INTRODUCTION:

Alzheimer’s disease (AD) is a neurodegenerative disease. In 1906, Alois Alzheimer published the first description of AD in reference to a recently reduced patient who had been under his care since 1901¹. It is the primary cause of dementia and is rapidly rising to the top of the list of our centuries most costly, deadly, and debilitating illnesses². In addition to a significant buildup of amyloid-beta (Ab) plaques and neurofibril tangles (NFTs) in their brains, patients with AD also have a number of other pathological conditions, including neuroinflammation, synaptic dysfunction, mitochondrial and bioenergetic abnormalities, and vascular abnormalities. All of these mechanisms could eventually cause neurons to die³. The main clinical characteristic of AD is amnestic cognitive impairment. Anxiety, despair, social disengagement, and irregular sleep habits are some of the initial signs. As the illness worsens, symptoms include significant memory loss, neuropsychiatric symptoms such delusions and hallucinations, and in its latter stages, more severe emotional and behavioural problems. Furthermore, different degrees of dysfunction in visual-spatial language, executive processes, behaviour, or motor skills may be present in certain people with non-amnestic cognitive impairment⁴.

Therapies:

1. Cholinergic Hypothesis:

The cholinergic hypothesis highlights the crucial role of acetylcholine (ACh) in cognitive functions, suggesting decreased activity of key enzymes like choline acetyltransferase and impaired muscarinic receptor function, particularly subtype M1, in Alzheimer's disease (AD). AChE inhibitors (AChEIs), such as rivastigmine, galantamine, and donepezil, were the first drugs approved for AD treatment. Despite interest in M1 agonists, clinical trials for compounds like arecoline and its derivatives were halted due to side effects and lack of selectivity. Research is now focusing on positive allosteric modulators (PAMs) of M1 receptors, which could reduce peripheral side effects. Meanwhile, nicotinic receptor agonists like encenicline and ABT-126 show promise in improving cognitive functions, with ongoing clinical trials indicating good tolerance and efficacy. However, some nicotinic compounds have been discontinued due to adverse effects.

2. Amyloid Cascade Hypothesis:

The amyloid cascade hypothesis focuses on the formation of toxic amyloid beta (Aβ) plaques, primarily Aβ1-40 and the more aggregation-prone Aβ1-42, linked to nerve cell death in Alzheimer’s disease (AD). However, the relationship between plaque quantity and dementia severity remains unclear, suggesting that soluble Aβ forms may play a more significant role in pathology. Despite extensive research, no Aβ-targeting drugs have been approved, although several are in advanced clinical trials. Notable among these are β-secretase inhibitors, like thalidomide and minocycline, and PPAR-γ modulators, such as pioglitazone, which is being evaluated for its ability to cross the blood-brain barrier. Furthermore, semagacestat and other γ-secretase inhibitors have demonstrated limited efficacy and raised safety concerns. Other strategies use substances like tramiprosate and epigallocatechin gallate, which are also being studied in clinical trials, to stop Aβ aggregation or to promote α-secretase for neuroprotective benefits.

3. Hypothesis of Hyperphosphorylated Tau Protein:

Tau protein stabilizes microtubules in nerve cells and is regulated by phosphorylation. Cognitive loss is associated with neurodegenerative illnesses that cause tau to become hyperphosphorylated and aggregate. Disaggregating tau filaments or preventing hyperphosphorylation are examples of possible treatments. Lithium and valproic acid, both GSK-3β inhibitors (glycogen synthase kinase-3 beta), have been tested; lithium was halted due to mixed results, while valproic acid showed no cognitive improvement compared to placebo. Tideglusib also failed to improve cognition in trials. Methylene blue can dissolve tau filaments in vitro but did not meet cognitive improvement criteria in Phase II trials, with its derivative in Phase III.

4. Immunotherapy in the Treatment of AD:

Immunotherapy has emerged as a possible treatment for Alzheimer's disease (AD) because it targets the accumulation of Aβ. While active immunization experiments with non-aggregated Aβ 1-40 encountered severe adverse effects, passive immunization with monoclonal antibodies demonstrated a drop in Aβ but no increase in cognitive performance. Since Aβ load rises before clinical signs, early management may be essential. On the other hand, since neurofibrillary tangles are linked to cognitive loss, addressing tau pathology might produce better outcomes. Beginning in 2013, the AADVac1 study, which targets tau peptides, demonstrated safety in preliminary human trials. Nevertheless, even while animal models are essential for comprehending the pathophysiology of AD and testing new treatments, their effectiveness may not always translate to clinical efficacy, necessitating additional research^5,6.

Herbal remedies have been studied as supplemental methods for Alzheimer's disease management in addition to immunotherapeutic and pharmaceutical therapies. In preclinical models, compounds from plants like ginkgo biloba, bacopa monnieri, and curcumin have demonstrated antioxidant, anti-inflammatory, and neuroprotective properties, providing a viable substitute for treating symptoms and altering illness⁷.

Epidemiology:

1. Prevalence and Incidence:

Furthermore, the prevalence of AD rises sharply with age, peaking at 65 years of age. The prevalence of dementia, especially Alzheimer disease, rises by more than 15 times between the ages of 60 and 85⁸. Dementia affects over 50 million people globally, and as the population ages, this number is predicted to triple by 2050, increasing the risk of disability, the burden of illness, and the cost of medical care⁹. In order to manage this growing worldwide burden, early diagnosis using cutting-edge methods like brain imaging may be essential¹⁰. Currently, there are about 44 million people with AD; however, as the number of elderly people increases every year, this number could increase to 65.7 million in 2030 and 135 million in 2050.

2. Demographics:

Age: AD is primarily a disease of older adults, with risk increasing substantially after age 65.

Gender: Women are disproportionately affected, with about two-thirds of AD patients being female, possibly due to their longer life expectancy.

Race and Ethnicity: Studies suggest that African Americans and Hispanics may have higher rates of AD compared to Caucasian populations, influenced by social determinants and health disparities.

3. Risk Factors:

A history of diabetes, high blood pressure, smoking, obesity, and dyslipidaemia are risk factors. Interestingly, cerebrovascular illness—which includes large cortical infarcts, a single strategically placed infarct, many minor infarcts, cerebral haemorrhage, cortical changes due to hypoperfusion, white matter, and vasculopathies—occurs before dementia in general. 2689 patients with clinically confirmed MCI (mild cognitive impairment), primarily aMCI, were included in a meta-analysis of 24 studies (up to 2018) to examine the potential of neuropsychological testing to predict the onset of AD dementia. An average of 37% of these patients acquired AD dementia. AD is a complex neurological illness that is impacted by lifestyle, genetics, and aging¹¹.

4. Trends:

As the population ages, more people are predicted to have AD, especially in low- and middle-income nations. Understanding the fundamental processes of AD and determining viable prevention strategies are the main goals of ongoing research.

5. Public Health Implications:

Increased awareness and education about risk factors are crucial for prevention. Strategies to support caregivers and healthcare systems are necessary to manage the growing burden of AD.

MECHANISM OF ALZHEIMER’S DISEASE:

Many theories have been put up to explain the pathophysiology of AD, but a single, cohesive hypothesis has yet to be developed, most likely as a result of the disease's complexity. There are two primary types of ADs: sporadic forms (which make up more than 95%) and familial forms (which make up 1-5% of instances). Autosomal dominant genetic mutations in the amyloid precursor protein (APP), presenilin 1 (PS1), and presenilin 2 (PS2) genes are the main characteristic of familial AD (FAD), which usually appears between the ages of 30 and 65 and advances quickly. On the other hand, sporadic AD (SAD), sometimes referred to as late-onset AD, typically appears after the age of 65 and is impacted by a number of comorbidities, environmental factors, numerous genetic risk loci linked to SAD have been found by genome-wide association studies (GWAS) and genome-wide meta-analyses, which have implicated pathways in immune response, lipid metabolism, Aβ plaque. Non-genetic factors, including as lifestyle choices, behavioural factors, environmental factors, and conditions linked to AD (comorbidities and sequelae), may raise the risk of developing AD. It is difficult to pinpoint a direct cause of clinical pathology in AD since they may do this via modifying genetic susceptibility and metabolic pathways. Biochemical alterations like oxidative damage and neurotransmitter imbalance are part of the course of AD¹². Additionally, a variety of clinical symptoms may be present in both typical and atypical AD subtypes. Third, there are additional pathological features of AD, including Aβ plaques, NFTs, neuroinflammation, and synaptic and neuronal loss. Generally speaking, a range of causes, clinical manifestations, and neuropathological traits contribute to the variability of AD. Consequently, developing a comprehensive theoretical framework that links the molecular mechanisms, genetic foundations, and clinical manifestations of AD is exceedingly challenging. The limitations in existing research further hinder a comprehensive understanding of the pathophysiology of AD. Furthermore, the high failure rate of clinical studies—which could be brought on by the existence of several ideas—makes it difficult to adequately validate theories¹³.

Pathophysiology of Alzheimer’s Disease:

Figure 1: Pathophysiology of Alzheimer’s Disease¹⁴

1. Hyperphosphorylated tau protein:

Figure 2: Brain changes in Alzheimer disease

Microtubule stimulation, tubulin polymerization, microtubule stabilization, and intracellular organelle transport are among the primary physiological roles of tau, a microtubule-associated protein. The loss of cytoskeletal microtubules and tubulin-related proteins might result from abnormal filaments of hyperphosphorylated tau that eventually tangle to form paired helical filaments (PHF) and accumulate in the perinuclear cytoplasm, axons, and dendrites. The primary constituent of NFT (neurofibrillary tangle) in AD patients' brains, this protein loses its role in microtubule formation and stabilization¹⁵.

2. Oxidative stress hypothesis:

Reactive Oxygen Species (ROS) and Responsive Nitrogen Species (RNS) are created in numerous typical and anomalous forms in people, they play double part as both have advantageous capacities in cellular flagging pathways and venomous forms that can lead to harm of cellular structures (counting cell film, lipid, protein, and DNA).The tall oxygen utilization of the brain, which utilizes 20% more oxygen than other mitochondrial respiratory tissues, implies that the brain is more powerless to oxidative stretch. The neuron is the essential useful unit of the brain, which contains an expansive number of polyunsaturated greasy acids. It can associate with ROS, driving to the lipid peroxidation response and atomic apoptosis, in addition, less glutathione in neurons is additionally one of the causes of oxidative push damage¹⁶.

3. Metal ion hypothesis:

Metal dyshomeostasis is included within the movement and pathogenesis of maladies, counting neurodegenerative diseases and cancer¹⁷. It is well recognized that ionosphere and metal chelators can assist regulate the body's transition metal balance, and some of these compounds are undergoing clinical testing. There are other medications that can help regulate the body's transition metal balance besides metal-binding ones¹⁸. There is currently evidence of shifts in the redox transition metal equilibrium, primarily with regard to copper (Cu), iron (Fe), and other trace metals. Other neurological diseases involve copper, manganese, aluminium, and zinc¹⁹.

4. Cholinergic hypothesis:

The impact of the APOE gene type on how well acetyl-cholinesterase inhibitors (AChEIs) help patients with Alzheimer’s disease.AchEI drugs are the main treatment for Alzheimer's disease (AD), and a person's APOE gene type is the most important factor linked to the disease.The small impact of APOE is looked at in relation to the "Cholinergic Hypothesis" of Alzheimer's Disease (AD), which started in 1976.This is due to the fact that AD does not primarily target cholinergic neurons. Mood swings and other mental health problems are associated with mild to moderate Alzheimer's disease because of reduced cholinergic receptor binding in specific brain regions. A slower rate of thought may be associated with fewer receptors in healthy elderly adults. Investigating the binding of cholinergic receptors in living things may reveal links to significant alterations in the brain that occur with age and Alzheimer's disease. This may result in novel molecular treatments for various disorders. A decrease in brain function is linked to a significant loss of certain nerve cells in the front part of the brain and a drop in the chemical called for more than 20 years, drugs like cholinesterase inhibitors (ChEIs) and donepezil have been used to help manage the symptoms of Alzheimer's disease by stabilizing acetylcholine levels²⁰.

5. β -Amyloid (A β) Deposition Theory:

The amyloid hypothesis is still the most well-known and proven mechanism for AD, despite the fact that several other theories have been put up recently. Amyloidosis is a complicated clinical and pathological condition where the body's cells and organs accumulate amyloid protein, which finally forms amyloid plaques and gradually causes organ dysfunction. Amyloid proteins are the building blocks of amyloid plaques. The primary factor that contributes significantly to the pathophysiology of AD and is thought to be the primary cause is amyloid beta peptide (A β)²¹. A single transmembrane protein that is highly expressed in the brain and produced by brain neurons, blood vessels, blood cells, and a small number of astrocytes, amyloid precursor protein (APP) is concentrated in neuronal synapses. Two hydrolysates, extracellular β secretase and intracellular γ, then break down APP. They form the Aβ after their interaction, and this process is illustrated in Figure 3.

Figure 3: Aβ is released from APP by β-secretase and y-secretase

APP mutation can lead to increase Aβ synthesis. Monomeric A β fragments are soluble substances that cause metabolic problems when an imbalance between synthesis and clearance, which leads to protein misfolding, aggregation and extracellular accumulation, and ultimately the formation of amyloid plaque. As shown in Figure 4. At the same time, the high concentration of A β may induce APP synthesis and trigger amyloidosis in peripheral neurons. Partial A β misfolds and accumulates in the brain to form hydrophobic extracellular oligomers presented in plaques and fibres, and β plaques initially develop in the basal, temporal, and orbitofrontal neocortical regions of the brain, later to the entire neocortex, hippocampus, amygdala, diencephalon, and basal ganglia. In critical cases, A β plaques can also be found in the midbrain, lower brainstem, and cerebellar cortex. As a consequence of this process, the neurons and synapses involved in memory processes, learning, and other cognitive functions are damaged, leading to the typical cognitive decline²².

Figure 4: Aβ deposition process²³

Immunotherapy:

Immunotherapy has emerged as a potential treatment strategy for a number of diseases, such as cancer, autoimmune disorders, and more recently, neurodegenerative diseases. The idea of immunotherapy was developed when scientists discovered the immune system's natural ability to combat tumours in the 19th century²⁴. Since then, sophisticated contemporary technologies that may specifically target and modify immune responses have been created. The two main types of immunotherapies are passive and active. Active immunotherapy stimulates the immune system by administering antigenic peptides, such as vaccines or nonspecific immunomodulators. On the other hand, passive immunotherapy involves the use of immunologically active substances like adaptive T cells or monoclonal antibodies (mAbs)²⁵. The use of immunotherapy to treat neurodegenerative diseases has advanced significantly in recent years. Because of its clinical effectiveness in oncology, researchers are now looking into similar approaches for long-term neurological conditions including Alzheimer's disease (AD)²⁶. Treatment approaches for Alzheimer's disease are now using immunotherapeutic principles, which have been studied extensively in oncology²⁷. AD is the most prevalent chronic neurological disease that causes dementia globally. According to the Global Burden of Disease (GBD), dementia prevalence and associated mortality are concerningly increasing worldwide²⁸. Research on polyherbal formulations has indicated possible adjunctive roles by demonstrating neuroprotective efficacy in models of AD caused by colchicine²⁹.

Active and Passive Immunotherapy:

Figure 5: Mechanism of active and passive immunotherapy in AD. At the left, active immunotherapy involves vaccines with fragments of Aβ or tau, which are processed by APCs (antigen-presenting cells) and presented to CD4+ T cells. These T cells activate B cells to produce specific antibodies against Aβ and tau, facilitating their clearance from the brain and reducing neuroinflammation and neurodegeneration. On the right, passive immunotherapy involves the administration of monoclonal antibodies that directly target Aβ and tau. These antibodies bind to the pathological proteins, triggering structural alterations and promoting their degradation or phagocytic clearance by microphase. Both approaches aim to reduce the accumulation of Aβ plaques and tau tangles, there by mitigating the neurotoxic effects and slowing the progression of AD³⁰.

1. Pharmacology and Efficacy of Donepezil Pharmacology: First approved by the FDA in 1996 for mild to moderate AD, donepezil (marketed by Eisai Pharmaceuticals and Pfizer, Inc.) was later expanded to include severe AD in 2006. Donepezil comes in standard 5mg and 10mg instant release pills that can be taken with or without food. Based on the findings of a multinational RCT involving 1371 patients, a formulation of donepezil in the form of 23mg sustained-release (SR) tablets was recently approved. In this trial, mild to moderate AD patients' cognitive function increased when they received 23mg/day SR donepezil instead of the traditional 10mg/day immediate release version. This second-generation ChEI hydrolyses in place of acetylcholine after binding to acetylcholinesterase in a reversible and non-competitive manner. Unlike butyrylcholinesterase, which is more prevalent in the periphery than in the central nervous system, it is strong and very selective for acetylcholinesterase. Because of its intrinsically long plasma half-life and low peripheral anticholinesterase activity, donepezil can be used once daily. There is evidence that donepezil reduces Aβ synthesis and Aβ-induced toxicity, enhances expression of nicotinic receptors, inhibits apoptotic cell death, and shields cortical neurons from glutamate toxicity⁶⁵.

Efficacy: According to a meta-analysis by Birks et al., donepezil (5–10mg/day) considerably enhanced cognitive function in Alzheimer's patients when compared to a placebo, showing improvements across a range of cognitive tests. Global results showed few differences; however, Ritchie et al. observed a dosage-dependent effect favouring the 10mg dose. While the contentious AD2000 trial revealed methodological flaws and failed to show appreciable improvements in primary outcomes, the American College of Physicians validated donepezil's cognitive and global advantages. All things considered; donepezil slightly improves cognitive performance but has erratic behavioural consequences that call for more research.

2. Pharmacology and Efficacy of Rivastigmine Pharmacology: Every nation in the US, Canada, and the EU has approved rivastigmine. Rivastigmine's inhibitory impact on acetylcholinesterase is known as "pseudo-irreversible" since it continues to work even after the drug's plasma levels have dropped. After the acetyl moiety of rivastigmine dissociates by hydrolysis, the carbamoyl moiety stays attached to its substrate, inactivating the acetylcholinesterase enzyme for longer than twenty-four hours. Although rivastigmine is known to block butyrylcholinesterase, it also has selectivity for the most common types of acetylcholinesterase. There is some consensus that the development of AD is linked to alterations in butyrylcholinesterase. According to one study, in affected brain regions, butyrylcholinesterase concentration rises while acetylcholinesterase concentration falls. It has also been demonstrated that the rate of cognitive decline is correlated with the activity of this enzyme in the temporal cortex. Rivastigmine may also have an impact on cerebral blood flow, an established risk factor for AD. Since rivastigmine is not extensively bound to plasma proteins or processed by cytochrome P450s, no significant drug-drug interactions are expected. The usual dosage for this oral formulation is 1–4mg/day or 6–12mg/day, given twice daily with food. In 2007, the FDA approved a once-daily transdermal patch, which may help older patients who take several medications every day comply with their treatment plans⁶⁶.

Efficacy: According to a Cochrane analysis, at 26 weeks, high-dose rivastigmine (6–12mg daily) increased function by 2.2 points on the Progressive Deterioration Scale and cognition by 2 points on the ADAS-Cog. Although they had less of an effect on function, low dosages (1-4mg) demonstrated notable cognitive gains. Global gains were observed with both doses, especially on the CIBIC-Plus; however, benefits on the GDS required high doses. On a number of metrics, the IDEAL trial found no distinction between oral and transdermal rivastigmine. Overall, rivastigmine exhibits a dose-dependent impact that mostly improves global and cognitive outcomes; however, there are no appreciable behavioural changes and inconsistent functional results.

3. Pharmacology and Efficacy of GalantaminePharmacology: The FDA initially authorized galantamine, a tertiary alkaloid, in 2001. Janssen, Inc. is the company that primarily markets it. Additionally, it is accepted in the majority of EU nations. Furthermore, galantamine allosterically regulates nicotinic acetylcholine receptors to enhance nicotinic transmission, another pathway linked to the pathophysiology of neurodegenerative illnesses, in addition to acting as a reversible and competitive cholinesterase inhibitor. Its modest volume of distribution, low plasma protein binding (18%), low plasma clearance rate (about 300mL/min), and relatively good bioavailability are also noteworthy. Galantamine is believed to be glucuronidase by cytochrome P450 enzymes, primarily CYP2D6 and CYP3A4, which aid in its excretion through urine. Galantamine was first offered as an immediate-release formulation that was taken twice daily. There is currently a once-daily extended-release capsule formulation that can be taken with or without food and exhibits a similar adverse event profile to the immediate release form⁶⁷.

Efficacy: Although no significant dose-dependent effects were found, meta-analyses of galantamine, which included 6–10 randomized controlled trials, revealed modest improvements in overall status (CIBIC-Plus, CGI) and cognitive performance (ADAS-Cog) across dosages of 8–36mg. With the exception of 8 mg, there was a greater chance of improvement or stabilization on global measures, and there were notable cognitive advantages, especially at 6 months. The overall impact was modest and differed throughout trials, despite statistically significant minor effect sizes in the cognitive, global, functional (ADCS-ADL, DAD), and behavioural (NPI) domains.

4. Pharmacology and Efficacy of Cerebrolysin:

Pharmacology: Cerebrolysin, another noncholinergic therapy, is authorized in a number of European and Asian nations for AD and other dementias. This medication is made from purified brain proteins that have been enzymatically broken down to produce single amino acids and active tiny peptides that are able to pass through the blood-brain barrier. It has similar neurotrophic effects to endogenous nerve growth factors (NGF), which may contribute to the pathophysiology of AD. Specifically, it supports and protects neuronal function. in addition to maintaining brain structure and function in stressful and promoting environments.

Efficacy: A meta-analysis of six double-blind, placebo-controlled RCTs with 772 participants examined the effects of cerebrolysin in mild to severe Alzheimer's disease (AD). There were noteworthy improvements in Clinical Global Impression of Change (CGIC) ratings and a slight effect on the MMSE, indicating possible benefits in global change and cognition, but no significant effects were seen on cognitive measures such as the ADAS-cog or daily living scales. The results are, however, constrained by the small sample sizes of the included trials, which range from 53 to 178 people. Cerebrolysin's effectiveness was also demonstrated via active-comparator experiments. Cerebrolysin, donepezil, and a combination treatment were examined in one trial; while there were no significant differences in cognitive or behavioural traits between the groups, there were gains in overall function. The greatest cognitive improvement was obtained with combo therapy. Furthermore, a smaller study that contrasted Cerebrolysin and rivastigmine found that both were beneficial, with the Cerebrolysin group experiencing greater effects. In conclusion, even if early evidence favours the use of cerebrolysin in mild to moderate AD, more extensive, placebo-controlled research is required to confirm its effectiveness and safety as well as to evaluate its acceptability in comparison to oral drugs⁶⁸.

CONCLUSION:

To conclusion, acetylcholinesterase immunotherapy is a potential new strategy in the complex field of treating Alzheimer's disease. Cholinesterase inhibition is the mainstay of traditional medicines, although immunotherapy, a newer approach, offers a more focused mechanism that targets the disease's underlying pathophysiological processes. This strategy not only lessens the breakdown of acetylcholine, a neurotransmitter essential for cognitive function, but it also may lessen neuroinflammation and support neuronal health by strengthening the body's immunological response to acetylcholinesterase. According to promising findings from clinical trials, acetylcholinesterase immunotherapy may help Alzheimer's sufferers' cognitive abilities and reduce the progression of their illness. There is great potential for more successful and long-lasting therapy results due to the twin impact of improving cholinergic signaling and modifying immunological responses. Additionally, this approach may open the door for combination treatments that work together to target several pathways implicated in Alzheimer's pathogenesis, so tackling the disease's complexity in a more thorough manner. Numerous approaches have limited effectiveness despite continuous study, which has led to a trend toward more specialized and creative treatments⁶⁹. Artificial intelligence has the potential to improve therapeutic outcomes by enabling early AD diagnosis and treatment tailoring⁷⁰. Even with the possible advantages, there are still a number of difficulties. Research must continue to address concerns about patient selection, the best dosing methods, and the long-term safety and effectiveness of immunotherapy. Additionally, the need for biomarkers to predict patient response to treatment is crucial for tailoring therapies effectively. Overall, the integration of acetylcholinesterase immunotherapy into the therapeutic arsenal against Alzheimer's disease could mark a significant advancement in our fight against this debilitating condition. As future aspects continue to evolve, it is vital to maintain a multidisciplinary approach that encompasses immunology, neurology, and pharmacology, ensuring that we harness the full potential of this innovative treatment strategy to enhance the quality of life for Alzheimer's patients and their families.

ACKNOWLEDGEMENT:

We sincerely express our gratitude to Dr. Subhash University for their invaluable guidance and support in the completion of this review work.

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Received on 08.04.2025 Revised on 24.05.2025

Accepted on 30.06.2025 Published on 08.10.2025

Available online from October 17, 2025

Asian J. Pharm. Tech. 2025; 15(4):346-356.

DOI: 10.52711/2231-5713.2025.00051

This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. Creative Commons License.

Sr. No.	Antibody (Ab)	Subtype	Target	Keyfindings
1.	Aducanumab	IgG1	Aβ peptide	Proof of effectiveness: remove 64 CL amyloid to 21 CL amyloid and 53 CL amyloid to 31 CL⁴⁴
2.	Bapineuzumab	IgG1	Aβ peptide	Ineffective at removing amyloid and delaying cognitive deterioration⁴⁵
3.	Crenezumab	IgG4	Aβ peptide	failed to minimize clinical deterioration and eliminate amyloid⁴⁶
4.	Donanemab	IgG1	Aβplaques	Reduce 88–87 CL amyloid to 14.4–16.5 CL, demonstrating effectiveness⁴⁷
5.	Gantenerumab	IgG1	Aβfibrils	Lower amyloid levels, evidence of ineffectiveness, and a delayed rate of cognitive decline⁴⁸
6.	Lecanemab	IgG1	Aβprotofibrils	Reduce 55.48 CL amyloid to 22.44 CL, demonstrating effectiveness⁴⁹
7.	Solanezumab	IgG1	Aβpeptide	Amyloid removal is unsuccessful and ineffective⁵⁰
8.	Gosuranemab	IgG4	InsolubleTau	Reduced unbound N-terminal tau fragments but inability to decrease tau accumulation in the brain⁵¹
9.	Tilavonemab	IgG4	Extracellulartau	Tau deposition cannot be decreased, and cognitive decline cannot be slowed⁵²
10.	Zagotenemab	IgG4	Soluble tau	Inability to reduce cognitive decline⁵³

Drug Compound	Tacrine (Aminoacridine)	Donepezil (Piperidine)	Metrifonate (Organo-phosphate)	Rivastigmine (Carbamate)	Physostigmine (Carbamate)	Eptastigmine (Carbamate)	Galanta- mine (Phenan-threne alkaloid)
Half-life	2-3h	70h	1-2mo	10h	bid	12h	5-6h
Dosage frequency	qid	od	od	bid or tid	bid	tid	bid
Interaction with drugs metabolized by CYP-450 isoenzymes	yes	yes	no	yes	yes	yes	Yes
Discontinuation rate in trials (% of patients)	42-58	12-29	8-18	22	-	14	-
Dose in trials (mg/day)
12 weeks	20-80	1-5	30-60	-	18-30	15-20	-
24 weeks	-	5-10	30-60	-	-	-	-
26 weeks	-	-	-	6-12	-	-	-
30 weeks	80-160	-	-	-	-	-	-
Others	-	-	-	-	-	-	12

Sr. No.	Compound Name	Therapy Type	Target	Effect
1.	AN1792	Vaccine	Aβ42	Low tau level, decreased Aβ deposition, and increased IgG titters in CSF. terminated because 6% of treated patients developed meningitis³¹.
2.	CAD106	Vaccine	AβN- terminus Aβ1−6	Elicit an antibody response. terminated because of unexpected alterations in brain volume and cognitive function³².
3.	ACC-001	Vaccine	Aβ1−7	Reduced CSF p-tau and elevated plasma Aβ40 levels. discontinued because of the negative consequences³³.
4.	LuAF20513	Vaccine	Aβ1−12	Decrease in the amount of Aβ40 and Aβ42 in soluble form. prevented the development of amyloid plaque. cancelled because of decreased effectiveness³⁴
5.	UB-311	Vaccine	Aβ1−14	Boost immunogenicity and mental capacity³⁵.
6.	ACI-24	Vaccine	Aβ1−15	Decrease in the amounts of soluble Aβ42 and insoluble Aβ40 and 42³⁶
7.	V-950	Vaccine	Aβ1−15	Aβ antibody production in CSF³⁷
8.	ABvac40	Vaccine	C-terminus of Aβ33−40	All volunteers produced antibodies, and none of the patients developed meningitis³⁸
9.	Affitope AD02	Vaccine	Mimotope of Aβ N-terminal	No thorough results were released, and it was safe³⁹
10.	AV-1959D	DNA Vaccine	Aβ1−11	Produced an anti-Aβ42 antibody and showed no toxicities of any kind⁴⁰
11.	Y-5a15	Vaccine	Aβ1−15	Aβ-specific antibody production, decreased Aβ levels, and enhanced cognitive performance⁴¹.
12.	AADvac1	Vaccine	Tau	Decreased tau aggregate levels and enhanced cognitive function⁴²
13.	ACI-35	Vaccine	Tau	Decrease in both soluble and insoluble tau levels⁴³

Table 2: Different Passive Immun other apies and Their Effects