life

Review
Phytochemicals: A Promising Alternative for the Prevention of
Alzheimer’s Disease
Bhupendra Koul 1, *,† , Usma Farooq 2,† , Dhananjay Yadav 3,† and Minseok Song 3, *

1 Department of Biotechnology, Lovely Professional University, Phagwara 144411, Punjab, India

2 Department of Botany, Lovely Professional University, Phagwara 144411, Punjab, India
3 Department of Life Sciences, Yeungnam University, Gyeongsan 38541, Republic of Korea
* Correspondence: bhupendra.18673@lpu.co.in (B.K.); minseok@yu.ac.kr (M.S.)
† These authors contributed equally to this work.

Abstract: Alzheimer’s disease (AD) is a neurological condition that worsens with ageing and affects
memory and cognitive function. Presently more than 55 million individuals are affected by AD all
over the world, and it is a leading cause of death in old age. The main purpose of this paper is to
review the phytochemical constituents of different plants that are used for the treatment of AD. A
thorough and organized review of the existing literature was conducted, and the data under the
different sections were found using a computerized bibliographic search through the use of databases
such as PubMed, Web of Science, Google Scholar, Scopus, CAB Abstracts, MEDLINE, EMBASE,
INMEDPLAN, NATTS, and numerous other websites. Around 360 papers were screened, and, out
of that, 258 papers were selected on the basis of keywords and relevant information that needed to
be included in this review. A total of 55 plants belonging to different families have been reported
to possess different bioactive compounds (galantamine, curcumin, silymarin, and many more) that
play a significant role in the treatment of AD. These plants possess anti-inflammatory, antioxidant,
anticholinesterase, and anti-amyloid properties and are safe for consumption. This paper focuses on
the taxonomic details of the plants, the mode of action of their phytochemicals, their safety, future
prospects, limitations, and sustainability criteria for the effective treatment of AD.

Keywords: Alzheimer’s disease; medicinal plants; phytochemicals; neurological diseases treatment

Citation: Koul, B.; Farooq, U.; Yadav,

D.; Song, M. Phytochemicals: A
Promising Alternative for the 1. Introduction
Prevention of Alzheimer’s Disease. Alzheimer’s disease (AD) is a neurological disorder in humans caused by complex
Life 2023, 13, 999. https://doi.org/
pathophysiological mechanisms that lead to loss of memory and cognition, death of neu-
10.3390/life13040999
rons, loss of synapses, and damage of the brain, which culminates in death [1,2]. It is the
Academic Editor: Stefania Lamponi world’s most prevalent form of dementia and the dominant neurodegenerative disorder.
Neurodegenerative diseases signify a great public health alarm and social and economic
Received: 20 March 2023
problem due to the high death rates and high treatment costs. Additionally, current treat-
Revised: 6 April 2023
ments for AD are only able to lessen its symptoms and cannot halt the progression of
Accepted: 9 April 2023
neurodegeneration [2]. Alois Alzheimer, a German psychiatrist (1864–1915), gave the first
Published: 12 April 2023
explanation of it in 1906. Henceforth, the condition was given the term “Alzheimer’s
disease” by Kraepelin [3]. About half of the world’s population above the age of 80 years
are suffering from AD which has been ranked as the seventh leading cause of death [4].
Copyright: © 2023 by the authors. Presently, more than 55 million AD patients are reported across the globe, and it is predicted
Licensee MDPI, Basel, Switzerland. that number may double every five years, so as to reach 115 million by 2050 [4,5]. The two
This article is an open access article primary pathological symptoms of AD are considered to be senile plaques and neurofibril-
distributed under the terms and lary tangles. In the ageing brain, misfolded protein accumulates and leads to metabolic
conditions of the Creative Commons loss, oxidative stress-induced damage, and synapse dysfunction. In AD, oxidative damage
Attribution (CC BY) license (https:// is indicated by high levels of DNA oxidation products such as 8-hydroxydeoxyguanosine
creativecommons.org/licenses/by/ in the brain cell nucleus and mitochondria [6–8].
4.0/).

Life 2023, 13, 999. https://doi.org/10.3390/life13040999 https://www.mdpi.com/journal/life

Life 2023, 13, 999 2 of 35

AD is divided into five stages, mild cognitive impairment (MCI), mild, moderate,
severe, and very severe AD [4]. According to several studies, the very early stage is
called MCI, which can last for years without changing and is primarily associated with
memory loss as well as cognitive impairments. The mild AD stage is characterised by
forgetfulness and short-term memory loss, loss of interest in hobbies, repetitive questioning,
and change of routine. Patients may become unable to execute a variety of duties on their
own as the condition progresses, especially in those tasks that require cognition [9,10].
In moderate AD, more abrupt shifts and impaired routine are seen along with early-
stage psychological dementia, which follows ongoing cognitive deficits and care-related
transitions. At this point, 30% of patients may also experience illusionary misidentifications,
which is long-term memory loss [9]. Severe AD, the fourth stage, is marked by disturbed
and restless sleep patterns, rising indications of psychological disorders associated with
dementia, and may even require assistance in bathing, feeding, or dressing [11]. Hence,
these patients are totally dependent on caretakers. The most advanced stage of AD is
referred to as very severe AD and is characterised by limited verbal speech, such as the use
of single words or short sentences that finally lead to no speaking, bed rest, and the loss of
fundamental psychomotor abilities. Patients eventually lose the ability to perform any task
independently. In addition to AD, at this stage, conditions such as pneumonia or ulcers
may also cause death [12].
There are different mechanisms of neurodegeneration such as inflammation of neurons,
oxidative stress, environmental conditions, genetics, aggregation of Aβ (β-amyloid) in the
brain, and dysfunction of the mitochondria [13–15]. There is currently no known cure for
AD, however, preventative strategies are a hot topic of discussion. Currently, there is a low
rate of clinical development for AD medications, and the majority of medical research is
focused on slowing the progression rather than treating patients [16]. Very few drugs such
as donepezil, rivastigmine, galantamine, and memantine are approved by the FDA for the
treatment of AD [17,18]. These drugs only manage the early symptoms, show various side
effects, and are costly. Each year, more than $600 billion is spent globally on the treatment of
AD [19]. Therefore, it is crucial to look for novel approaches for the treatment of AD [20,21]
and studies have suggested that phytochemicals such as huperzine, galantamine, quercetin,
resveratrol, rosmarinic acid, and many more are obtained from various plants and have the
potential to safely reduce the risk of AD [22–24].
Unfortunately, explicit information regarding the use of phytochemicals in the treat-
ment of AD and AD-related symptoms is fragmentary. We intend to bridge this gap
and provide information regarding the same. This review focuses on the use of different
phytochemicals and their clinical trials for the prevention of AD, their limitations, and
future prospects.

2. Factors Contributing to AD
AD is thought to be a complex disorder with a number of risk factors (Figure 1) such
as age, consumption of alcohol, smoking, poor diet, sedentary lifestyle, environmental
factors, and certain health issues such as damage to the vascular system, dysfunctioning of
the immune system, high blood pressure, diabetes, atherosclerosis etc., [25,26].

2.1. Age Factors

Considering that several pathological alterations in AD are similar to those seen during
ageing, with the exception of their intensity, it has been suggested that AD may represent
an accelerated form of ageing. Therefore, in AD there is an age-related reduction in brain
weight and volume, ventricle widening, and dendritic and synaptic loss in specific parts
of the cognitively intact brain [27]. There may be two additional ageing processes playing
a role in AD. First, a myelin breakdown brought by ageing [28] and, the second is the
damage of locus caeruleus cells (LC), which induces microglia to reduce Aβ production
and transmit noradrenaline via terminal varicosities to the cortex [29]. Early occurrence of
tau-immunoreactive tumor necrosis factor in the LC is linked with AD [30]. This suggests
 Life 2023, 13, 999 3 of 35

Life 2023, 13, x FOR PEER REVIEW 3 of 34

that vascular factors could contribute to Alzheimer’s illness. The blood–brain barrier may
deteriorate with ageing due to cell death in the LC.

Figure 1. Factors contributing to Alzheimer’s disease (AD). APP-amyloid precursor protein, PSEN-
Figure 1. Factors contributing to Alzheimer’s disease (AD). APP-amyloid precursor protein, PSEN-
presenilin, ApoE-apolipoprotein E.
presenilin, ApoE-apolipoprotein E.
2.1.
2.2.Age Factors of Anatomical Pathways
Degeneration
Considering
This is anotherthathypothesis
several pathological
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arebeen suggested that AD may rep-
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resent an accelerated form of ageing. Therefore, in AD there is an age-related reduction in
2.2.1.weight
brain Cholinergic Pathwayventricle widening, and dendritic and synaptic loss in specific
and volume,
parts One
of theof cognitively intact brain
the initial hypotheses for[27]. Thereofmay
the origin AD bewastwo additional
a particular ageing processes
degradation of the
cholinergic
playing neurotransmitter
a role system.breakdown
in AD. First, a myelin Many studies have shown
brought the loss
by ageing [28]ofand,
acetylcholine
the second inis
thedamage
the AD brain. of Further investigations
locus caeruleus revealed
cells (LC), decreased
which induceslevels of choline
microglia acetyltransferase
to reduce Aβ produc-
(CAT)
tion and[31]. In addition,
transmit it is noted
noradrenaline that neurons
via terminal are lostto
varicosities inthe
thecortex
nucleus basalis
[29]. Earlyofoccur-
the
Meynert (nBM), a region of the brain that receives diffuse cholinergic
rence of tau-immunoreactive tumor necrosis factor in the LC is linked with AD [30]. This projection [32].
Several researchers
suggests that vasculardiscovered elevated
factors could 5-hydroxytryptamine
contribute to Alzheimer’s (5-HT) turnover
illness. in AD and
The blood–brain
hypothesised
barrier that this was
may deteriorate withcaused
ageingbydue
a selective loss ofincortical
to cell death the LC.5-HT neurons [33].

2.2. Degeneration of Anatomical Pathways

This is another hypothesis regarding the pathology of AD. These pathways generally
link action to perception. Under these two pathways are included.
Life 2023, 13, 999 4 of 35

2.2.2. Cortico-Cortical Pathways

Multiple lines of evidence suggest that AD is characterized by the degradation of
anatomical networks connecting various regions of the cerebral cortex [34,35]. The dupli-
cated local neuronal circuit represented by “columns” or “modules” is a key aspect of the
cerebral cortex’s architectural structure. Numerous studies indicate a connection between
AD and the deterioration of these cortical circuits. Many researchers identified a decrease
in synaptophysin reactivity in the cortex associated with AD and linked it to synapse loss
in the temporal lobe [36]. Some studies discovered a reduction in the synaptic marker SP6
in every area of the AD brain [36,37].

2.3. Environmental Factors

There are several environmental factors linked to AD, although the majority of research
focuses on three of them: exposure to aluminium (Al), the impact of head injury, and the
influence of food and malnutrition [38].

2.3.1. Aluminium Toxicity

The evidence that aluminium causes AD is somewhat circumstantial and argumen-
tative. Additionally, out of 13 studies that examined aluminium levels in gross brain
tissue, 9/13 discovered elevated levels in AD, compared to the controls [39], whereas
4/13 showed no significant differences. Since injured brains accumulate aluminium, there-
fore, the chances of AD increase. Pyramidal neurons that contain neurofibrillary tangle
(NFT) have also been found to possess Al. It may bind to DNA and modify cytoskeletal
proteins, causing NFT to develop. Apart from establishing that Al can be neurotoxic in
acute dosages, neuropsychological diseases are caused by intense exposure to Al, for exam-
ple, bladder irrigation which is used to treat haemorrhagic cystitis with a 1% alum solution,
or dialysis dementia [40,41].

2.3.2. Head Injury

Primary head trauma from injury extends to initially unaffected areas via inflammatory
cytokines and worsens the initial injury as a result of the immune and microglial cell
activation in the CNS [42]. Several findings pointed towards the connection between AD
and head trauma. Amyloid precursor protein (APP) is present around Aβ deposits in
neuronal perikarya. These results imply that one mechanism by which AD originates and
spreads in the brain through cell-to-cell transfer is the brain injury-mediated formation of
pathogenic proteins [43,44].

2.3.3. Food and Malnutrition

Studies on how diet affects AD have been more prevalent in recent years. Antioxidants,
vitamins, polyphenols etc. are a few dietary supplements that have been shown to reduce
the risk of AD, although high-calorie foods and saturated fats exacerbate the risk of AD [45].
As a consequence of the nonenzymatic glycation of free amino groups in proteins, lipids,
and nucleic acids, heat-sensitive micronutrients such as vitamin C and folates degrade, a
significant quantity of water is lost, and hazardous secondary products (advanced glycation
end products: AGEs) are formed [46,47]. The harmful impact of AGEs is their capacity
to cause oxidative stress and inflammation by altering the structure and function of the
body’s proteins and cell surface receptors. Several investigations have shown that a raised
AGEs serum level is linked to cognitive deterioration and the development of AD [48].
The AGE receptor (RAGE), which is present in the microglia and astrocytes among other
body tissues, has been shown to be overexpressed in the brains of AD patients where it
serves as a cell surface receptor and a transporter for Aβ [49]. An additional AD risk factor
is malnutrition, as low levels of minerals, including vitamin D, vitamin B12, and folate,
may impair cognitive performance. Patients with AD also face difficulties swallowing and
eating, which raises the chances of malnutrition [50].
Life 2023, 13, 999 5 of 35

2.4. Genetic Factors

There is proof that first-degree relatives of AD patients have a higher probability of
developing AD. A few genes (APP, PSEN, and Apo E) have been associated with AD [50].

2.4.1. Amyloid Precursor Protein (APP)

The APP gene which is located on chromosome 21 codes for a type I transmembrane
protein that is cleaved by the enzymes α-, β-, and γ-secretase to release Aβ and other
proteins. The APP gene has thirty mutations, of which twenty-five are linked to AD and
result in increased quantities of Aβ. Strong evidence links some uncommon variants of
early-onset familial Alzheimer’s disease (EO-FAD) to particular genetic variables and a few
cases of AD seen during the early 1990s were connected to APP gene alterations [51,52]. The
most prevalent Aβ-peptide formed by the cleavage of APP is Aβ-42, which is mostly seen
in senile plaque (SP). The greater soluble Aβ-40 is also found in connection with cerebral
micro vessels and may manifest later in the disease’s progression [53]. Furthermore, Aβ-38
may accumulate in vessel walls as a result of alterations in the Aβ coding region of the
APP, particularly in cases of severe cerebral amyloid angiopathy (CAA) [54].

2.4.2. Presenilin (PSEN)

PSEN genes are the autosomal dominant form of early-onset Alzheimer’s disease
(EO-AD) present in chromosome 14. The most prevalent form of familial Alzheimer’s
disease (FAD) is connected to alterations in the PSEN genes, and it is also hypothesised
that these mutations, though more indirectly, cause the elevated deposition of Aβ [55]. The
ER membrane has nine transmembrane domains that make up the full length of PSEN [56].
It is of two types, PSEN-1 and PSEN-2.
PSEN-1 is a key protein that plays a crucial part in the synthesis of Aβ from APP by
activating the α, β, and γ-secretase complex. PSEN-1 has a crucial role in maintaining mem-
ory and neurons, as demonstrated by the synaptic dysfunction and memory impairment
that result from PSEN1 knockout experiments in mice [57]. By lowering the levels of Aβ-40,
and alterations in the PSEN-1 gene, the ratio of Aβ-42 to Aβ-40 is raised.
PSEN-2 mutations, in contrast, are uncommon and have a negligible effect on the
production of Aβ. If there are normal PSEN-1 alleles present, any mutation in PSEN-2 may
significantly affect the Aβ 42/40 ratio and cause familial AD [57].

2.4.3. Apolipoprotein E (Apo E)

Glycoprotein ApoE is abundantly expressed in some microglia, the liver, and the brain.
It assists as a ligand for receptor-mediated endocytosis for cholesterol-containing lipopro-
tein particles, which are necessary for the synthesis of myelin and healthy brain working.
Due to single-nucleotide polymorphisms (SNPs) that alter the coding sequence, the ApoE
gene present on chromosome 19 has three isoforms, ApoE2, ApoE3, and ApoE4 [58,59].
The frequency of ApoE4 in people with AD is 2–3 times higher than in people with normal
cognition. Additionally, Apo E4 is frequently linked to an early onset of the disease since
it can accelerate the emergence of AD in the aged brain. A recognised indicator of AD is
cerebral amyloid angiopathy (CAA) which is caused by ApoE4 activity and plays a crucial
part in the deposition of Aβ as a senile plaque [60].

2.5. Mitochondrial Dysfunction

Mitochondria are the main source of oxidative stress due to the unavoidable leakage
of electrons that occurs during electron transfer, which results in the continuous production
of superoxide anion, which accounts for 90% of the endogenic ROS despite the presence
of an effective mitochondrial–cellular antioxidant system [61]. It is hypothesised that
defective mitochondria are less effective in producing ATP but more effective at producing
ROS, which may be a significant contributor to oxidative imbalance, as seen in AD [61,62].
Certainly, a significant and early sign of AD is mitochondrial dysfunction [63]. Some of the
impairments reported in mitochondria during AD are discussed below.
Life 2023, 13, 999 6 of 35

2.5.1. Reduction in Energy Metabolism

One of the most well-known anomalies in AD is a decreased rate of energy metabolism
in the diseased brain. Low glucose metabolism is actually thought to be a sensitive measure,
helpful for tracking changes in cognition and functionality in AD and mild cognitive
impairment (MCI). This method assists in analysis and facilitates the anticipation of future
cognitive decline [64–66].

2.5.2. Changes in the Primary Oxidative Phosphorylation Enzymes

According to a genome-wide transcriptome investigation, reduced neural expression
of nuclear genes encoding components of the mitochondrial ETC may be related to cerebral
glucose metabolic impairment in AD. In fact, several important oxidative metabolism
enzymes, such as the pyruvate dehydrogenase complex, α-ketoglutarate dehydrogenase
complex, and cytochrome oxidase, all show decreased expression in AD [67].

2.5.3. Dyshomeostasis of Calcium

ER calcium channels are directly impacted by dysfunctional mitochondria, which
results in decreased buffering capacity, which leads to calcium dyshomeostasis [68]. The
ER develops calcium overload and calcium uptake is reduced as a result of calcium mis-
management in peripheral cells from AD patients.

2.5.4. Mitochondrial DNA (mtDNA)

The brains of AD patients show elevated levels of spontaneous mtDNA alterations,
including the most prevalent 5-kb deletion [69]. The mtDNA regulatory areas had a number
of alterations that were specific to AD. MtDNA is susceptible to ROS attack since it lacks
protective proteins such as histone, has a relatively ineffective DNA repair machinery,
and is located near the place where ROS are produced. In the mtDNA of AD brains, the
presence of an oxidised nucleoside indicated a three-fold increase in oxidative damage [70].

2.6. Vascular Factor

It was proposed by de la Torre and Mussivand in 1993. These scientists noticed that
cerebral blood flow, glucose metabolism, and oxygen consumption decreased in accordance
with the severity of the disease in AD patients. Several studies confirm the relation between
various vascular factors and an elevated chance of developing AD. According to research,
arterial hypertension raised the risk of AD in older people who had never taken antihyper-
tensive medication [71]. Several researchers showed that middle-aged individuals with
systolic hypertension and high blood cholesterol levels had a higher risk of AD in the
future [72,73]. Atherosclerosis and AD are related as atherosclerotic individuals have a
threefold increased risk of AD. The blood–brain barrier (BBB) plays a significant role in
controlling how circulating metabolites reach brain tissue and disruption of the BBB may
significantly affect the accumulation of hazardous chemicals in the brain [74]. There has
been evidence that AD causes a decrease in the levels of numerous tight-junction and
adherens-junction proteins and their adaptor molecules, causing changes in BBB perme-
ability. There are pieces of evidence that the BBB plays a role in controlling Aβ levels in the
CNS. RAGE, or the receptor for advanced glycation end products, controls the spread of
toxicity and their transfer to the brain. RAGE expression in the brain’s endothelium offers
a mechanism for the influx of Aβ and monocytes carrying Aβ across the BBB [75].

2.7. Immune System Dysfunction

There are numerous pieces of evidence that indicate AD patients have immune system
abnormalities. Immunoglobulins, helper and cytotoxic/suppressor T-cells, circulating
immune complexes (CIC) in peripheral tissue, and cerebral blood vessels complement
proteins linked to the ‘classical pathway’, brain reactive antibodies, immunoglobulins,
abundant reactive microglia, and more, have been seen in AD [76,77]. Complement system
proteins serve as pattern recognition molecules that help glial cells that carry complement
Life 2023, 13, 999 7 of 35

receptors that take up Aβ. Major histocompatibility locus (MHC) antigens have also been
shown to undergo significant changes indicating either enhanced antigen resistance or
susceptibility in AD. These immune responses may be a response to AD’s pathogenic
processes, particularly the Aβ deposition [78].
A further immunological contributor to AD includes the conversion of arginine to
citrulline through the activity of peptidyl-arginine deiminases (PAD), enzymes that catalyse
the post-translational, and this process is known as the ‘citrullination process’. Citrullinated
proteins are expressed in the hippocampus and cerebral cortex as a result of the selective
expression of PAD2 and PAD4 in astrocytes and neurons, respectively. As a result, the loss
of neurons, and the loss of cellular components, such as citrullinated proteins in AD, may
cause an autoimmune reaction and the formation of autoantibodies [79].

2.8. Infections
Some studies revealed that infection might be a factor in AD. A viral invasion could
activate microglia and pericytes, resulting in the development of amyloid. In addition,
antibodies against the herpes simplex virus (HSV) might be present in the cerebral spinal
fluid (CSF) of AD patients. HSV can cause aberrant protein production, which can lead
to the paired helical filament (PHF) and neurofibrillary tangles (NFT) [80,81]. The BBB
that selectively regulates the movement of molecules in and out of the brain shields the
CNS with microvascular endothelial cells (pericytes and astrocytes). A wide range of
microorganisms, however, can enter the BBB and cause a number of serious disorders.
Viruses can directly infect endothelial cells, pass through the BBB, and enter the central
nervous system, though bacteria are capable of traversing the BBB using a variety of meth-
ods, including transcellular traversal, paracellular traversal, and trojan horse, so an acute
inflammatory state becomes a chronic one [82]. Uncertainty exists regarding the potential
for COVID-19 to either initiate or accelerate the new onset of Alzheimer’s. One latest study
demonstrating an elevated risk for SARS-CoV-2 infections in fully immunized individuals
with Alzheimer’s disease was conducted using the TriNetX Analytics network technol-
ogy [83]. The study’s sample included 6,245,282 older persons (age 65) who had medical
interactions with healthcare organizations between 2 February 2020 and 30 May 2021 but
had not previously been diagnosed with Alzheimer’s. The population was divided into
COVID-19 cohorts and non-COVID-19 cohorts. Using closest neighbour greedy matching,
cohorts were propensity-score matched (1:1) for demographics, negative socioeconomic
health determinants, including issues with education, occupational exposure, physical,
social, and psychosocial environment, and recognized risk factors for Alzheimer’s dis-
ease [84]. Within 360 days of the COVID-19 diagnosis, the likelihood of a new diagnosis of
Alzheimer’s disease was estimated using a Kaplan–Meier analysis. Before propensity-score
matching, the COVID-19 cohort had a total risk of 0.68% for receiving a new diagnosis of
Alzheimer’s disease compared to a non-COVID-19 cohort’s 0.35%. After matching based on
propensity scores, the COVID-19 cohort had a higher chance of receiving a new diagnosis
of Alzheimer’s disease than the matched non-COVID-19 group [85].

3. Treatment of AD
There are already more than 55 million cases of AD documented globally, and by
2050, the overall number of AD patients is expected to more than triple [4,5]. Even though
it is a serious health issue proper and complete treatment is not available, treatment
strategies used today concentrate on assisting patients in managing behavioural symptoms,
sustaining mental function, and delaying or preventing the signs of illness. Two treatment
strategies can be adopted as discussed below.

3.1. Chemical-Based Treatment

Despite the fact that AD is a public health problem, there are currently only two
classes of medications that have been approved by the FDA to treat AD: cholinesterase
Life 2023, 13, 999 8 of 35

enzyme inhibitors (naturally occurring, synthetic, and hybrid analogues), and antagonists
to N-methyl D-aspartate (NMDA).

3.1.1. Cholinesterase Inhibitors

According to the cholinergic theory, a reduction in the synthesis of acetylcholine (ACh)
causes AD. A reduction in acetylcholinesterase along with an increase in cholinergic levels
is one therapy that enhances neuronal cell and cognitive function [86]. Acetylcholine
breakdown in synapses is prevented by acetylcholinesterase inhibitors (AChEIs), leading
to continuous ACh build up and cholinergic receptor activation. Another approach to
treating AD may involve raising choline reuptake and, consequently, the generation of
acetylcholine at presynaptic terminals. This might be done by focusing on the choline
transporter (CHT1), which is in charge of supplying the choline required for the synthesis
of ACh [86,87]. Different AChEIs are donepezil, rivastigmine, and galantamine.

Donepezil
The most effective medication for treating AD is donepezil, which is a derivative of
indanonebenzylpiperidine and a member of the second generation of acetylcholinesterase
inhibitors (AChEIs). Due to donepezil’s reversible binding to acetylcholinesterase, there is
more ACh present at the synapses and prevents it from being hydrolysed. With transient
cholinergic side effects that affect the neurological, as well as gastrointestinal systems,
the medicine may be tolerated by the patient. Notably, donepezil is used to treat AD
symptoms, such as improving cognition and behaviour [88,89]. Due to an imbalance in
acetylcholine, unusual adverse reactions such as extrapyramidal side effects are more
likely to occur when AD medication is used along with psychiatric medicines. A case of an
extrapyramidal adverse response brought on by the donepezil and risperidone combination
was reported [90]. The patient experienced fatigue, nausea, panic, sweating, and vomiting.

Rivastigmine
It is a butyrylcholinesterase (BuChE) and acetylcholinesterase (AChE) pseudo-
irreversible inhibitor. In order to function, it binds to the two active sites of AChE which
are estearic and anionic sites, which stops acetylcholine (Ach) metabolism [91]. In the
healthy brain, glial cells contain BuChE and have only a 10% activity level compared to
the AD brain, where it has a 40–90% activity level, while simultaneously reducing ACh
activity. This implies that BuChE activity can be a sign of mild to severe AD. Rivastigmine
is metabolised by AChE and BuChE at the synapses and dissociates slower than AChE,
which is why it is known as a pseudo-irreversible. The drug is used for the treatment of
mild to moderate AD. It ameliorates daily activities and cognitive processes [92,93]. The
most common adverse effects of rivastigmine are gastrointestinal problems such as bladder
pain, painful urination, etc.

Galantamine (GAL)
For mild to severe AD cases, it is regarded as a conventional first-line medication.
Galantamine is a dual-mode selective tertiary isoquinoline alkaloid, which not only acts as
a competitive inhibitor of AChE but also has the ability to allosterically bind to and activate
the nicotinic acetylcholine receptors subunit. Like other AChE inhibitors, GAL has good
efficacy and tolerability and can reduce behavioural symptoms and improve daily activities,
cognitive performance, and mood [94,95]. For transporting the medicine only to the areas
of the brain that were injured, it is linked to hydroxyapatite particles that contain ceria. To
transport GAL hydrobromide, some researchers have used solid-lipid nanoparticles and
nano emulsification techniques [96]. The results of these tests are promising for the safe
administration of the drug. Nasal delivery of a GAL hydrobromide–chitosan combination
of nanoparticles has good pharmacological potential, while the controlled release dose of
the drug has been transported via the patch technique by another group. The common
Life 2023, 13, 999 9 of 35

problems associated with this drug are gastrointestinal problems, headache, dizziness,
insomnia, weight loss, loss of appetite, etc. [96,97].

3.1.2. N-methyl D-aspartate Receptor (NMDAR) Antagonists

It is thought that NMDAR performs an important role in the pathophysiology of AD.
Ca2+ influx brought on by NMDAR activation promotes signal transduction, and results in
gene transcription that is required for the growth of long-term potentiation (LTP), which is
essential for the establishment of synaptic neurotransmission, plasticity, and memory [98].
Excessive NMDAR activation overstimulates glutamate, the main excitatory amino acid
in the CNS, which results in excitotoxicity, synaptic malfunction, neuronal cell death, and
damage to cognitive abilities. Numerous NMDAR uncompetitive antagonists have been
created and tested in clinical settings, though the majority of them were ineffective and had
undesirable side effects [99]. The sole drug in this class that is approved for the treatment
of moderate to severe AD is memantine.

Memantine
It is an uncompetitive, low-affinity antagonist of the glutamate receptor subtype.
To treat mild to severe AD, memantine is administered alone or in combination with
AChEI [95]. The drug has a low affinity and is quickly displaced from NMDAR by high
quantities of glutamate. It blocks excitatory receptors without impairing regular synaptic
communication, which makes it harmless, well tolerable, and avoids a long-lasting blockage.
Possible adverse effects of memantine are dizziness, constipation, vomiting, hypertension,
and headache [100].

3.2. Plant-Based Treatment

Currently available synthetic medicines are effective only for 1–4 years for mild to
moderate AD. Synthetic medicine exhibits many negative side effects [101]. Scientific
evidence related to the efficacy of phytochemicals in the prevention and treatment of AD
has been accumulating which shows that they are safe and cost effective. Oxidative stress
is one of the proven causes of AD. However, plants are reservoirs of antioxidants which
can mitigate the effects of AD [102,103]. Several plants were examined for their ability
to combat AD as listed in Table 1 and also shown in Figure 2. A diet high in plants has
repeatedly been linked to a lower risk of AD. It is advised to consume fruits, vegetables,
cereals, and nuts on a regular basis for overall health, to promote healthy ageing, and to
reduce the risk of age-related disorders such as AD [104,105].
Life 2023, 13, 999 10 of 35

Table 1. Different plants possessing anti-Alzheimer properties.

Plant Botanical Name Family Part Used Active Compounds Properties References
Glycowithanolides (Withaferin A,
Ashwangdha Withania somnifera Solanaceae Roots It has neuroprotective functions. [106,107]
Withasomniferin A)
Brahmine, bacosides A and B,
Brahmi Bacopa monnieri Plantaginaceae Arial parts It works as a memory enhancer. [108]
apigenin, and quercetin
It has acetylcholinesterase
Calabar bean Physostigma venenosum Fabaceae Seeds physostigmine [109]
inhibitor activities.
It is effective against Alzheimer’s
Coffee Coffea arabica Rubiaceae Seeds Caffeic acid, chlorogenic acid [110]
disease.
It acts as a scavenger of free
radicals and protects the central
Milk thistle Silybum marianum Asteraceae Seeds Silymarin [111]
nervous system against any injury
and memory impairment.
Ferulic acid, commiphoric acid,
It acts as a scavenger of
Guggulu Commiphora wightii Burseraceae Bark eugenol, and [112]
superoxide radicals.
commophorinic acid
It helps in stimulating the brain
German chamomile Matricaria recutita Asteraceae leaves apigenin [113]
and calms the nerves.
It has anti-inflammatory and
Antioxidants, vitamins C, B, antidiabetic, properties, and also
Blueberry Vaccinium corymbosum Ericaceae Fruit [114,115]
β-carotene, lutein, and zeaxanthin helps in preventing
Alzheimer’s disease.
Carnosic acid, carnosol,
It has antioxidant properties and
Rosemary Rosmarinus officinalis Lamiaceae Leaves rosemanol, rosmarinic acid, and [116]
reduces the risk of AD.
α-pinene
Galanthamine, nivalidine, It has antioxidant and
Snowdrop Galanthus nivalis Amaryllidaceae Bulbs [117]
narwedine, and lycorine antiamyloid activities.
Life 2023, 13, 999 11 of 35

Table 1. Cont.

Plant Botanical Name Family Part Used Active Compounds Properties References
Curcumin,
bisdemethoxycurcumin, eugenol
It has antioxidant properties so it
demethoxycurcumin, zingiberene
Turmeric Curcuma longa Zingiberaceae Rhizome helps in preventing [118,119]
dihydrocurcumin, azulene,
Alzheimer’s disease.
D-camphene, caprylic acid, cineol,
and turmerone
quercetin, Hypericin, rutin It possesses antioxidant and
St. John Wort Hypericum perforatum Hypericaceae Entire plant [120,121]
quercetin, and isorhamnetin, antiamyloid activities.
It reduces acetylcholinesterase
levels and shows better results in
Black pepper Piper nigrum Piperaceae Seeds piperine [122]
the treatment of
Alzheimer’s disease.
S-allyl-cysteine,
S-allyl-mercaptocysteine It shows antiamyloid and
Garlic Allium sativum Lilliaceae Cloves [123,124]
Biophenols: caffeic acid, and antitangle properties.
ferulic acid
It has antioxidant properties. It
Ginkgolides A, B, C, J and M,
increases the blood flow in the
bilobalide, quercetin,
Ginkgo Ginkgo biloba Ginkgoaceae Leaves brain and acts as a scavenger of [125,126]
sesquiterpene kaempferol,
free radicals and shows
and isorhamnetin
neuroprotective properties.
Camphor, limonene, alpha-pinene, It helps in improving memory
Coriander Coriandrum sativum Apiaceae Leaves geraniol, petroselinic acid, and also helps in managing [127,128]
and linalool Alzheimer’s disease.
It shows
Sesame Sesamum indicum Pedaliaceae seeds Sesaminol, sesamine [129]
neuroprotective properties.
Quercetin, catechin,
Apple Malus pumila Rosaceae Fruit It improves cognitive functions. [130]
and epicatechin
It improves the functioning of the
Ginseng Panax ginseng Araliaceae Roots Ginsenosides, gintonin central nervous system, and it also [131,132]
shows anti-amyloid activity.
Life 2023, 13, 999 12 of 35

Table 1. Cont.

Plant Botanical Name Family Part Used Active Compounds Properties References
resveratrol, oxyresveratrol,
It has antioxidant properties and
Mulberry Morus alba Moraceae Fruit chlorogenic acid, mulberroside, [133]
helps in lowering the risk of AD.
moracin, and maclurin
Quercetin, myricetin, kaempferol, It possesses
Gotu kola Centella asiatica Apiaceae Leaves [134]
rutin, and apigenin anti-amyloid properties.
Tenuigenin, tenuifolin, and It acts as an acetylcholinesterase
Seneca snakeroot Polygala tenuifolia Polygalaceae Roots [135,136]
xanthone glycosides and beta-secretase 1 inhibitor.
It has very good antioxidant
Rosavin, salidroside, rosin,
Golden root Rhodiola rosea Crassulaceae Roots activity and also acts as a [137,138]
cinnamoyl alcohol, and tyrosol
cognitive enhancer.
Citral, protocatechuic acid, caffeic
Lemon balm Melissa officinalis Lamiaceae Leaves It acts as a memory enhancer. [139]
acid, and rosmarinic acid
Vinpocetine, apovincaminic acid,
kaempferol glycosides, It acts as a memory enhancer and
Dwarf periwinkle Vinca minor Apocynaceae Upper parts [140]
hydroxybenzoic acids, and also shows antioxidant properties.
chlorogenic acid
Gallocatechin, Gallic acid,
epigallocatechin, epicatechin, It possesses antioxidant and
Green tea Camellia sinensis Theaceae Leaves [141,142]
epigallocatechin gallate, antiamyloid activities.
and caffeine
It has antioxidant and antiamyloid
Resveratrol, quercetin,
Grapes Vitis vinifera Vitaceae Fruit properties and is used in [143]
and catechins
preventing neurodegeneration.
Tetrahydrocannabinol,
Marijuana Cannabis sativa Cannabaceae Bud and leaves It shows antiamyloid activity. [144]
cannabidiol
Oleuropein, tyrosol, It possesses antioxidant,
Olive Olea europaea Oleaceae Fruit, oil, leaves hydroxytyrosol, caffeic acid, anti-inflammatory, and [145]
verbascoside, and rutin antiamyloid properties.
It increases the level of
Brazil nut Bertholettia excelsa Lecythidaceae Nut Lecithin [146]
acetylcholine n AD patients.
firmoss Huperzia serrata Lycopodiaceae Aerial parts Huperzines It possesses antiamyloid activity. [147]
Life 2023, 13, 999 13 of 35

Table 1. Cont.

Plant Botanical Name Family Part Used Active Compounds Properties References
Ellagic acid, gallagic acid It possesses antioxidant and
Pomegranate Punica granatum Punicaceae Fruit [148,149]
punicalagin, and punicic acid antiamyloid activities.
It possesses antiamnesic,
Ptychonal, muirapuamine,
Marapuama Ptychopetalum olacoides Olacaceae Roots anticholinesterase, and [150,151]
and theobromine
neuroprotective properties.
It shows an inhibitory effect
Estragole, limonene, fenchone,
Fennel Foeniculum vulgare Apiaceae Seed against acetylcholinesterase and [152]
and β-myrcene
butyrlcholinesterase.
It possesses radical
Papaya Carica papaya Caricaceae Fruit Quercetin, β-sitosterol [153]
scavenging activity.
Crocin, crocetin, picrocrocin, It possesses antioxidant and
Saffron Crocus sativus Iridaceae Stigma [154]
safranin, and safranal, antiamyloid activities.
Ginger Zingiber officinale Zingiberaceae Rhizome Shagol, gingerol, zingerone It shows antioxidant properties. [155]
It shows antioxidant properties. It
Rosmarinic acid, thujone, cineol, has cognitive-enhancing
Sage Salvia officinalis Lamiaceae Leaves [156]
and camphor properties and helps in preventing
age-related problems.
Gallic acid, quinic acid, quercetin,
Camb Caryocar brasiliense Caryocaracea Leaf It has neuroprotective effects. [157]
and quercetin 3-o arabinose
Caproic acid, Caprylic acid,
It helps in preventing
Coconut Cocos nucifera Arecaceae Seed Capric acid, Lauric acid, and [158]
Alzheimer’s disease.
Myristic acid
It shows free radical scavenging
Rhynchophylline,
activity and also exhibits
Gouteng Uncaria rhynchophylla Rubiaceae Stem isorhynchophylline, [159]
protection against kainic
and hirsuteine
acid-induced neuronal damage.
Aloe vera Aloe barbadensis miller Aloaceae Juice Aloin, β-secretase, aloe-emodin It improves brain functioning. [160]
It increases the blood flow in the
Evodiamine, rutaecarpine,
Wuzhuyu Tetradium ruticarpum Rutaceae Fruit brain and also inhibits the effect of [161]
evocarpine, and quinoline
acetylcholinesterase.
Life 2023, 13, 999 14 of 35

Table 1. Cont.

Plant Botanical Name Family Part Used Active Compounds Properties References
It maintains the monoamine level
Glycoside niazirin, niaziminim A
Moringa Moring oleifera Moringaceae Leaves in the brain and helps in treating [162]
and B,
Alzheimer’s disease.
It reduces the risk of Alzheimer’s
α-tocopherol, ellagic acid, disease by reducing oxidative
Walnut Juglans regia Juglandaceae Kernel [163,164]
and juglone stress and it also shows
amyloidogenic activity.
It promotes the disassembly of tau
Cinnamaldehyde, eugenol, and
Cinnamon Cinnamomum verum Lauraceae Extract of bark filaments and also shows [165]
trans cinnamaldehyde
anti-inflammatory activity.
It lowers oxidative stress,
decreases lipid peroxidation, and
Tahitian gooseberry Phyllanthus acidus Phyllanthaceae Fruit Terpine [166]
helps in increasing the level of
antioxidant enzymes in the brain.
It has antioxidant activity, exhibits
Fig Ficus carica Moraceae Fruit Quercetin, C-Sitosterol memory-enhancing effects and [167]
better learning abilities.
Ferulic acid, caffeic acid, and It has antioxidant properties and
Pumpkin Cucurbita maxima Cucurbitaceae seeds [168]
coumaric acid helps in relieving stress.
It is consumed as a tonic for
Flavonol glycosides,
Shankhpushpi Convolvulus pluricaulis Convolvulaceae Whole plant enhancing memory and it calms [169,170]
anthocyanins, and triterpenoids
the nerves.
Strawberry Fragaria ananassa Rosaceae Fruit Pelargonidin It has antioxidant properties. [171]
Root and leaf It shows antioxidant properties
Butterfly pea Clitoria ternatea Fabaceae Myricetin, quercetin [172]
extract and AChE inhibitor activities.
Brassica oleracea var. It possesses antioxidant activities
Broccoli Brassicaceae Floret Kaempferol, sulforaphane [173]
italica and reduces cerebral oedema.
Ferulic acid, coumaric acid,
It reduces the neuronal death and
Spinach Spinacia oleracea Amaranthaceae Leaves quercetin, spinacetin, [174]
production of ROS.
and myricetin,
Cinnamic acid, caffeic acid,
It has antioxidant properties and
Date palm Phoenix dactylifera L. Arecaceae Fruit protocatechuic, gallic acid, [175]
helps in enhancing memory
dactylifiric acid, and epicatechin
 Spinach Spinacia oleracea Leaves acid, quercetin, spina- ronal death and pro- [174]
thaceae
cetin, and myricetin, duction of ROS.
Cinnamic acid, caffeic
It has antioxidant
Phoenix dactylifera acid, protocatechuic,
Date palm Arecaceae Fruit properties and helps [175]
Life 2023, 13, 999 L. gallic acid, dactylifiric 15 of 35
in enhancing memory
acid, and epicatechin

Figure 2. Different plant-based foods used for the prevention of Alzheimer’s disease (AD).
Figure 2. Different plant-based foods used for the prevention of Alzheimer’s disease (AD).

4. Plants with Anti-Alzheimer Properties

Different plants belonging to the families Solanaceae, Plantaginaceae, Fabaceae, Rubi-
aceae, Asteraceae, Ericaceae, Amaryllidaceae, Zingiberaceae, Pedaliaceae, Hypericaceae,
Piperaceae, Lilliaceae, Ginkgoaceae, Apiaceae, Araliaceae, Polygalaceae, Crassulaceae,
Lamiaceae, Apocynaceae, Theaceae, Vitaceae, Cannabaceae, Oleaceae, Lycopodiaceae, Puni-
caceae, Iridaceae, Lamiaceae, Caryocaracea, Arecaceae, Aloaceae, Rutaceae, Moringaceae,
Juglandaceae, Lauraceae, Phyllanthaceae, Moraceae, Convolvulaceae, Halymeniaceae,
Rosaceae, etc., have anti-Alzheimer properties and have been used for the treatment of AD.

4.1. Ginseng
Panax ginseng (family: Araliaceae), commonly known as ‘ginseng’ is one of the well-
known herbs in China, Japan, and Korea used to treat AD. It consists of phytochemi-
cals such as ginsenosides (saponins), a derivative of the triterpenoid dammarane, and
20(S)-protopanaxadiol, which prevents β-amyloid from aggregating and clears it from
neurons, relieves mitochondrial dysfunction, and boosts the secretion of the neurotrophic
factor [127,128]. According to a molecular enzyme study, ginsenosides have substan-
tial AChE inhibitory activities, which is an efficient strategy for lowering the symptoms
of AD [176,177]. Through the stimulation of phosphatidic acid receptors involved in
hemolysis, the bioactive glycoprotein gintonin lowers the production of Aβ and enhances
learning and memory. Additionally, it reduces AD symptoms by promoting autophagy,
anti-inflammatory mechanisms, antiapoptosis, and management of oxidative stress, as
proven by comprehensive in vivo and in vitro investigations [178]. Gintonin modulates the
G protein-coupled lysophosphatidic acid receptors which affect the cholinergic system and
neurotrophic factors, reducing the level of plaque formation. In a clinical experiment with
a limited sample size of 10 people who had mild cognitive impairment or early dementia,
gintonin intake (300 mg/day, 12 weeks) significantly enhanced Korean mini mental state
test scores at 4 and 8 weeks compared to baseline scores. In contrast, gintonin consumption
Life 2023, 13, 999 16 of 35

(300 mg/day, 4 weeks) significantly raised the ADAS-Cog-K and ADAS-non-Cog-K scores
on the Korean cognitive subscale of the Alzheimer’s disease assessment scale after 4 weeks
compared to the baseline scores. When it comes to gintonin toxicity in humans, none of the
patients reported any negative side effects during the 12-week dose of gintonin. Hence,
gintonin administration to older subjects with cognitive impairment was safe and well
tolerated [179].

4.2. Gotu Kola

Centella asiatica (family: Apiaceae) is commonly called ‘gotu kola’. It is a widespread
persistent herbaceous climber in Asia. It is used in traditional medicines for the purpose
of regenerating brain cells and enhancing memory, lifespan, and intellect [134]. Animal
studies have shown that Centella asiatica has an impact on neuronal structure, learning
ability, and memory-retaining ability. It has been shown to improve cognitive performance
by reducing phospholipase A2 (PLA2) activity, suppressing acetylcholinesterase activity,
preventing the formation of amyloid, and preventing brain damage [180,181]. In preclinical
studies, Centella asiatica was also discovered to have antidepressant, anxiolytic, antistress,
and seizure-prevention properties [182,183]. It has been shown to affect metabolic path-
ways connected to AD when administered to 5xFAD mice [184]. In rats overexpressed
with β-amyloid, Centella asiatica extract has been demonstrated to enhance memory and
decision-making, while it lowers hippocampus mitochondrial dysfunctioning. In a clinical
investigation, a 70% water-ethanol extract of C. asiatica demonstrated promising anxiolytic
properties by reducing anxiety and stress in patients [184].

4.3. Ginkgo
Ginkgo biloba (family: Ginkgoaceae) is commonly known as ‘ginkgo’. It is the most
well-known herb for treating Alzheimer’s and its symptoms. Terpene lactones and flavone
glycosides are both present in plant extracts. The terpene lactones include bilobalide A, B,
and C, and ginkgolides, while the flavone glycosides include kaempferol, quercetin, and
isorhamnetin [121]. Through the control of glutathione peroxidase, catalase, and superoxide
dismutase (SOD) activity, this herbal extract shields against Aβ generated neurotoxicity by
preventing apoptosis of neurons, reactive oxygen species (ROS) collection, glucose assimi-
lation, mitochondrial dysfunctioning, and activation of the extracellular signal-regulated
kinase (ERK) pathway [125,126]. Numerous studies have connected astrocytosis, microglio-
sis, and the presence of proinflammatory substances to the deposition of Aβ peptides [185].
G. biloba extracts demonstrated therapeutic advantage in AD, compared to donepezil, with
few unfavourable side effects. It is most recognized for its capacity to improve circulation
(vasorelaxing effect) throughout the body. G. biloba can thus reduce blood pressure and
prevent platelet aggregation [186]. In an experiment involving 18 randomized clinical
trials (RCTs) with 1642 individuals, 842 of them were in the experimental group (donepezil
hydrochloride plus G. biloba formulations) and 800 were in the control group (donepezil), it
was observed that donepezil with G. biloba can enhance clinical efficacy rates and verbal
memory. However, to validate this, more stringent trials will be required in the future [187].

4.4. Turmeric
Curcuma longa (family: Zingiberaceae) is commonly known as ‘turmeric’. Curcum-
inoids, such as curcumin, demethoxycurcumin, and bis-demethoxycurcumin, are the
phytochemicals present in turmeric. The primary curcuminoid is curcumin, which gives
turmeric roots their characteristically yellow colour. According to research, curcumin may
be a potential drug for treating AD [188]. The level of oxidative damage in the brain can be
reduced by curcumin. It has been shown that curcumin can reverse β-amyloid pathology
in a mouse model with AD [189]. The antioxidant and anti-inflammatory properties of
curcumin also facilitated in alleviating of some AD symptoms [118,119]. The capacity
of the Early Growth Response-1 (Egr1) protein to bind DNA is inhibited by curcumin,
which reduces inflammation. Activated microglia and astrocytes produce chemokines
Life 2023, 13, 999 17 of 35

which are known to cause monocyte chemotaxis and are also inhibited by curcumin at the
CNS. Effective ways to stop proinflammatory cytokine activation include decreasing the
production of ROS by stimulating neutrophils and suppressing the tumor necrosis factor α
(TNF-α) and interleukin-1 (IL-1) inflammatory cytokine expression [190,191]. Curcumin
inhibits the activity of the activator protein (AP-1), a transcription factor involved in the
synthesis of amyloid. The capacity of curcuminoids to prevent the generation and spread
of free radicals is proof that they possess potent antioxidant effects. It also prevents the
oxidation of free radicals and low-density lipoproteins which causes the destruction of
neurons in AD and other neurodegenerative diseases.

4.5. Brahmi
Bacopa monnieri (family: Plantaginaceae) commonly known as ‘brahmi’ is a persistent
creeper that is indigenous to the swamps of eastern and southern India, together with Aus-
tralia, Europe, Africa, Asia, North and South America, and the Middle East. In traditional
medicine, it is frequently used as a cardiotonic, diuretic, and nerve tonic [192,193]. The
main phytochemicals of Brahmi are Brahmine, bacosides A and B, apigenin, quercetin,
bacosaponins A, and bacosaponins B. Protein kinase activity is increased by B. monnieri
extracts, which has a nootropic effect. Rats administered Brahmi extract displayed reduced
cholinergic degradation and an improvement in cognition. Additionally, it also shields
neural cells from the harm done by β-amyloids [193]. B. monnieri extract treatment resulted
in decreased ROS levels in neural cells, indicating that it reduces intracellular oxidative
stress. Cognitive abilities significantly increase with regular use of Brahmi, which also
reduced their levels of inflammation and oxidative stress [194]. In addition, a team of
researchers found that an extract of standardised B. monnieri corrected the cognitive ab-
normalities brought on by the intracerebroventricular administration of colchicines and
ibotenic acid into the nucleus basalis magnocellularis. In the same study, Bacopa monnieri
also restored acetylcholine depletion, choline acetyltransferase activity reduction, and
reduction of muscarinic cholinergic receptor binding in the frontal cortex and hippocampal
regions [195]. By suppressing cellular acetylcholinesterase activity, Brahmi extracts prevent
beta-amyloid-induced cell death in neurons. In a study (randomized, double-blinded trial)
involving 81 persons of the age group 55 and above, a 12-week cycle of Bacopa considerably
improved memory acquisition and retention [196].

4.6. Ashwagandha
Withania somnifera (family: Solanaceae) is commonly known as ‘ashwagandha’ and is
regarded as a Rasayana (rejuvenating). It possesses antioxidant properties, characteristic
of free radical scavengers. The chemical composition of ashwagandha root includes alka-
loids, anolides, many sitoindosides, and flavonoids [197,198]. According to a molecular
study, ashwagandha root helps in treating AD by preventing nuclear factor B activation,
promoting nuclear factor erythroid 2-related factor 2 (Nrf2) migration to the nucleus,
where it enhances the expression of antioxidant enzymes, to reduce the formation of
amyloid, decrease apoptotic cell death, restore synaptic function, and boosts the immune
system [199]. In certain research, ashwagandha root methanolic preparations were used
to treat human neuroblastoma SK-N-SH cells, which led to an increase in dendritic ex-
tension, neurite outgrowth, and synapse formation. Researchers have hypothesised that
the ashwagandha root extracts are effective in treating neurodegenerative illnesses and
also promote neurite growth, and have anti-inflammatory, antiapoptotic, and anxiolytic
effects. Moreover, they have the capacity to minimise mitochondrial dysfunctioning, boost
antioxidant defence levels, reduce glutathione levels, and can cross the blood–brain barrier
and reduce inflammation in the brain [200]. In a double-blind, randomized, placebo-
controlled study, 50 participants with moderate cognitive impairment (MCI) were treated
with a 300 mg dose of W. somnifera root extract twice daily for an eight-week period. After
eight weeks, the W. somnifera-treated group displayed considerable improvements in their
ability to process information, concentrate, and use executive functions [201].
Life 2023, 13, 999 18 of 35

4.7. Saffron
Crocus sativus (family: Iridaceae) commonly known as ‘saffron’, possesses antioxi-
dant, anticancer, and aphrodisiac properties and also improves memory in adults. Nu-
merous studies have shown that saffron possesses antioxidative, anti-inflammatory and
antiamyloidogenic properties. Additionally, saffron is said to be helpful in reducing
acetylcholinesterase and protecting against toxins (AChE). AChE is connected to the neu-
rofibrillary tangles and beta-amyloid plaques that are characteristic of AD [202].
To analyse the effect of saffron on learning abilities, and the prevention of oxidative
stress, each rat was administered five and ten grams of saffron extract, twice a week.
Oxidative stress markers were assessed seven days later. The group that received saffron
treatment was found to have a reduced memory deficit along with enhanced spatial
learning and antioxidant activity of enzymes [203]. The main bioactive compound of
saffron is crocin. It has the ability to bind to the hydrophobic region of Aβ and thus inhibits
its aggregation [204]. A double-blinded/phase II study using the AD assessment scale,
cognitive subscale, clinical dementia rating scale, and sums of boxes scores was conducted
on a total of 54 patients who were 55 years of age or older with AD. These patients received
saffron extractive (30 mg) or donepezil (10 mg) as a positive control once daily for 22 weeks.
As a result, donepezil and saffron extractives had similar effects on patients with mild to
moderate AD, suggesting that saffron extractives have a therapeutic effect [154].

4.8. Ginger
Zingiber officinale (family: Zingiberaceae) commonly called ‘ginger’ is a spice having
both culinary and therapeutic uses. It is frequently used as a nutritional supplement, in
ginger tea preparation, or as an extract. The primary bioactive components in ginger
include gingerols, shagols, volatile oils such as bisabolene and zingiberene, and monoter-
penes. In vitro research has been done on the AChE inhibitory activity of red and white
ginger [205]. Inhibition of AChE causes acetylcholine to accumulate in synapses, which is
followed by an increase in the cholinergic pathway activity and results in better cognitive
performance in AD patients.
Ginger’s ability to decrease lipid peroxidation is vital for the prevention of AD. Pro-
oxidants such as quinolinic acid (QUIN) and sodium nitroprusside (SNP) are utilised to
cause lipid peroxidation in the rat-brain homogenate. Due to the overstimulation of NMDA
receptors and the significant rise in malondialdehyde level brought on by the incorporation
of SNP and QUIN, free radicals are produced [155]. Ginger extract was demonstrated
to boost brain SOD and CAT expression, decrease NF-κB, interleukin-1 beta (IL-1β), and
malondialdehyde (MDA) levels and improve behavioural impairment in a rat model of AD
caused by oral AlCl3 and injection of intracerebroventricular β-amyloid protein [206]. In a
similar study, the fermented ginger extract had more bioavailability and has been shown to
greatly reduce synaptic dysfunction and neuron cell loss, compared to the fresh extract, in
a mouse model of AD produced by injection of β-amyloid plaques [207].

4.9. Rosemary
Rosmarinus officinalis (family: Lamiaceae) is commonly called ‘rosemary’. Other than
its native Mediterranean region, several other countries are known to use the plant in
traditional medicine.
It possesses antioxidant and anti-inflammatory properties. To learn how drinking
rosemary tea affects the working of the brain, an investigation on adult male mice was done.
The testing revealed that rosemary tea consumption for four weeks had a favourable effect
(anxiolytic- and antidepressant) without changing the memory or learning [112]. Other
researchers have shown that it possesses antidepressant properties and is able to reverse
ACHE changes despite spatial learning impairment [208]. Carnosic acid has also been
found to have neuroprotective effects on cyanide-induced brain damage in cultured rodent
and human-induced pluripotent stem cell-derived neurons in vitro and in vivo in several
brain locations in a non-Swiss albino mouse model [209]. In vitro, the intercellular adhesion
Life 2023, 13, 999 19 of 35

molecule (ICAM-1) expression is suppressed and tumour necrosis factor (TNF)-induced

monocyte adherence to endothelial cells is inhibited by carnosol and rosemary essential
oils [210]. Carnosol decreases the activity of the nuclear factor kappa-B inhibitor and
increases the production of heme oxygenase-1 (HO-1), both of which block the signalling
pathways triggered by TNF-α [211]. According to a study conducted on 68 students in
Kerman, Iran, using 500 mg of rosemary twice daily for a month improved students’
prospective and retrospective memory [212].

4.10. Date Palm

Phoenix dactylifera (family: Arecaceae) is commonly called ‘date palm’. They have
been used since Mesopotamian civilization, and their historical, theological, and medicinal
significance is well known [213,214]. Three to four date fruits per day were recommended
for improving memory in Palestine [214]. Turkish people drink “Hurma coffee,” an herbal
brew made from date fruit seeds, to improve their memory. It reduces glutathione, glu-
tathione reductase, and glutathione peroxidase levels [215]. In addition, mice with AD
were fed diets supplemented with 2 and 4% acetone-extracted date fruit, for 14 months,
and the results were compared to mice receiving a control diet. When mice were fed
dates at 2 and 4% levels, oxidative stress markers such as protein carbonyl levels, lipid
peroxidation, and the restoration of anti-oxidative stress enzymes were all considerably
reduced [216].

4.11. Pumpkin Seeds

Cucurbita maxima (family: Cucurbitaceae) is commonly known as ‘pumpkin’. Pumpkin
seeds are included in the category of nuts. Despite their significant nutritional content
and therapeutic qualities, pumpkin seeds are typically seen as agricultural waste and
are thrown away. In addition to being added to food preparations, they can be eaten
in their fresh or roasted form. Pumpkin seeds are rich in choline (63 mg/100 g) and
L-tryptophan (576 mg/100 g) [94]. L-tryptophan is frequently used to treat a variety of
medical disorders, including anxiety, sleeplessness, and depression [217,218]. The body can
convert tryptophan to serotonin, which in turn may control a number of cognitive functions.
It is known that choline serves as a precursor for the synthesis of the neurotransmitter
acetylcholine in cholinergic synapses, which deliver stimulatory signals to nerve cells.
Moreover, choline promotes brain growth [219]. In adult male Wistar rats, oral treatment of
pumpkin-seed oil (100 mg/kg and 200 mg/kg for 5 days) is reported to have antiamnesic
benefits against scopolamine-induced amnesia. It suppresses acetylcholine esterase, reduces
TNF expression in the hippocampus, and raises glutathione levels in the brain [219].

4.12. Garlic
Allium sativum (family Liliaceae) is commonly known as ‘garlic’. It is widely used
in traditional medicines for the treatment of numerous diseases, including AD. The most
popular garlic preparation used is called AGE, and it is often made by keeping slices of
garlic in a solution of water and ethanol for more than 10 months at ambient temperature.
Aggregation of unusually folded Aβ and tau proteins in amyloid plaques and neuronal
tangles are the main pathologies of AD. The two primary types of Aβ are Aβ40 and Aβ42.
AGE at dosages of 250 and 500 mg/kg BW can improve short-term memory deficits in
humans [123,124]
It has been discovered that raw garlic has strong antineuroinflammatory capabilities,
and this is due to organosulfur compounds (OSCs) that are produced from alliin (such
as allicin, diallyl trisulfide, and diallyl disulfide). In lipopolysaccharides (LPS)-activated
microglial cells, these substances, particularly diallyl trisulfide and diallyl disulfide, reduce
the generation of TNF-α, lipopolysaccharide (LPS) induced nitric oxide, monocyte chemoat-
tractant protein-1, and interleukin-1 (IL-1) [220]. Similar to this, glial cell activation caused
by LPS and inflammatory mediators that are implicated in amyloidogenesis is reduced by
the sulphur-containing substance thiacremonone [221].
Life 2023, 13, 999 20 of 35

5. Phytochemicals
Phytochemicals have long been employed as treatment options for a number of
pathological conditions, and a balanced diet rich in phytochemicals can reduce the risk of
AD [107]. The mechanisms of many phytochemicals have been discussed and, for some
phytochemicals, it has to be established yet, and their amount in food that makes them
bioavailable is still under research [116]. Phytochemicals have been shown in in vitro
and in vivo investigations to have a possibility for AD treatment, allowing for a few of
Life 2023, 13, x FOR PEER REVIEW them to go into the clinical trial phases [187]. According to research, phytochemicals
20 of 34
can raise α-secretase activity, decrease Aβ formation, reduce tau hyperphosphorylation,
increase antioxidant enzymes, and improve learning and memory [185,190,200], and shows
significant potential in treating AD by acting on various mechanisms, as shown in Figure 3.

Figure 3. Mechanism of Alzheimer’s disease (NO—nitric oxide, iNOS—inducible nitric oxide syn-
Figure
thase, 3. Mechanism of Alzheimer’s
COX-2—cyclooxygenase disease
2, BACE (NO—nitric
1—Beta oxide,
site amyloid iNOS—inducible
precursor nitric oxide
protein cleaving syn-
enzyme,
thase, COX-2—cyclooxygenase
NF-kB—nuclear factor kappa B). 2, BACE 1—Beta site amyloid precursor protein cleaving enzyme,
NF-kB—nuclear factor kappa B).
5.1. Huperzine A
5.1. A
Huperzine
substanceA called Huperzine A was produced from a specific kind of club moss
(Huperzia serrata). called
A substance H. serrate extract A
Huperzine can
wasbeproduced
utilized as a dietary
from supplement
a specific tomoss
kind of club enhance(Hu-
memory. Huperzine
perzia serrata). A hasextract
H. serrate a significant
can beimpact onasAChE
utilized inhibition.
a dietary Its mechanism
supplement to enhance is
comparable to that of the anti-AD drugs galantamine, donepezil, and rivastigmine
memory. Huperzine A has a significant impact on AChE inhibition. Its mechanism is com- [222].
According
parable toto clinical
that of thestudies,
anti-ADhuperzine A has extremely
drugs galantamine, few negative
donepezil, side effects,
and rivastigmine such
[222]. Ac-
ascording
stomachaches and headaches. Huperzine A also decreases oligomeric and β-amyloid
to clinical studies, huperzine A has extremely few negative side effects, such as
plaques in the cortex
stomachaches and hippocampus,
and headaches. respectively.
Huperzine Additionally,
A also decreases huperzine
oligomeric andA can block
β-amyloid
the brain’s
plaques inNMDA receptor
the cortex and potassium
and hippocampus, channel [223,224].
respectively. Additionally, huperzine A can block
the brain’s NMDA receptor and potassium channel [223,224].
5.2. Epigallocatechin-3-gallate
5.2. A catechin of the flavonoid group called epigallocatechin-3-gallate is found in Camellia
Epigallocatechin-3-gallate
sinensis. Numerous researchers have examined the impact of epigallocatechin-3-gallate
A catechin of the flavonoid group called epigallocatechin-3-gallate is found in Camel-
on a wide range of illnesses, including cancer and cardiovascular and neurological disor-
lia sinensis. Numerous researchers have examined the impact of epigallocatechin-3-gallate
ders [225,226]. Strong antioxidant activity is exhibited by epigallocatechin-3-gallate. In mice
on a wide range of illnesses, including cancer and cardiovascular and neurological disor-
with streptozotocin-induced dementia, epigallocatechin-3-gallate has been demonstrated
ders [225,226]. Strong antioxidant activity is exhibited by epigallocatechin-3-gallate. In
to boost glutathione peroxidase activity, reduce AChE activity, and prevent the accumula-
mice with streptozotocin-induced dementia, epigallocatechin-3-gallate has been demon-
tion of NO metabolites and ROS [227]. In mutant PS2 Alzheimer mice, epigallocatechin-
strated to boost glutathione peroxidase activity, reduce AChE activity, and prevent the
3-gallate also improved memory and reduced the activity of the enzyme γ-secretase.
accumulation of NO metabolites and ROS [227]. In mutant PS2 Alzheimer mice, epigallo-
catechin-3-gallate also improved memory and reduced the activity of the enzyme γ-secre-
tase. Epigallocatechin-3-gallate also reduced amyloid precursor protein expression, de-
creased the activity of enzyme one that cleaves beta-sites from APP, and decreased β-am-
yloid buildup to defend against apoptosis and memory loss brought on by LPS [141].
Life 2023, 13, 999 21 of 35

Epigallocatechin-3-gallate also reduced amyloid precursor protein expression, decreased

the activity of enzyme one that cleaves beta-sites from APP, and decreased β-amyloid
buildup to defend against apoptosis and memory loss brought on by LPS [141].

5.3. Resveratrol
Resveratrol is a polyphenolic substance that is a member of the stilbene family. Al-
monds, grapes, and other fruits contain resveratrol. Numerous research has demonstrated
that it possesses cardiovascular, anticancer, anti-inflammatory, antioxidant, and blood-
glucose-lowering characteristics, as well as a neuroprotective impact. By scavenging ROS,
raising glutathione levels, and enhancing endogenous antioxidants, resveratrol exerts a
powerful antioxidant effect [228]. By triggering APP’s nonamyloidogenic cleavage and
enhancing β-amyloid clearance, resveratrol can also lower levels of β-amyloids. Addition-
ally, resveratrol reduced AChE activity in neural cells. Resveratrol was shown to be safe,
well tolerated, and to be able to reduce cerebrospinal fluid (CSF) and plasma A40 levels in
AD [229].

5.4. Rosmarinic Acid

Many Lamiaceae plants contain polyphenol-type carboxylic acid and rosmarinic acid.
Rosmarinic acid is associated with antioxidant, antibacterial, anti-inflammatory, anticancer,
antiviral, and neuroprotective properties [230]. The ability of rosmarinic acid to decrease
NF-κB and TNF expressions is the mechanism by which it greatly reduces amyloid-induced
memory loss [231,232]. Additionally, it has been demonstrated that rosmarinic acid shields
neuronal PC12 cells against cytotoxicity brought on by beta-amyloid. It could lessen the
tau protein’s hyperphosphorylation. According to a rat model of AD, by lowering lipid
peroxidation and inflammatory processes, rosmarinic acid assists in lessening locomotor
activity, short-term spatial memory, and metabolic changes in brain tissue [232].

5.5. Galantamine
Galantamine has been utilized for age-related cognition or memory. This selective,
reversible, and competitive inhibitor of AChE was first obtained from snowdrops and is
presently commercialized for preventing neurological deterioration and in the treatment
of AD. Galantamine is also extracted from the Narcissus species [117]. In the 1950s, a
Bulgarian pharmacologist observed individuals using the common snowdrop growing in
the wild and applying it on their skin to relieve the discomfort of their foreheads [233].
However, the first study to demonstrate the acetyl cholinesterase inhibitory activities of
galantamine isolated from Galanthus was reported by Mashkovsky and Kruglikova-Lvov
in 1951.

5.6. Curcumin
Curcumin, a key chemical component of turmeric (Curcuma longa), is used as a spice
to provide taste and colour to Indian curries, as well as for preserving food. It is interesting
to note that compared to the United States, AD prevalence among adults aged 71 to 80 is
4.4 times lesser in India [234,235]. There is strong in vitro evidence that curcumin possesses
anti-inflammatory, antioxidant, and antiamyloid properties. Curcumin prevents lipid
peroxidation, stimulates glutathione S-transferase, and increases heme oxygenase-1 (HO-1).
Due to its potent inhibition of COX-2 and lipoxygenase, curcumin has been demonstrated to
have anti-inflammatory properties. Additionally, curcumin inhibits iNOS and is a powerful
inhibitor of NF-κB and AP-1 initiation. Important phases in the pathophysiology of AD
include the accumulation of Aβ into fibrils and the subsequent development of amyloid
plaques. Curcumin has been discovered to destabilize preformed Aβ fibrils and limit Aβ
fibril production and extension in a dose-dependent manner between 0.1 and 1 M [236].
According to a clinical trial on AD mice, those given low doses of curcumin had a 40% lower
level of beta-amyloid than those who weren’t given curcumin [237]. The health advantages
of 80 mg/day of lipidated curcumin were investigated in a four-week clinical experiment.
Life 2023, 13, 999 22 of 35

According to the study, plasma levels of Aβ (1–40) were reduced [238]. Sine AD is a
multifactorial disorder involving many pathological mechanisms. Treatments focusing
on a single causative or modifying factor will likely have limited advantages. As a result,
there is increased interest in therapeutic drugs such as curcumin with a pleiotropic effect
that targets numerous pathological mechanisms [239]. Cox et al. (2015) demonstrated that
supplementation with solid lipid curcumin formulation (80 mg as Longvida® ) increased
cognitive function and decreased fatigue and psychological stress in an older population,
suggesting curcumin has protective properties against neurodegeneration [240].

5.7. Caffeic Acid

Caffeic acid is abundantly present in coffee, tea, and wine, and shows a variety
of pharmacological effects, including immunological modulation, antioxidant, and anti-
inflammatory effects. Recent research has shown that caffeic acid has the ability to protect
against toxicities caused by acrolein, 6-hydroxydopamine (6-OHDA), 1-methyl-4-phenyl-
1,2,3,6-tetrahydropyridine (MPTP), and 6-hydroxydopamine (6-OHDA), as well as oxida-
tive brain damage caused by hydrogen peroxide and stroke. It has been demonstrated
that caffeine protects PC12 cells from amyloid-β-induced neurotoxicity [110]. Addition-
ally, caffeic acid has been shown to increase acetylcholine levels in the brain and promote
learning and memory. Tau proteins and β-amyloid peptides are the major constituents of
plaques that are detected in the brains of people with AD. Tau phosphorylation is a crucial
stage in the formation of tau protein aggregates and may potentially be involved in the
onset of amyloid toxicity. Glycogen synthase kinase-3 beta (GSK3) is one of the kinases that
phosphorylate tau protein; insulin signalling decreases the activity of this kinase. Thus, it
is hypothesised that GSK3 dysregulation in neurons may be a key factor in the onset of
AD [154]. Caffeic acid restored glutathione levels and glycogen synthase kinase 3 (GSK3)
activity in the brains of hyperinsulinemic rats, inhibited GSK3 activity, and lower levels of
β-amyloid and phosphorylated tau protein [241]. NF-B-p65 protein expression, oxidative
stress, inflammation, and caspase-3 activity are all reduced by the intake of caffeine.

5.8. Silymarin
Silymarin is a combination of flavonolignans, flavonoids, and other polyphenolic
chemicals that are derived from milk thistle (Silybum marianum), a perennial or biennial
plant (family: Asteraceae) that is commonly grown in the Mediterranean region [242,243].
The anti-injury and memory-impairing properties of silymarin make it a valuable tool. Ani-
mal models of neurodegenerative illnesses, as well as neuronal and non-neuronal cellular
models, have provided evidence for silymarin’s neuroprotective effects [111]. Addition-
ally, the capacity to halt the course of neurodegeneration was examined in the AD model
Caenorhabditis elegans CL4176. Chronic silymarin therapy for APP transgenic mice allevi-
ated AD-like symptoms, decreased cerebral plaque and brain microglial activation, and
improved the behavioural abnormalities brought on by AD disease. Silymarin dramatically
increased cell survival and reduced behavioural abnormalities in APP-transgenic mice by
preventing the Aβ fibrilization and deposition that occurs when APP is overexpressed in
the brain [244]. It can greatly reduce the high level of TNF-α and increase the percentage of
NF-κB mRNA expression brought on by aluminium in the rat cerebral cortex and reduce
the memory deficit [242].

6. Algal Phytochemicals for Prevention of AD

Micro- and macroalgae are eukaryotic photosynthetic organisms that are found in
tropical and intertidal environments. They are classified into different types, such as red
algae, green algae, brown algae, diatoms, dinoflagellates, etc., having different shapes
and sizes [245,246]. To date, approximately 32,000 compounds with a wide range of
applications have been discovered [247]. Compounds having anti-Alzheimer’s properties
have been discussed.
Life 2023, 13, 999 23 of 35

6.1. Fucoidan
Fucoidan is a sulphated polysaccharide obtained from brown algae. According to
certain reports, fucoidan has an impact on the inflammation process at various stages.
It inhibits several enzymes, prevents lymphocyte adhesion and invasion, and triggers
apoptosis [248]. As caspase-9 and caspase-3 play a significant role in apoptosis processes,
the ability of fucoidan to limit their activation raises the possibility that fucoidan primarily
prevents neuronal death by inhibiting apoptosis. It has been reported that fucoidan therapy
can lessen the repressive effects of amyloid-beta on protein kinase C (PKC) phosphory-
lation [249,250]. Some studies reveal that fucoidan decreases the production of ROS and
TNF-α in lipopolysaccharide (LPS)-induced primary microglia [251].

6.2. Phlorotannins
Phlorotannins are polyphenols extracted from the brown algae species Ecklonia stolonifera,
Ecklonia cava, and Eisenia bicyclis. The significant neurotransmitter in the brain, acetylcholine,
is increased by phlorotannins such as phlorogucinol, eckol, dieckol, phloroeckol, and
phlorofurofucoeckol by decreasing the action of the enzyme acetylcholinesterase and
butyrylcholinesterase. Hence, the discovery that phlorotannin inhibits the BACE-1 enzyme
shall enhance the AD treatment regime. It was recently demonstrated, for the first time,
that the phlorotannin dieckol controls the PI3K/Akt/GSK-3β signalling pathway, which in
turn controls APP proteolytic processing and Aβ synthesis [252].

6.3. Homotaurine
Homotaurine is a tiny natural amino sulfonate molecule that was initially isolated
from several types of marine red algae. It was later chemically synthesised and utilised in
medicine as tramiprosate [253]. In three phase II and three phase III clinical investigations,
homotaurine’s therapeutic effectiveness in treating AD was examined. Due to its unique
antiamyloid action and affinity for type A-aminobutyric acid receptors, it also offers a perti-
nent neuroprotective effect [254,255]. According to a therapeutic mechanism, tramiprosate
is an antineurotoxic drug that inhibits the synthesis of neurotoxic amyloid-oligomers by
coating the amyloid peptide to stop it from misfolding.

6.4. Spirolides
Spirolides are a new class of lipophilic marine toxins produced by the dinoflagellates
Alexandrium ostenfeldii and Alexandrium peruviaunum [256]. They interact with neuronal
nicotinic acetylcholine (nAChR) receptors and muscle types to exert their effect. No human
toxicity has been documented. The leading member of this category is 13-desmethyl
spirolide C, and it resulted in elevated levels of N-acetyl aspartate (NAA), which had
healing effects on AD symptoms; 13-Desmethyl spirolide C has anti-AD properties and can
penetrate the blood-brain barrier [257].
Many other compounds from algae such as caulerpin, racemosin A-C, caulersin,
fucosterol, fucoxanthin, and α-Bisabolol have the potential to attenuate the symptoms of
AD as they are reported to show anti-inflammatory and anticholinesterase activities.

7. Future Prospective
Alzheimer’s disease is a complex illness brought on by a series of accumulating
hereditary and environmental risk factors. Finding the best treatment has proven to be
particularly challenging due to the varied nature of factors contributing to the disease, as
one medication will not be effective in all cases. The numerous failures during the clinical
trials in the treatment of memory loss could be due to a number of factors, including a
delay in initiating therapies during the course of the disease, inadequate medicine dose,
wrong target for treatment, and, most significantly, little knowledge of the cause of memory
loss and neurodegeneration.
Finding the root cause and creating new treatment options that address AD’s numer-
ous pathways are urgently needed. Herbal medicines could be utilized as an alternative for
Life 2023, 13, 999 24 of 35

neurodegenerative diseases and could also make patients feel better. Herbal drugs have
been time tested and provide a variety of synergistic effects, are bioavailable, less harmful
than their synthetic counterparts, and enhance cognition.
Psychoeducation, meticulous pharmaceutical, environmental and social treatment
regimes, as well as dementia care are essential for the effective treatment of AD. There
are numerous studies that are being conducted to evaluate the efficacy of an Alzheimer’s
vaccine (having a constituent of an antigenic amyloid protein, amyloid enzyme inhibitors,
and nerve growth-factor therapies). Edible vaccines can also be designed and synthesized
using the techniques of genetic engineering.
The limitation of using a plant-based treatment for AD is the slow response and the
requirement of having a large amount. Some phytochemicals have low bioavailability and
are not absorbed by the body, and also do not reach the target site. For solving this problem,
Phytotherapeutics and a nanomedicine approach (green nanotechnology) can be used for
the targeted delivery of the drug. Plant-based nanoparticles (e.g., such as those synthesized
from the bark of the Terminalia arjuna) can be used, as these nanoparticles will be less toxic
than metallic ones [258]. Further studies in the field of green nanotechnology may open up
new vistas for sustainability in the treatment of AD.
Homotaurine or tramiprosate is the only plant-based (algae) compound in the clinical
phase. The expenses associated with bringing a novel treatment to market after its invention,
clinical testing, and approval, and converting these compounds into usable pharmaceuticals
are the most significant hurdles. A large amount of biomass, year-round availability,
processing and marketing cost, and public acceptability are bottlenecks in the process
of developing drugs from marine flora. Thus, marine-based medications may not be
available in the market until the supply is managed in a way that is both commercially and
ecologically viable.
These phytochemicals can also be used to fight against many viral diseases such
as chikungunya, hepatitis, measles, and COVID-19 as these phytochemicals inhibit the
entry of viruses into the body, destroy their genetic material and nucleocapsid, and inhibit
replication. Finding the exact mode of action of different phytochemicals will help in
combating this pandemic virus by creating powerful treatments and therapies.

8. Conclusions
Many natural substances have shown promise for treating AD in both in vitro and
in vivo investigations. However, clinical trials are still required to confirm the safety and
effectiveness of these substances, due to physiological variations between tested animals
and human subjects. Most phytochemical clinical trials are done with a small number of
participants and for a short period of time. The conflicting findings from these clinical trials
imply that larger-scale studies with longer treatment periods will be necessary to validate
or disprove the therapeutic efficacy of these phytochemicals in the treatment of AD. Herbal
medicines are easily procurable, have several synergistic effects, including an increase in
cognitive and cholinergic functioning, are bioavailable, and are substantially less toxic.
They can also easily cross the blood–brain barrier (BBB). Due to the small sample sizes used
in some of the clinical trials with natural substances for the treatment of AD, no definitive
findings were obtained. Yet, several substances demonstrated safety in human testing and
were permitted to move on to later stages. As aforementioned, herbal medications seem
to be a potential and sustainable alternative therapy for AD patients. However, indepth
studies on each herb in terms of extraction methodology, dosage, consortium, mode of
action, efficacy, etc. in carefully planned clinical trials are required for the sustainable
treatment of AD.

Author Contributions: Conceptualization, B.K. and D.Y.; writing—original draft preparation, B.K.
and U.F.; writing—review and editing, B.K., D.Y., U.F. and M.S.; supervision, B.K. and M.S. All
authors have read and agreed to the published version of the manuscript.
Life 2023, 13, 999 25 of 35

Funding: This work was supported by the National Research Foundation (NRF) of Korea (NRF-
2021R1I1A3055750) and the National Institute of Biological Resources (NIBR202325101).
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: Not applicable.
Acknowledgments: The authors are thankful to Lovely Professional University (LPU), Punjab, India
for the infrastructural support.
Conflicts of Interest: The authors declare no conflict of interest.

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