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Alzheimer’s Disease: An Insightful Review on the Future Trends of the Effective Therapeutics

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Afreen Hashmi, Vivek Srivastava, Syed Abul Kalam and Devesh Kumar Mishra

Submitted: September 16th, 2021 Reviewed: January 19th, 2022 Published: March 15th, 2022

DOI: 10.5772/intechopen.102762

Alzheimer's Disease Edited by Montasir Elahi

From the Edited Volume

Alzheimer's Disease [Working Title]

Ph.D. Montasir Elahi

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Alzheimer’s disease (AD) is a disorder of brain which progressively weakens the cognitive function. It is occur due to formation of β-amyloid plaques, neurofibrillary tangles, and degeneration of cholinergic neurotransmitter. There is no effective treatment capable of slowing down disease progression, current pharmacotherapy for AD only provides symptomatic relief and limited improvement in cognitive functions. Many molecules have been explored that show promising outcomes in AD therapy and can regulate cellular survival through different pathways. Present study involves current directions in the search for novel, potentially effective agents for the treatment of AD, as well as selected promising treatment strategies. These include agents acting upon the β-amyloid, such as vaccines, antibodies and inhibitors or modulators of γ- and β-secretase; agents directed against the tau protein. Current clinical trials with Aβ antibodies (solanezumab, bapineuzumab, and crenezumab) seem to be promising, while vaccines against the tau protein (AADvac1) are now in primary-stage trials. Most phase II clinical trials ending with a positive result do not succeed in phase III, often due to serious side effects or lack of therapeutic efficacy but Abucanumab (marketed as Aduhelm) now approved by USFDA in 2021 for the treatment of AD.


  • neurodegeneration
  • novel strategies
  • clinical trials
  • medicinal plants

1. Introduction

Alzheimer’s disease (AD) is a brain disorder described in 1906 by Aloes Alzheimer, a German physician [1]. It is a progressive and neurodegenerative disorder which mainly occur in old aged people of over 65 years of age [1, 2, 3]. For progression and development of disease various pathways are involved such as formation of plaque, inflammatory cascade, cholinergic deficit, oxidative stress, and many more. Senile plaques formation and neurofibrillary tangles persist significant neuro-pathological symbols of this disease. Senile plaques are the main component of amyloid beta (Aβ) peptide that are covered by dystrophic neurites and activated microglia. Accumulation of Aβ results changed process of proteolytic amyloid precursor protein (APP) through beta and gamma secretase. The β-amyloid peptide, with 39–42 amino acid residues (BAP), perform vital role in development of AD. There are mainly two types of AD, familial AD which affects the people who have age less than 65. The other type of AD is sporadic AD which affect the people older than 65. At present there is no cure for Alzheimer’s disease but it could me managed to some level by using available medications (Table 1) [4, 5].

FactorsDementiaAlzheimer’s diseaseNormal aging
DefinitionCNS disorder due to disease or any other pathological condition.Common form of dementia.Condition occur due to programmed cell death with time (gene therapy) and causes various disability.
CauseAD, stroke, thyroid issues, vitamin deficiency, etc.Deposition of beta amyloid protein in brain.May cause biological systems to fail (DNA oxidation, DNA methylation, and apoptosis).
Duration and agePermanent damage and 65 years and olders.Average 8–20 years and 65 year but can occur as early as 30s.Gradual and progressive condition until death.
SymptomsIssues with memory, poor judgment, less focus and attention.Difficulty to remembering newly learned information.Bone break more easily, decrease overall energy, greater risk of heart stroke or hypothermia.

Table 1.

Alzheimer’s disease versus dementia and normal aging [6, 7].

1.1 Epidemiology

In 2020 approx. 50 million individual dealing with dementia worldwide. In India more than four million of people suffering from AD and dementia while in USA approx. 5.8 million living with dementia and AD. It is estimated that it is the fifth main source of death in USA and the number of death increased 146% between 2000 and 2018. It is predicted the causality will increase to 13.8 million which number of patient increases to 13.5 million by 2050. Elderly persons are more prone to younger one [8].

1.2 Etiology

In maximum case genetic lifestyle choices aging stress and environmental factors induces AD [9].

1.2.1 Age

Researchers have claimed that older adults have more risk of having AD. Scientists are still learning, how age-related changes in the brain may harm neurons and contribute to Alzheimer’s [10].

1.2.2 Genetic factors Early onset

It occur due to mutation in chromosome 1, 14, and 21. The changes on chromosome 1 produces PRESENILIN-2 (PSEN2) named protein while chromosome 14 produces PRESENILIN-1 (PSEN1). These PSEN 1 and PSEN 2 directly and indirectly both trigger/encode for membrane protein convoluted for amyloid precursor protein. These mutations reduce the effectiveness of γ-secretase, an enzyme which is responsible for formation of beta amyloid peptide (βAP) [11]. Amyloid precursor protein is coded on chromosome 21 and this mutation results in overproduction of beta amyloid peptide. Mutation on chromosome 1, 14, and 21 results in early onset AD [12]. Late onset

Apo-lipoprotein E (APOE) gene is responsible for late onset AD. APOE gene is lipid metabolism regulator which have an affinity for beta amyloid protein and increases the risk of AD. Chromosome 19 produces APOE gene. The inheritance of APOEe4 allele own genetic risk in sporadic AD. APOEe4 allele, age elevate the risk for development of late AD by two to three folds and two copies of five folds [13].

Variations in gene for receptor sortilin, SORT1, that is important for transferring APP from surface of cell to Golgi-endoplasmic reticulum complex, have been found in familial and sporadic types of AD [14]. Environmental factors

Conditions such as heart disease, stroke, high blood pressure, diabetes, and obesity are also linked as risk factors for AD [15].


2. Pathogenesis and clinical findings

The real origin of this disease is not well known but problems are linked with brain protein that work abnormally and cause malfunction. As a result neurons were damaged then fail to connect other neuron as a result they die. Initially the degradation starts within the region of brain which control memory ultimately dementia occur (Figure 1) [16].

Figure 1.

Clinical findings in Alzheimer’s disease [17].

2.1 Beta-amyloid protein aggregation and deposition

In the initial stage of AD amyloid proteins works abnormally and cause overproduction of beta amyloid secretase named enzyme split amyloid processor protein and due to deviation from this process, especially sudden change in gamma and beta secretases leads to unnatural production of amyloid beta [18].

2.2 Neurofibrillary hypothesis

Tau protein is known for its stabilizing property. It is useful in the transportation of nutrients and others essential matter within the neurons while in AD. Tau protein cause mutation and changes its structure which is known as neurofibrillary tangles [18, 19].

2.3 Cholinergic hypothesis

It is observed in the patient of AD there is deficiency of ACh due to abnormal functioning of choline acetyl transferase. This will treat as a clinical hallmark to support cholinergic hypothesis there is also a possible treatment of AD by increasing the level of ACh by reducing the activity of AChE cholinergic depletion observed after neurodegenerative cascade various cholinesterase inhibitors currently used in the treatment of AD [20].

2.4 Excitotoxicity

It is defined as the excess interaction of neurotransmitter glutamate and other excitatory neurotransmitter which may act as a potent neurotoxins for Alzheimer [21].

2.5 Vascular diseases and high cholesterol

Apo-lipoprotein E play important role in the cholesterol transportation and catabolism of triglyceride lipoprotein. Cholesterol also alter the clearance of amyloid beta and generation of NFT in neuronal membrane APOE4 also enhance the deposition of beta amyloid protein. High level of cholesterol in brain there by alter the member functioning this leads to plaque formation resulting AD [22].

2.6 Oxidative stress

Oxidative stress is generated due to imbalance of ROS generation and its quenching. Brain is more prone for oxidative stress due to high consumption of O2. High level of polyunsaturated fatty acid. Low level of antioxidants and high level of redox transition metal ions. These all factors facilitate the production of reactive oxygen species like superoxide, hydrogen peroxide, etc. These ROS interact with surroundings proteins nucleic acids, etc. and cause cellular dysfunction [23]. There is also a close relationship between amyloid beta and oxidative stress because amyloid beta elevate the formation of ROS and initiate mitochondrial damage. This will also cause oxidative damage. These effects can also be observed in brain of triple transgenic mouse model of AD where tocopherol and GSH level decrease while lipid peroxidation is increased [24]. However this was observed before any plaque formation. While in another model dual mutant APP was expressed, oxidative stress and inflammation was induced by thiamine deficiency provoke plaque formation and enhance the level of amyloid [25].

2.7 Mitochondrial dysfunction

It is observed in the marphotric analysis of AD patients brain showed significant deficiency of mitochondria while its DNA and protein concentration elevate in cytoplasm and in the vacuoles associated with lipofuscin [26]. These mitochondria may be damaged due to autophagy and oxidative stress. Mitochondrial cytochrome oxidase activity also reduced in cortical region of AD brain. Due to this deficiency mitochondrial dysfunction occur and ROS generated and energy stores were decreased and ultimately neurodegeneration occur [27].

2.8 Inflammatory mediators

Amyloid deposition in brain also associated with local inflammation and immunologic alleviations [28]. This association induces the release of NO3, cytokines which cause neural damage and cause inflammation [29, 30].


3. Role of sex hormone in Alzheimer’s

Evidence from animal and human studies support functional roles of sex hormones like estrogens, progesterone, and androgens in behavior and cognition. With several neuroprotective activity involved, age reduces level of sex hormones were connected with greater possibilities of cognitive degeneration and AD. For example, in females development of AD is associated with decreased exposure to estrogens across the lifetime, while in males age related degeneration in both levels of peripheral and brain testosterone is linked with greater susceptibilities of AD development. Also, alterations in receptors of sex hormone and downstream signaling pathways during aging have been stated. For example, the nonfunctional splicing estrogen variants receptor alpha in the hippocampus was enhanced throughout aging and AD, with advanced levels in female old age subjects in comparison to males. Moreover, studies recognized polymorphisms of estrogen receptors related with intellectual decay and AD development in females, especially in APOE ε4 (APOE4) transporters. These information recommended diminished responsiveness of brain to sex hormones during aging and disease development. However, clinical trial outcomes of sex hormone therapy in AD are rather contentious. Despite prior studies associating protective activity of estrogen replacement against AD in females, huge clinical studies failed to exhibit any useful possessions. It was suggested that replacement of hormone initiation in the serious window of perimenopause may diminish the risks of dementia, while it might raise the risks if started a very long time after menopause. Moreover treatment timing, reduced responsiveness at receptors of brain and downstream signaling pathways might add to the uselessness of hormonal therapy. Together, these investigations recommend the complication of sex hormones association in AD [31].


4. Strategies used in the treatment of Alzheimer’s disease: A clinical data

4.1 Conventional approaches

Currently there is no cure for this disease, the objective of several medicine is used to reduce symptoms linked with disease and to reduce disease progression (Table 2) [32, 33, 34, 35, 36].

Drug nameIndicationMode of actionAdverse effect
DonepezilMinor to chronicIt stops the breakdown of ACh by preventing the function of acetyl cholinesteraseFatigue, abnormal dreams, hallucinations, confusion, hypertension, abdominal pain
Treats intellectual indication of AD
GalantamineMinor to mediumStops the breakdown of Ach and stimulates receptors to discharge extra AChSomnolence, bradycardia, insomnia, urinary tract infection, anorexia, syncope
Treats intellectual indication of AD
RivastigmineMinor to mediumStops the breakdown of Ach by preventing the enzymes that abolish AChDizziness, diarrhea, anxiety, vertigo, asthenia, tachycardia
Also used to treat dementia from Parkinson’s diseaseTreats intellectual indication of AD
MemantineMedium to severeBlocks glutamatergic (NMDA) receptors and controls the action of glutamateHeadache, constipation, vomiting, backache
Treats intellectual indication of AD
Donepezil/memantineMedium to severeit binds to NMDA receptor-operated caption channels, and gives therapeutic effects by preventing persistent stimulation in CNSHallucination, headache, cough, fatigue, cramping, syncope, increased frequency of bowel movements

Table 2.

Currently used drug for the treatment of Alzheimer’s disease.

4.2 Current scenario

4.2.1 Antiamyloidogenic pathway and amyloidogenic route as approaches for development of therapeutic treatments adjusting the course of Alzheimer’s disease

From the previous eras, the pharmaceutical industry has decided to chiefly focused on the amyloidocentric method, dedicating significant possessions to form useful AD drugs. Nevertheless, numerous failures of drug candidates in clinical trials have led investigators to question the viability of this approach [10, 11, 12]. Possible cause for failure is a absence of biomarkers that could consistently recognize AD in comparatively initial phases. It is totally promising that the patients presently enrolled for phase III trials are in such advanced phases of AD that any attempted interference is possibly inadequate. In the meantime, there is still a number of new management under development, that focused the amyloidogenic route. In order to decrease generation of Aβ from the APP, inhibition of γ- and β-secretase and the potentiation of activity of α-secretase have been deliberated.

4.2.2 Inhibitors and modulators of β-secretase

β-secretase enzyme complex contributes in the primary phases of the amyloidogenic APP-processing pathway. The inhibitors of β-secretase development is a task because, besides the APP, this complex has several substrates. To give just one example, neuregulin-1, that included in the CNS axons myelination and synaptic elasticity, is a target β-secretase. Substrates wide range results to substantial adverse effects, even if the precise enzyme inhibition is reached. But, E2609 (clinical trial ID# NCT01600859), MK-8931 (NCT01739348), and LY2886721 (NCT01807026 and NCT01561430) have all exposed efficiency in decreasing the production of Aβ by up to 80–90% in the cerebrospinal fluid (CSF) in humans. None of inhibitors of β-secretase have touched the market so far [37, 38, 39, 40].

4.2.3 Inhibitors and modulators of γ-secretase

In the final stage of amyloidogenesis, γ-secretase complex is responsible for the production of Aβ(1–40) and Aβ(1–42). Inhibition of γ-secretase was firstly proposed strategy for the management of Alzheimer’s disease but the substrate promiscuity shows equal issues facing γ-secretase inhibitors. γ-secretase proposed to target the Notch protein which is responsible for the regulation of cell proliferation, development, differentiation and cellular communication but off target secondary effects are major concern [41, 42, 43].

Semagacestat (LY450139) named γ-secretase inhibitor reduces the Aβ level in the blood and in cerebrospinal fluid [44]. The results obtained from the clinical study conducted on 3000 patients shows the major adverse effects like decrease cognition abilities and difficulty in the carry out daily living activities and elevated skin cancer incidence and increased risk of infection and weight loss. Another γ-secretase named avagacestat discontinued in the development stage due to lack of efficacy (NCT00810147, NCT00890890, NCT00810147, NCT01079819, [45, 46, 47]).

Several nonsteroidal anti-inflammatory drugs like indomethacin, ibuprofen, flurbiprofen, sulindac also decreases the Aβ(1–42) peptide levels in in-vivo and in in-vitro studies. Ibuprofen is a cyclooxigenase inhibitor while R-flurbiprofen (tarenflurbil) is not, so the reduction of Aβ(1–42) peptide levels is not associated with the COX inhibition. Unfortunately, in clinical trials tarenflurbil and ibuprofen does not shows efficacy for the treatment of Alzheimer’s disease. The idea of long term use of NSAID’s for the treatments of Alzheimer’s disease as NSAIDS reduces the Aβ peptide level in blood but negative results reported in the clinical studies that’s why this hypothesis requires further investigations [48, 49].

Clinical studies with 8-hydroxiquinolines compounds like clioquinol and PBT2 also conducted for the treatment of Alzheimer’s disease. The mechanism of action is yet established, but the expected MOA suggested that the increased levels of oxidative stress is due to the copper ions binding to Aβ, leading to metal-mediated generation of ROS (reactive oxygen species). It is proposed that the 8-hydroxiquinolines may prevent Aβ aggregation and restoring homeostasis in the cellular levels of copper and zinc ions. But after in clinical development these compounds failed due to lack of efficacy [50, 51, 52].

4.2.4 Agents that stimulate the removal of amyloid deposits and aggregates

Another possible treatment choice that is involved on the amyloidogenic pathway is to stimulate the existing amyloid aggregates clearance. To achieve this, three different approaches have been assessed.

4.2.5 Activation of enzymes that destroy amyloid plaques

Amyloid plaques are destroyed by various proteases comprising neprilysin, IDE, plasmin, angiotensin converting enzyme, endothelin converting enzyme, and metalloproteinases. Levels of protein these enzymes reduces in AD, that promotes accumulation and formation of Aβ. Despite being an attractive approach for forming disease-modifying medicine, no compounds with this MOA have ever entered advanced clinical development because of lack of specificity.

4.2.6 Modulation of β-amyloid transport between the brain and the peripheral circulation

Transport of Aβ between the circulation of CNS and peripheral is controlled by: (i) apolipoproteins (e.g., Aβ might be transported from the blood to the brain when it is bound to APOE); (ii) low-density lipoprotein receptor-related protein (LRP-1), that enhances Aβ discharge from the brain to the blood; (iii) receptor for progressive glycation end products (RAGE), that enables the Aβ transport across the blood-brain barrier (BBB) [53, 54].

Any treatment goal, that is determined on this mechanism, is to decrease the load of cerebral amyloid by trying to control Aβ to the peripheral circulation. To this end, a different number of approaches have been suggested, particularly the administration of LRP-1 peripherally. Though, the only drug candidates that have entered the clinical phase are the RAGE inhibitors.

4.2.7 Antiamyloid immunotherapy Active immunotherapy

Immunotherapy approach designed to stimulate clearance of Aβ with the aimed of decreasing load of amyloid load in AD. Active immunization (vaccination) with either Aβ(1–42) (main form found in senile plaques) or other synthetic fragments has been positively assessed in transgenic mouse models of AD. Human tests were primarily hopeful; though first-generation vaccine (AN1792) treatment has shown major adverse events which results to the phase II trials cessation. AN1792 contained of a synthetic full-length Aβ(1–42) peptide with a QS-21 adjuvant. Because of a T cell-mediated autoimmune response, 6% of patients have established inflammation in brain that ended up being aseptic meningoencephalitis [55].

Second-generation vaccines were planned utilizing a limited portion of Aβ(1–6) peptide in an try to inhibit nonspecific immune response seen with the full-length vaccine. Novartis designed CAD 106, was the first second-generation vaccine which moved to development phase. Newly finished phase II trial have exposed a Aβ-specific antibody response in 75% of treated patients, without producing any side effect. Janssen developed ACC-001, has freshly finished two-phase II trials (NCT01284387 and NCT00479557) with an additional phase II trial still continuing (NCT01227564). Though, the pharmaceutical industry has canceled the ideas for this vaccine development. Further vaccines, comprising tetra-palmitoylated Aβ(1–15) re-formed in a liposome (ACI-24), MER5101 and AF205 are now in different phases of preclinical progression [56, 57, 58]. Passive immunization

It is the monoclonal or polyclonal antibodies administration directed against Aβ. This treatment contains intravenous administration of anti-Aβ antibodies to the patient. The advantage of this approach is to match to active immunization is which the proinflammatory T cell-mediated immune response should not arise. Reports have shown that in transgenic animals passive immunization decreases the load of cerebral amyloid and recovers cognition, even when the amyloid plaque numbers are not suggestively decreased. This could be recognized to the soluble amyloid oligomers neutralization, that progressively identified to play an important role in the pathophysiology of AD.

Bapineuzumab and solanezumab are two monoclonal antibodies which are reach now present in advanced phase of development. Though, two phase III trials had failed in 2012 due to low effectiveness in patients with mild-to-moderate AD [59]. Both are humanized monoclonal antibodies against Aβ(1–6) and Aβ(12–28), respectively. In bapineuzumab, noteworthy decrease in brain amyloid plaques and phosphorylated Tau in cerebrospinal fluid was stated. Though, the treatment unsuccessful to give noteworthy developments of brain function. In a solanezumab trial, infusions of 400 mg of solanezumab or placebo were given for 80 weeks once a month in patients with mild-to-moderate AD. The outcomes recommended that solanezumab might recover cognition in mild AD; but statistical significance was not attained in study. Presently solanezumab present in phase III trials in patients with AD (NCT01127633 and NCT01900665) and in older persons who have common thinking and memory function but who might be at danger of AD developing in the future (NCT02008357, [60, 61]).

Crenezumab (MABT5102A) is a humanized monoclonal antibody that uses IgG4 backbone. In April 2014 a stage II trial to measure the safety and effectiveness in patients with mild-to-moderate AD (NCT01343966) was accomplished, while the outcomes are not yet openly accessible. The supreme stage II trial pointing to assess the safety and effectiveness of crenezumab in asymptomatic transporters of E280A autosomal-dominant mutation of PSEN1 initiated in November 2013 (NCT01998841).

Other monoclonal antibodies against Aβ established so far contain PF-04360365 (ponezumab) that targets the free carboxy terminal amino acids 33–40 of the Aβ peptide; MABT5102A, that binds to Aβ monomers, oligomers, and fibrils with similarly great affinity; GSK933776A, that is likewise to bapineuzumab in which it binds to the N-terminal Aβ(1–5). Additional, other passive immunotherapies typically in stage I clinical trial involve NI-101, SAR-228810, and BAN-2401 [58, 62].

4.2.8 Approaches focused on Tau proteins

In neurons Tau proteins are extremely soluble and abundant where they play a important role in stabilization of microtubule, mainly in axons [63]. Tau hyperphosphorylation resulting the insoluble paired helical filaments (PHF) development that form neurofibrillary tangles. The microtubule-binding capacity damage initiate destabilization of cytoskeleton, that ultimately develops neurodegeneration and neuronal death [64]. As a substitute to amyloidocentric strategies, this treatments goal to prevent the phosphorylation of Tau protein. Additional, microtubule-stabilizing drugs can be utilized as a disease-modifying approach in AD. In current years, immunomodulation was recommended as a feasible choice for stimulating operative Tau aggregates clearance [65].

4.2.9 Hyperphosphorylation of Tau inhibitors

All Tau proteins are a result of different splicing of a microtubule-associated protein Tau (MAPT) gene. Primary mechanism that controls Tau binding to microtubules is phosphorylation. The protein remains soluble under physiological circumstances; though, in this disease, pathological hyperphosphorylation of Tau compromises its regular functions [66, 67]. Imbalance between the catalytic activity of kinases and phosphatases occurs hyperphosphorylation. Enhanced expression of active forms of several kinases in the areas proximal to neurofibrillary tangles has been labeled in AD, comprising CDK5, GSK3β, Fyn, stress-activated protein kinases JNK and p38, and mitogen-activated protein kinases ERK1 and ERK2 [68]. Certain kinases promote continuation of tau phosphorylation in neurofibrillary tangles. Resulting, noteworthy research determinations have been dedicated to the kinase inhibitors development as a probable treatment approach for AD. For example, SP600125, a extensively utilized pan-JNK inhibitor, employs valuable effects on cognition and decreases neurodegeneration in an APP/PS1 transgenic mouse model of AD. It has been planned which precise inhibition of JNK3 can be adequate to carry comparable benefits as seen with SP600125 in rodent models. Human data in AD patients designate a positive correlation between the JNK3 and Aβ(1–42) levels in the brain. Moreover, JNK3 upregulation was distinguished in the CSF and was related with loss of memory. Consequently, inhibition of JNK3 remains a capable goal for future treatments [69, 70, 71].

4.2.10 Tau aggregation inhibitors

Tau hyperphosphorylation contribute to neurotoxicity detected in AD brain. Methylene blue dye derivatives have revealed certain potential Tau aggregates formation inhibition. Methylene blue disturbs the Tau aggregation, has the capability to prevent amyloid aggregation, recovers the effectiveness of mitochondrial electron transport chain, decreases oxidative stress, stops mitochondrial impairment, and is also an autophagy modulator. The first-generation molecule resulting from methylene blue (Rember) seemed to stabilize AD development in a clinical trial that continued 50 weeks. These outcomes encouraged investigators to form a next-generation form of methylene blue, TRx 0237. This agents is a purified derivative of methylene blue that not only prevents aggregation of Tau protein but also liquefies brain tau aggregates. Various trials are presently ongoing (NCT01626391, NCT01689233, NCT01689246, NCT01626378) to assess the possible effectiveness of this agent in AD [72, 73].

4.2.11 Stabilizers of microtubule

Stabilization of microtubule might possibly attain a comparable end-result as which seen with the Tau hyperphosphorylation inhibitors. Paclitaxel is a microtubule-stabilizing agents presently in utilize in the oncology arena. Inappropriately, this agents is unable of BBB crossing and its utilize is related with major adverse events, that limits its efficacy in AD. In addition to paclitaxel, other microtubule-stabilizing agents like TPI 287 have been measured as a probable AD remedy. TPI 287 is a derivative of taxane, also utilize in the treatment of cancer. TPI 287 alleviates the microtubules by binding to tubulin. NCT01966666 trial will estimate TPI-287 safety, pharmacokinetic possessions, and tolerability by intravenous infusion in mild-to-moderate AD.

Epothilone D is a microtubule-stabilizing agent that enhanced axonal transport, decrease axonal dystrophy, reduced Tau neuropathology, and decreased hippocampal loss of neuron; though, in 2013 drug development for AD was discontinued after an unsuccessful clinical trial. With respect to Tau, more research are essential in order to better understand the exact molecular mechanisms elaborate in neurotoxicity of Tau. Current research associating the neurotoxic profiles of different forms of Tau recommend which is a soluble form is probable the greatest toxic. Thus, future therapeutic approaches should be focused on aiming Tau soluble forms [74].

4.2.12 Anti-Tau immunotherapy

Just as with the immunotherapies aiming Aβ, both passive and active immunization approaches against Tau have been measured. It was established that decrease in formation of Tau aggregate and enhanced Tau oligomers clearance and insoluble aggregates could all be reached with either active or passive immunotherapies. In rodents, treatment with monoclonal antibodies directed against hyperphosphorylated Tau has results to improvements in cognition and was not connected with noteworthy side effects.

Axon neuroscience began a stage I trial in 2013 to estimate the safety and tolerability of AADvac-1, an active immunotherapy that contains synthetic peptide derived from the Tau sequence coupled to keyhole limpet hemocyanin; the precise molecular nature of the antigen has not been disclosed (NCT01850238 and NCT02031198). AADvac-1 uses aluminum hydroxide as an adjuvant. At the 2014 Alzheimer’s Association International Conference (AAIC) in Copenhagen, good preclinical safety profile was reported for the treatment period of up to 6 months in rats, rabbits, and dogs. These initial outcomes are hopeful and it remains to be seen whether AADvac-1 will prove satisfactory safety and efficiency in patients [75, 76].

4.2.13 The cholinergic hypothesis

The hippocampus, the chief region of brain elaborate in memory processing, is influenced by modulation of cholinergic neurotransmitter. One of the well categorized irregularities linked with neurotransmitter deviations is the cholinergic neurons degeneration in the nucleus basalis of Meynert and the cholinergic inputs loss to the neocortex and hippocampus. Various studies reported reduced in choline acetyltransferase (ChAT), acetylcholine (ACh) release, as well as decreases in nicotinic and muscarinic receptors in the cerebral cortex and hippocampus of postmortem AD brains. Acetylcholinesterase inhibitors (AChEI), one of the only two classes of compounds that presently accepted for AD treatment, act by stimulating ACh bioavailability at the synapse. Inappropriately, none of these agents are proficient of withdrawing the course of AD nor of even noticeably reducing down the degree of disease development. Their clinical effect is basically palliative; though, their possible utilize in combination therapy with other disease-modifying agents should not be omitted [77, 78].

4.2.14 Altering the perception: AD as a metabolic disorder

As revealed by clinical study data and research articles that diabetes is a one of the key factor that leads to AD pathology and unfolds the close connection between insulin-deficient diabetes and cerebral amyloidosis. These data also suggests about insulin signaling impairments (both peripheral and central) is possibly be existing in both diseases. Hence, considering insulin hormone at the core, “type 3 diabetes” hypothesis of AD was developed, observing metabolic phenotypes into a coherent framework [79].

The most anticipated mechanisms for the development of AD due to diabetes could be: glucose toxicity, insulin resistance, oxidative stress, elevated levels of advanced glycation end products, and cytokine-mediated neuroinflammation. Recently, Clarke and colleagues demonstrated that neuroinflammatory cascades can be initiated by the administration of soluble hypothalamic Aβ oligomers that ultimately causes disturbances in peripheral glucose homeostasis. Tumor necrosis factor α (TNFα) may have a significant role during this process [80].

Rosiglitazone and pioglitazone are used as antidiabetic drugs, which regulate glucose homeostasis by increasing insulin sensitivity, reducing blood glucose levels, and improving lipid metabolism. Both compounds have also been studied as potential therapeutics for AD treatment, with reported improvements in mitochondrial oxidative metabolism [81]. In animal models, pioglitazone modified various indices of brain aging but did not slow down the cognitive decline. Rosiglitazone and pioglitazone also induce the expression of peroxisome proliferator-activated receptor-γ co-activator 1 alpha (PGC-1α), a molecule that plays multiple roles in mitochondrial biogenesis, energy metabolism, and mitochondrial antioxidants expression. Previous studies have demonstrated that, in the human brain tissues, the expression of PGC-1α decreases with progression of AD dementia. Thus, PGC-1α upregulation may improve the mitochondrial energy metabolism and AD pathology [82, 83, 84, 85, 86].

In a small scale clinical trial on mild-to-moderate AD patients, it was found that pioglitazone enhances memory and cognition. On the other hand clinical trial (phase II) with larger group of patients (who did not possess an ApoE4 allele) were on treatment with rosiglitazone (6 months) shows improvement in memory retention and attention. However, similar study (phase III trial) using rosiglitazone failed to show efficacy in AD (NCT00550420). It is important to note that rosiglitazone was administered at much lower dosage than required to exert efficacious effects on AD pathophysiology in these trials, in rodent models of the disease. NCT00348140 recently completed clinical trial in which rosiglitazone was administrated in combination with AChEIs in patients with AD (mild-to-moderate) and until now no further outcome yet reported.

As a treatment possibility for AD, intranasal insulin have also been considered as it bypasses the BBB easily; adding the advantage of possibly minimum adverse events in peripheral tissues. Theoretically it is well established that direct delivery of insulin to the brain will activate cerebral insulin signaling leading to enhancements in memory processing resulting into neuroprotection. A recent ongoing clinical trial (with NCT017679090 is assessing long-term (12 months) efficacy of intranasal insulin (Humulin R U-100) among mild AD patients [87].

Also, it has been found that reduced plasma amylin concentrations may contribute in the progression of AD. As revealed by transgenic animal models of AD, amylin and pramlintide (amylin analog) reduced the brain Aβ levels and advances cognition. Interestingly, amylin inhibits β-secretase, whereas pramlintide did not [88].


5. Medicinal plants for the treatment of Alzheimer’s disease

Here is the number of herbal plants reported to might have anti-Alzheimer activity (Table 3).

Sr. No.Work donePlant usedCommon nameAuthorYearRef.
1.Effects of the hydroethanolic extract of Lycopodium selagoL. on scopolamine-induced memory deficits in zebrafishL. selagoFir clubmossValu et al.2021[89]
2.Evaluation of traditional herb extract Salvia officinalisin treatment of Alzheimer’s diseaseS. officinalisSageDatta et al.2020[90]
3.Protective effects of tenuifolin isolated from Polygala tenuifoliaWilld roots on neuronal apoptosis and learning and memory deficits in mice with Alzheimer’s diseaseP. tenuifoliaYuan zhiWang et al.2019[91]
4.Convolvulus pluricaulis(Shankhapushpi) ameliorates human microtubule-associated protein tau (hMAPτ) induced neurotoxicity in Alzheimer’s disease DrosophilamodelC. pluricaulisShankhapushpiKizhakke et al.2019[92]
5.Malva parvifloraextract ameliorates the deleterious effects of a high fat diet on the cognitive deficit in a mouse model of Alzheimer’s disease by restoring microglial function via a PPAR-γ-dependent mechanismM. parvifloraCheeseweedJiménez et al.2019[93]
6.Antioxidant, anti-Alzheimer and anti-parkinson activity of Artemisia nilagiricaleaves with flowering topsA. nilagiricaIndian wormwoodPal and Pradeep2018[94]
7.Antioxidant and anti-acetylcholinesterase activities of essential oils from garlic (Allium sativum) BulbsA. sativumGarlicAkinyemi et al.2018[95]
8.Nootropic activity of ethanolic extract of Alangium salvifoliumleaves on scopolamine mouse model of Alzheimer’s diseaseA. salvifoliumAnkolParameshwari et al.2018[96]
9.Moringa oleiferaalleviates homocysteine-induced Alzheimer’s disease-like pathology and cognitive impairmentM. oleiferaDrumstick treeMahaman et al.2018[97]
10.Ameliorative effect of Cleome gynandraL. against scopolamine induced amnesia in miceC. gynandraShonna cabbageManasa et al.2017[98]
11.Evaluation of nootropic activity of green peas in micePisum sativumGreen peasKaura et al.2017[99]
12.Ameliorative effect of Apium graveolensLinn on scopolamine-induced amnesia miceA. graveolensCeleryPhetcharat et al.2017[100]
13.Evaluation of effect of alcoholic extract of Tinospora cordifoliaon learning and memory in alprazolam induced amnesia in albino miceT. cordifoliaGuduchiJyothi et al.2016[101]
14Effect of Camellia sinensison spatial memory in a rat model of Alzheimer’s diseaseC. sinensisGreen teaMahmoodzadeh et al.2016[102]
15.Evaluation of nootropic activity of Curcuma longaleaves in diazepam and scopolamine-induced amnesic mice and ratsC. longaTurmericReddy et al.2015[103]
16.Effect of ethanolic seed extract of Bauhinia purpurealinn on cognition in scopolamine induced Alzheimer’s disease rat’s modelB. purpureaOrchid treeNemalapalli et al.2015[104]
17.Mori fructusimproves cognitive and neuronal dysfunction induced by beta-amyloid toxicity through the GSK-3β pathway in vitro and in vivoM. fructusMoraKim et al.2015[105]
18.Anticholinesterase and antioxidant properties of aqueous extract of Cola acuminateseed in vitroC. acuminateCola nutOboh et al.2014[106]
19.Antiamnesic effect of piracetam potentiated with Emblica officinalisand C. longain aluminum induced neurotoxicity of Alzheimer’s diseaseE. officinalisAamlaRamachandran et al.2013[107]
20Antiamnesic activity of Syzygium cuminiagainst scopolamine induced spatial memory impairments in ratsS. cuminiJamunAlikatte et al.2012[108]
21Acetylcholine and memory-enhancing activity of Ficus racemosabarkF. racemosaCluster figFaiyaz et al.2011[109]
22Protective effect of Morinda citrifoliafruits on beta-amyloid (25–35) induced cognitive dysfunction in mice: an experimental and biochemical studyM. citrifoliaNoniMuralidharan et al.2010[110]

Table 3.

Plants studied in Alzheimer’s disease.


6. Recent advances in the treatment of Alzheimer’s disease

In 2021 USFDA approved Aducanumab(marketed as Aduhelm) for the treatment of Alzheimer’s disease. It is an amyloid beta-directed antibody approved under the accelerated approval pathway based on reductioning amyloid β plaques observed in patients treated with this drug.

It was approved for medical use in the United States. Aducanumab has since been approved by the Ministry of Health and Prevention in the United Arab Emirates as of October 3, 2021, making it the second country in the world to approve the treatment.

Pharmacology-Mechanism of Action:Immunoglobulin gamma 1 (IgG1) monoclonal antibody directed against aggregated soluble and insoluble forms of amyloid beta. The buildup of beta amyloid plaques in brain is crucial pathophysiological hallmark of Alzheimer’s disease.

Dosage Form and Strength:Aduhelm is a clear to opalescent and colorless to yellow solution, accessible as: Injection: 170 mg/1.7 mL (100 mg/mL) in a single-dose vial and 300 mg/3 mL (100 mg/mL) in a single-dose vial [111].

Who should take this drug?

It is suggested for mild cognitive impairment (MCI) or mild dementia stage of Alzheimer’s disease [112, 113].

6.1 Novel compound under investigation

Here is the figure that shows the agents which is in developing stage involve in the trials for the management of Alzheimer’s disease. Most of agents in the trial target disease modification [114] (Figure 2).

Figure 2.

Drugs in clinical trials for treatment of Alzheimer’s disease in 2021. In which the shape of icons shows the population involve in trials; the outer ring shows drugs in Phase I; the middle rings shows drugs in Phase II; the inner most ring shows drugs in Phase III trials [17].

In which the shape of icons shows the population involve in trials; the outer ring shows drugs in phase I; the middle rings shows drugs in phase II; the inner most ring shows drugs in phase III trials [115].


7. Conclusion

Alzheimer’s disease is serious brain disorder, at present there is no cure for this disease but currently it can be controlled by using a drugs which symptomatically treat AD. AChE inhibitors are the first approved anti-AD drugs by the FDA, and they are also the first and the most useful drug used in the clinical treatment of AD. But now few of drugs also approved by USFDA in 2021 for the treatment of AD and few also in the trial phase. Results from clinical studies have shown different new drugs in pipeline and various novel approaches may also beneficial for treating AD. Interests in the utilization of different herbal products also increase day by day. This study provides the details about recent advancement the medicinal plants against the Alzheimer’s disease. Availability of these new medicinal plants for AD will further increase the treatment options and thus provide a significant benefit to patients who remain uncontrollable to existing therapy.


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Written By

Afreen Hashmi, Vivek Srivastava, Syed Abul Kalam and Devesh Kumar Mishra

Submitted: September 16th, 2021 Reviewed: January 19th, 2022 Published: March 15th, 2022