Aβ aggregation remains unclear, but factors such as peptide sequence, concentration, and environmental stability play a crucial role. Alongside Aβ deposition, abnormal phosphorylation of tau proteins results in the formation of neurofibrillary tangles (NFTs) within neurons. ^[10] These tangles disrupt microtubule stability and impair intracellular transport, contributing significantly to neurodegeneration and correlating strongly with cognitive decline.

3.2Oxidative stress hypothesis

Oxidative stress plays a major role in the progression of Alzheimer’s disease. The brain, despite accounting for only a small fraction of body weight, consumes a disproportionately high amount of oxygen—about 20% of the body's total—which makes it particularly vulnerable to oxidative damage. Reactive oxygen species (ROS) and reactive nitrogen species (RNS), although essential for certain cellular signaling processes, can become harmful when produced excessively. ^[10] Neurons are rich in polyunsaturated fatty acids, which are highly susceptible to lipid peroxidation by ROS. Furthermore, the relatively low levels of antioxidants like glutathione in neurons make them more prone to oxidative injury. This oxidative imbalance leads to DNA damage, protein modification, mitochondrial dysfunction, and eventually neuronal death. These cellular changes are believed to contribute significantly to the onset and progression of AD. ^[10]

3.3Metal ion hypothesis

Disturbances in metal ion balance, particularly involving transition metals like copper (Cu), iron (Fe), and zinc (Zn), have been linked to the development and progression of Alzheimer’s disease. In AD patients, abnormal accumulation of these metals has been observed in the brain. These elements can catalyze the production of reactive oxygen species through redox reactions, contributing to oxidative stress and neuronal damage. ^[12][13] Additionally, amyloid-beta (Aβ) peptides exhibit a strong affinity for binding with metal ions, and this interaction can promote peptide aggregation and plaque formation. Metal-binding compounds and chelators are currently being explored as potential therapeutic agents to restore metal homeostasis and limit Aβ toxicity. Dysregulation of metals such as manganese, aluminum, and copper is also implicated in other neurodegenerative disorders, further emphasizing the role of metal imbalance in brain pathology. ^[12][13]

3.4Cholinergic hypothesis

The cholinergic hypothesis is one of the earliest and most studied theories explaining cognitive decline in Alzheimer’s disease. It suggests that degeneration of cholinergic neurons in the basal forebrain leads to a significant reduction in acetylcholine (ACh) levels, a neurotransmitter vital for memory and learning. ^[14] This neurotransmitter deficit correlates with the severity of cognitive symptoms in AD. Although not the sole cause of the disease, cholinergic dysfunction plays a crucial role in symptom development. Consequently, medications such as acetyl cholinesterase inhibitors (e.g., donepezil, glutamine, and rivastigmine) have been developed to enhance cholinergic transmission by preventing ACh breakdown. Moreover, research indicates that alterations in cholinergic receptor binding in specific brain regions contribute to both cognitive and behavioral disturbances observed in patients.

These therapeutic strategies, while offering symptomatic relief, highlight the need for deeper understanding and multi-target approaches to address the complex nature of AD pathology. ^[14][15]

3. Clinical criteria

In 1984, the National Institute of Neurological and Communicative Disorders and Stroke, in collaboration with the Alzheimer’s Disease and Related Disorders Association (NINCDS-ADRDA), introduced diagnostic guidelines aimed at improving the accuracy and consistency of Alzheimer’s disease (AD) diagnosis in clinical and research settings. ^[56] Despite being a significant milestone, the specificity of AD diagnosis under this system remained under 90%, as confirmation of the disease was only possible through postmortem detection of amyloid plaques and neurofibrillary tangles. ^[22] Updated diagnostic frameworks now recognize that AD symptoms may extend beyond memory impairment to include deficits in language, executive function, and behavior. To improve diagnostic accuracy, biomarkers—such as cerebrospinal fluid (CSF) tau and amyloid-beta levels, or amyloid imaging via PET scans—are increasingly used to support clinical assessments. ^[23] Typically, the diagnostic process begins with collecting a comprehensive patient history, often supported by information from caregivers. This is followed by cognitive and mental status evaluations, physical and neurological examinations, and imaging tests such as CT or MRI scans to rule out other causes of cognitive decline, like tumors or strokes. Standard sensitivity and specificity for diagnosing probable AD using NINCDS-ADRDA criteria are around 81% and 73%, respectively. ^[16]

CSF analysis may reveal elevated levels of tau proteins or decreased amyloid-beta42 concentrations, both of which are associated with AD pathology. However, further studies are needed to refine these markers for early and reliable detection. The clinical course of AD typically progresses from mild cognitive impairment (MCI) to more severe forms of dementia. Neurological examination in the early stages may be unremarkable, while advanced stages involve behavioral changes, incontinence, immobility, and complete dependence. Neuropsychological testing remains essential for diagnosing AD and tracking disease progression, especially when considering the effects of therapy. While postmortem brain examination remains the gold standard for a definitive diagnosis, advancements in imaging and biochemical biomarkers are bringing clinicians closer to accurate and earlier diagnosis during a patient’s lifetime. ^[22][23]

4. Biomarkers for AD

Biomarkers play a pivotal role in the diagnosis, monitoring, and therapeutic development of Alzheimer’s disease (AD). These biological indicators not only enhance diagnostic accuracy but also offer valuable insights into disease progression and treatment efficacy. In drug development, biomarkers help in identifying the most promising therapeutic candidates and serve as evidence that a drug affects the underlying disease mechanisms. ^[24] Demonstrating both clinical benefit and modulation of pathological processes is essential for a therapy to be considered disease-modifying. The most commonly studied biomarkers for AD include cerebrospinal fluid (CSF) levels of amyloid-beta 1–42, total tau protein, and phosphorylated tau (p-tau 181). Reduced levels of amyloid-beta in CSF suggest its deposition in the brain, while elevated tau levels indicate neuronal injury and degeneration. These markers can be detected in preclinical stages, even before cognitive symptoms become apparent, allowing for earlier intervention. ^[23] Neuroimaging techniques such as positron emission tomography (PET) scans using amyloid or tau tracers and magnetic resonance imaging (MRI) to detect brain atrophy also serve as non-invasive tools to support diagnosis. Structural changes, particularly in the hippocampus and other medial temporal lobe structures, are indicative of disease progression. ^[23] As research advances, the search continues for novel, reliable, and easily accessible biomarkers—especially those detectable in blood or plasma. Such developments could greatly improve early diagnosis and monitoring while reducing the need for invasive procedures like lumbar punctures. Ultimately, integrating biomarkers into clinical practice enhances the ability to tailor treatment strategies and monitor their impact over time. ^[24] A visual summary of current AD biomarkers is shown in Figure 2A.

4.1Galanthamine

Galanthamine is a naturally occurring alkaloid primarily isolated from plants in the Amaryllidaceae family, including Leucojum, Narcissus, and Galanthus species. It has gained prominence as a therapeutic agent for Alzheimer’s disease due to its dual action as a reversible acetylcholinesterase inhibitor and an allosteric modulator of nicotinic acetylcholine receptors. ^[23] By inhibiting acetylcholinesterase, galanthamine increases the availability of acetylcholine at synaptic junctions, thereby enhancing cholinergic neurotransmission, which is typically deficient in AD patients. Its nicotinic receptor modulation may also contribute to neuroprotection and improved cognitive performance. Galanthamine has been shown to be well-tolerated during long-term therapy and has demonstrated cognitive benefits in clinical settings. It is commercially available under brand names like Nivalin and is approved for use in countries such as Austria and Germany—not only for AD but also for conditions like facial neuralgia. ^[26]

4.2Cannabinoids

The cannabinoid system has emerged as a promising target for Alzheimer's disease (AD) therapy. It comprises various cannabinoid receptors, primarily CB1 and CB2, which are distributed throughout the central nervous system and immune cells. These receptors play key roles in regulating processes such as inflammation, neuroprotection, and synaptic plasticity. ^{[25] [26]} Preclinical studies have shown that activation of CB1 and CB2 receptors using natural or synthetic cannabinoids—at non-psychoactive doses—can produce neuroprotective effects in models of Alzheimer’s disease. These benefits include a reduction in amyloid-beta (Aβ) toxicity, decreased tau hyperphosphorylation, suppression of neuroinflammation, and stimulation of the brain’s intrinsic repair mechanisms. ^[25] Cannabinoids may also improve behavioral symptoms commonly associated with AD, such as agitation and loss of appetite. While the therapeutic potential is compelling, further clinical research is needed to evaluate long-term efficacy, optimal dosing, and safety in human populations.

4.3Antibodies

Immunotherapy targeting amyloid-beta (Aβ) peptides has gained attention as a novel approach to Alzheimer’s disease treatment. The administration of intravenous immunoglobulin’s or specifically designed anti-Aβ antibodies may help reduce the accumulation and toxicity of Aβ in the brain. These antibodies work by facilitating the clearance of Aβ or preventing its aggregation into plaques. ^[28]

4.4MTDL

Due to the complex and multifactorial nature of Alzheimer’s disease, multi-target directed ligands (MTDLs) have emerged as a promising therapeutic strategy. These compounds are designed to interact with multiple pathological targets simultaneously, such as cholinesterase enzymes, amyloid formation, oxidative stress pathways, and tau aggregation. ^[29] Many MTDLs consist of hybrid structures that combine pharmacophores from existing drugs (like tacrine, donepezil, galantamine, or memantine) or natural products. Their multi-functional nature allows them to exert synergistic effects, potentially offering broader neuroprotective outcomes compared to single-target therapies. Continued development of MTDLs could lead to more effective treatments for AD.

4.5Metal complexes

Metal-based compounds, particularly those incorporating ruthenium and iridium, have shown promise in Alzheimer's disease research due to their ability to interact with amyloid-beta (Aβ) fibrils. These luminescent metal complexes exhibit unique electronic properties and long fluorescence lifetimes, which allow them to bind selectively to Aβ aggregates and undergo measurable spectral changes. This makes them useful not only for studying amyloid formation but also for potential diagnostic imaging. ^[30] In addition to their imaging potential, some metal complexes form stable interactions with Aβ peptides, which can influence aggregation behavior and potentially reduce toxicity. However, for these compounds to be developed into effective therapeutics, they must meet stringent pharmacological and safety criteria, especially regarding their stability, bioavailability, and ability to cross the blood-brain barrier.

4.6Poly phenolic compounds

Polyphenols, which are naturally occurring compounds in many plants, have attracted significant interest for their role in neuroprotection. These molecules exhibit antioxidant, anti-inflammatory, antimicrobial, and anti-amyloid properties, making them highly relevant in Alzheimer’s disease research ^[31] Studies in AD models have shown that polyphenols can enhance cognitive function and reduce neuropath logical changes, including Aβ aggregation and oxidative stress. Their ability to act through multiple biological pathways—such as inhibiting enzymes, scavenging free radicals, and modulating signaling pathways—supports their potential use in multi-targeted therapy.

4.7Stem cells

Stem cell-based therapies are being actively explored as an innovative avenue for treating Alzheimer’s disease. These therapies involve neuroprotection, neuronal regeneration, and modulation of neuroinflammation. Stem cells may also assist in reducing Aβ accumulation and promoting synaptic repair. ^[30]

5. Therapeutic targets for Alzheimer disease

Alzheimer’s disease (AD) is pathologically recognized by the presence of neurofibrillary tangles inside neurons and amyloid protein deposits forming plaques outside cells. Investigating the mechanisms that initiate and drive the progression of this condition in humans is challenging, primarily because most brain tissue samples are obtained from patients in the late stages of the disease. ^[3][36] As a result, researchers often turn to laboratory-based models and animal studies, where neuroinflammation stands out as a key characteristic of AD. One area of interest in AD research is the purinergic receptor family, which includes P1 adenosine and P2 nucleotide receptors responsive to molecules such as ATP and UTP. These receptors play important roles in both normal and pathological brain functions, including inflammation. This makes them potential contributors to the development of neurodegenerative disorders like Alzheimer’s. ^[3][31]

Figure 2 Biomarkers (A) and therapeutic targets (B) for management of Alzheimer's disease.

Various pathological features have been associated with AD, including the accumulation of beta-amyloid around nerve cells, abnormal modifications of tau protein, oxidative damage, imbalances in essential metals, and decreased levels of acetylcholine in the brain. ^[36] These hallmarks are considered important therapeutic targets. G-protein coupled receptors (GPCRs), the most widespread receptor type in the brain, are involved in intricate signaling pathways. ^[33] Targeting these pathways might offer new therapeutic options. Among the leading theories explaining AD is the amyloid beta hypothesis, which proposes that the accumulation of Aβ peptides triggers a cascade of events that ultimately result in cognitive decline and memory loss.^[36][31]

6. Pharmacotherapeautics of AD

Currently, four main medications are approved for the treatment of Alzheimer’s disease-related dementia. Three of these drugs—donepezil, rivastigmine, and glutamine—target the brain's cholinergic system. ^[44] They function primarily by inhibiting the enzyme acetyl cholinesterase, thereby increasing the availability of the neurotransmitter acetylcholine. Galantamine, in particular, also acts as an allosteric modulator at nicotinic acetylcholine receptors, enhancing its effectiveness. These medications are available in generic forms and are prescribed for varying stages of AD, from mild to severe. However, they are frequently initiated in the earlier stages of cognitive decline, especially when memory deficits become apparent during cognitive testing. Intervening time, the most recent drug approved in the U.S. for AD, works differently from the others. It targets the N-methyl-D-aspartate (NMDA) receptors involved in glutamate signaling. Excessive glutamate activity can lead to neuronal damage—a phenomenon believed to be linked to Alzheimer’s pathophysiology. ^[44][37] Memantine helps regulate this process and has shown the ability to reduce amyloid-beta levels by influencing the processing of amyloid precursor protein (APP). Research also suggests that combining memantine with a cholinesterase inhibitor such as donepezil may provide additional benefits for patients. ^[44][45] Clinical studies have shown that this combination therapy is generally safe and may offer improved outcomes compared to monotherapy. Despite the availability of these drugs, they primarily manage symptoms rather than addressing the root causes of the disease. Therefore, new therapeutic approaches are being explored to slow down or modify the progression of AD.

7. Non-pharmacological therapy of AD

Non-pharmacological treatments play a significant role in improving the quality of life for individuals with Alzheimer’s disease. These approaches aim to manage behavioral symptoms, support cognitive functions, and enhance daily living without relying on medication. ^[46][47]

7.1Sleep

One important aspect of non-drug therapy is addressing sleep disturbances, which are commonly seen in AD patients. Disruptions in sleep, especially in non-rapid eye movement (NREM) sleep, have been linked to the buildup of amyloid-β, a protein associated with the disease. Poor sleep can worsen memory and cognitive decline, while healthy sleep patterns may help reduce the risk or progression of AD. Because of this, sleep quality is now considered both a potential biomarker and a modifiable risk factor for Alzheimer’s. ^[46][47]

Another effective strategy involves physical and cognitive activities. Regular physical exercise—such as walking, aerobic workouts, resistance training, and stretching—can positively impact brain function by reducing the risk of cognitive impairment and supporting mental well-being. These activities help maintain brain plasticity, circulation, and neurotransmitter balance. Cognitive stimulation, such as memory exercises, puzzles, social interaction, and engaging in hobbies, can also slow cognitive decline. ^[48] These interventions are especially beneficial in the early to moderate stages of the disease. Environmental modifications and behavioral strategies are used to reduce confusion, agitation, and other behavioral symptoms. ^[49] Examples include simplifying tasks, using memory aids, minimizing distractions, and creating a safe, familiar environment. Although these therapies don’t cure Alzheimer’s, they are crucial for comprehensive care and can significantly enhance patient comfort, function, and independence when used alongside pharmacological treatments. ^[46][47]

8. Medicinal Plant Use in Alzheimer's Disease

Alzheimer’s disease (AD) is a gradually worsening neurological disorder that primarily impairs memory, thinking abilities, and behavior. With the global incidence of AD on the rise, there has been a growing demand for effective treatments. While existing pharmaceutical drugs like acetylcholinesterase inhibitors and NMDA receptor antagonists offer temporary relief, they do not halt or reverse the progression of the disease. ^[51][52] This limitation has driven increasing interest in alternative and complementary therapies, especially those derived from medicinal plants. Numerous herbal remedies have demonstrated promise in easing symptoms of cognitive decline, reducing the formation of amyloid plaques, and addressing other pathological features of AD. These plants are being explored not only for their therapeutic potential but also for their safety and affordability.