Historical Background of Alzheimer’s Disease (AD)

Alzheimer’s disease (AD) was first clinically and neuropathologically described in 1906 by Dr. Alois Alzheimer, a German psychiatrist and neuropathologist. He observed the case of Auguste Deter, a 51-year-old woman suffering from progressive memory loss, disorientation, hallucinations, and unpredictable behavior. Following her death, Dr. Alzheimer examined her brain and reported the presence of two hallmark features: extracellular amyloid plaques and intracellular neurofibrillary tangles, which are now considered the pathological hallmarks of AD[1].

His findings were first presented at the 37th Meeting of South-West German Psychiatrists in Tübingen and later published in 1907. The term “Alzheimer’s disease” was formally coined by Dr. Emil Kraepelin in 1910 in the 8th edition of his Handbuch der Psychiatrie (Handbook of Psychiatry), in honor of Alois Alzheimer’s work.

For several decades, AD was considered a rare disease, primarily affecting middle-aged individuals with early-onset symptoms. However, during the latter half of the 20th century, advancements in medical science and increasing life expectancy revealed that AD was, in fact, the leading cause of dementia among the elderly. Epidemiological studies demonstrated that its prevalence significantly increases with age, particularly after 65 years[2].

Today, AD is recognized as a major public health concern. According to the World Health Organization (WHO) and Alzheimer’s Disease International (ADI), over 55 million people world wide are currently living with dementia, with AD accounting for 60–70% of these cases. This number is projected to rise to 78 million by 2030and 139 million by 2050, driven by aging populations, especially in low- and middle- income countries[10].

The increasing global burden of AD has led to the declaration of dementia as a public health priority by the WHO, sparking international efforts in early detection, treatment development, and caregiver support. Despite more than a century of research, no definitive cure exists for AD, underscoring the ongoing need for novel therapeutic strategies, including multi-targeted plant-based interventions explored in this review[3].

Alzheimer’s disease (AD) is a heterogeneous condition that can be broadly classified based on the age of onset, genetic involvement, and clinical progression. Understanding these subtypes is essential for improving diagnosis, treatment strategies, and the development of personalized interventions[4].

Early-onset AD occurs in individuals younger than 65 years of age and accounts for approximately 5–10% of all AD cases. It is often more aggressive in progression and may present with atypical symptoms, such as language impairment, visuospatial deficits, or executive dysfunction, rather than just memory loss[20].

Genetic basis: EOAD is frequently associated with autosomal dominant mutations in the following genes:

These mutations lead to abnormal processing of the amyloid precursor protein, resulting in excessive formation of amyloid-beta (Aβ42) peptides, which aggregate into neurotoxic plaques.

Familial Alzheimer’s Disease (FAD): A subset of EOAD with a strong hereditary pattern. Inheritance is typically autosomal dominant, and affected individuals often have a family history of similar cases across generations.

EOAD poses significant challenges as it affects individuals during their most productive years, leading to early loss of employment, independence, and increased caregiver burden.

Late-onset AD, also known as sporadic AD, occurs after the age of 65 and represents 90–95% of AD cases. It is a multifactorial disorder influenced by complex interactions between genetic, environmental, lifestyle, and aging-related factors.

While EOAD and LOAD are the major types, there are atypical clinical presentations or subtypes of AD that deviate from the typical amnestic profile:

These variants may be misdiagnosed as other forms of dementia (e.g., frontotemporal dementia) and require careful differential diagnosis using neuroimaging and biomarker analysis[6].

Alzheimer’s disease (AD) is characterized by progressive neurodegeneration that leads to cognitive decline, memory loss, and behavioral dysfunction. The underlying pathophysiology involves several interconnected processes:

Amyloid-β Plaque Formation

Neurofibrillary Tangles (NFTs)

Synaptic Dysfunction and Neurodegeneration

Neuroinflammation

Oxidative Stress

Cholinergic Hypothesis

Glutamatergic Excitotoxicity

Vascular Dysfunction

Given the complexity of AD pathophysiology and the limited efficacy of monotherapeutic drugs, the role of phytotherapy is gaining momentum. Medicinal plants contain diverse bioactive compounds capable of targeting multiple disease pathways simultaneously, often with fewer side effects. Traditional systems like Ayurveda, Siddha, and Traditional Chinese Medicine have long recognized the neuroprotective potential of various herbs[8].

Botanical Classification

Botanical characteristics

The Butterfly Pea Flower (Clitoria ternatea) is a perennial climbing vine with pinnate leaves and vibrant blue, purple, or white flowers. It produces oblong pods containing 6–10 seeds and has a deep taproot with nitrogen-fixing properties. Thriving in tropical climates, it prefers well-drained soils and full sunlight. Propagated by seeds or cuttings, it is valued for its ornamental appeal, soil enrichment, and natural dye properties[9].

Chemical Constituents and Bioactive Components of Clitoria ternatea

Pharmacological Activity

Mechanism of Action in Treating Alzheimer’s disease

Clitoria ternatea, commonly known as Aparajita or Butterfly Pea, has been traditionally used in Ayurvedic medicine as a brain tonic. Recent pharmacological studies highlight its multimodal neuroprotective mechanisms that make it a promising candidate in Alzheimer's disease (AD) therapy[10].

1. Acetylcholinesterase (AChE) Inhibition

The ethanolic and aqueous extracts of Clitoria ternatea exhibit significant AChE inhibitory activity, helping to increase acetylcholine levels in the brain. This compensates for the cholinergic deficit observed in AD, thereby improving memory and cognition.

2. Antioxidant Activity

Rich in anthocyanins, flavonoids, and other polyphenolic compounds, the plant effectively scavenges free radicals. This combats oxidative stress, a key contributor to neuronal damage and progression of AD.

3. Anti-inflammatory Effects

The bioactive components of C. ternatea suppress the release of pro-inflammatory cytokines (e.g., TNF-α, IL-1β) and inhibit microglial activation, thus reducing neuroinflammation, a major pathological feature of Alzheimer’s disease.

4. Neurogenesis and Synaptic Plasticity

Studies indicate that the extract enhances expression of brain-derived neurotrophic factor (BDNF) and other synaptogenic proteins, which promote neuronal survival, neurogenesis, and synaptic remodeling, essential for learning and memory.

5. Anti-amyloidogenic Effect

Preliminary studies suggest C. ternatea may also inhibit the aggregation of β-amyloid peptides, which are central to the formation of amyloid plaques in AD brains. Though more research is needed, this suggests potential disease-modifying effects.

6. Modulation of MAO Enzymes

Some extracts have demonstrated monoamine oxidase (MAO) inhibitory activity, which could improve neurotransmitter balance and mood-related symptoms commonly associated with Alzheimer’s.

Preclinical Evidence

Clinical Evidence

Toxicity & Side Effects

Standardized Dose

Evidence Gaps

Botanical Classification

Botanical characteristics

The plant Bacopa monnieri (L.) is semisucculent and creeping. Usually rectangular or spatulate, Bacopa leaves are thick and sessile, and the flowers are either light purple or white. Traditional medical practitioners have been using bacopa for thousands of years. The effects of bacopa on the central nervous system are mentioned explicitly in a number of ancient Ayurvedic writings, such as the Charaka Samhita (2500 B.C.) and the Sushruta Samhita (2300 B.C.)[11].

Chemical constituents of Bacopa monnieri and bioactive components

Mechanism of Action in Treating Alzheimer’s disease

Bacopa monnieri (Brahmi) exerts neuroprotective effects through multiple pathways:

Preclinical Evidence

Clinical Evidence

Toxicity & Side Effects

Drug - Herb Interactions

Standardized Dose 

Evidence Gaps

Botanical Classification

Botanical Characteristics

Short, erect shrub with greyish hairy shrub, Oval dull green leaves, Greenish yellow bisexual flowers Orange red berries in a papery covering, disc-shaped Fleshy medicinal roots[13].

Chemical constituents of Withania somnifera and bioactive components

W. somnifera contains chemical compounds that include alkaloids (isopelletierine, anaferine, cuseohygrine, anahygrine, etc.), steroidal lactones (withanolides, withaferins), saponins, sitoindosides and acylsterylglucosides. Major bioactive ingredients of W. somnifera consists of withanolides, withaferin A, withanolide A, withanolide D and Anaferin[14].

Mechanism of Action in Treating Alzheimer’s disease

Withania somnifera (Ashwagandha) supports brain health and counters Alzheimer’s disease through multiple pathways:

These mechanisms make Withania somnifera a potent herbal candidate for the prevention and management of Alzheimer’s disease.

Preclinical Evidence

Clinical Evidence

Toxicity & Side Effects

Drug–Herb Interactions

Standardized Dose

Evidence Gaps

Botanical Classification

Botanical characteristics

Ginkgo biloba is a deciduous tree with distinctive fan-shaped leaves that turn golden yellow in autumn. It has a tall, upright growth habit, reaching heights of up to 30–40 meters. The tree produces separate male and female reproductive structures, with female trees bearing fleshy, foul-smelling seeds. Ginkgo is highly resistant to pollution, pests, and diseases, making it a long-living and resilient species. It thrives in well-drained soils and temperate climates.

Chemical Constituents and Bioactive Components of Ginkgo Biloba

Pharmacological Activities of Ginkgo Biloba

Mechanism of Action in Treating Alzheimer’s disease

Ginkgo biloba, a traditional herbal remedy, exerts multiple neuroprotective effects through its rich phytochemical constituents such as flavonoids (e.g., quercetin, kaempferol) and terpenoids (e.g., ginkgolides, bilobalide). Its mechanism in Alzheimer’s disease (AD) therapy is multifactorial and involves the following key pathways[16].

Preclinical Evidence

Clinical Evidence

Toxicity & Side Effects

Drug Herb Interactions

Intrinsic risk of strong interaction with:

Standardized Dose

Evidence Gaps

Botanical Classification

Botanical Characteristics                    

Centella asiatica is a small, herbaceous plant with fan-shaped green leaves and small, pink or white flowers. It commonly grows in moist, swampy areas and spreads horizontally via stolons. The plant is prized for its adaptogenic and neuroregenerative properties in traditional Ayurvedic and Chinese medicine[17].

Chemical Constituents and Bioactive Components

Pharmacological Activities

Mechanism of Action in Treating Alzheimer’s Disease

Preclinical Evidence

Clinical Evidence

Toxicity & Side Effects

Drug - Herb Interactions

Standardized Dose

Evidence Gaps

Alzheimer disease is one of the most intricate and problematic neurodegenerative disorders on a worldwide scale, which is progressive, marked by impaired cognitive functions and multi-factorial pathological processes, such as oxidative stress, aggregation of amyloid-β, hyperphosphorylation of tau, neuroinflammatory processes, mitochondrial dysfunction, and cholinergic disabilities. Although there has been a great leap in the biology of various diseases, the available pharmacological treatment options are associated with minimal efficacy and may have side effects due to inadequate understanding and characteristics of symptoms.

The reviewed study is an overview of the neuroprotective effect of the chosen traditional medicinal plants: Clitoria ternatea, Bacopa monnieri, Withania somnifera, Ginkgo biloba, and Centella asiatica, which are multi-target proteins in the pathogenesis of Alzheimer disease. They are reported to have acetylcholinesterase, antioxidant and anti-inflammatory, amyloid-2 pathway modulation, synaptic relying plasticity, and neurotrophic support. These pharmacological actions are provided by bioactive compounds that include bacosides, withanolides, ginkgolides, flavonoids, and triterpenoid saponins.

It should however be noted that much of existing evidence is still preclinical and large burdens of randomized controlled trials in clinically diagnosed Alzheimer patients have not been done on a large scale and over extended period of time. Further, differences in extract formulations, absence of overall standardization, inadequate pharmacokinetic and evaluation of safety profiles and drug-herb interactions are major clinical translation problems.

Further studies must be done on rigorously designed clinical trials, standardized phytochemical characterization, dose-optimization, long-term safety assessment and mechanistic validation. As much as herbal neurotherapeutics have a promising future as complementary approaches, the evidence-based analysis of development on this disease has to define their role in daily clinical practices.