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The Journal of Prevention of Alzheimer’s Disease 12 (2025) 100004
Contents lists available at ScienceDirect
The Journal of Prevention of Alzheimer’s Disease
journal homepage: www.elsevier.com/locate/tjpad
Review
Dietary supplementation and the role of phytochemicals against the
Alzheimer’s disease: Focus on polyphenolic compounds
Rayees Ahmad Naik
a , 1
,Roshni Rajpoot
a , 1
,Raj Kumar Koiri
a , 1
,Rima Bhardwaj
b
,
Abdullah F. Aldairi
c
, Ayman K. Johargy
d
, Hani Faidah
d
,Ahmad O. Babalghith
e
,Ahmed Hjazi
f
,
Walaa F. Alsanie
g , h
, Abdulhakeem S. Alamri
g , h
,Majid Alhomrani
g , h
, Abdulaziz Alsharif
g , h
,
Anastasiia Shkodina
i , ∗
, Sandeep Kumar Singh
j , ∗
a
Biochemistry Laboratory, Department of Zoology, Dr. Harisingh Gour Vishwavidyalaya Sagar, Madhya Pradesh, 470003, India
b
Department of Chemistry Poona College, Savitribai Phule Pune University, Pune 411007, India
c
Department of Clinical Laboratory Sciences, Faculty of Applied Medical Sciences, Umm Al-Qura University, Makkah, Saudi Arabia
d
Department of Microbiology and Parasitology, Faculty of Medicine, Umm Al-Qura University, Makkah, Saudi Arabia.
e
Department of Medical Genetics, Faculty of Medicine, Umm Al-Qura University, Makkah, Saudi Arabia
f
Department of Medical Laboratory Sciences, College of Applied Medical Sciences, Prince Sattam bin Abdulaziz University, Al-Kharj 11942, Saudi Arabia
g
Department of Clinical Laboratory Sciences, The faculty of Applied Medical Sciences, Taif University, Taif, Saudi Arabia
h
Research Centre for Health Sciences, Deanship of Graduate Studies and Scientific Research, Taif University, Saudi Arabia
i
Department of Neurological diseases, Poltava State Medical University, Poltava, 36000, Ukraine
j
Indian Scientific Education and Technology Foundation, Lucknow, 226002, India
Keywords:
Alzheimer’s disease
Oxidative stress
Mitochondrial dysfunction
Phytochemical
Alzheimer’s disease is a complicated, multifaceted, neurodegenerative illness that places an increasing strain on
healthcare systems. Due to increasing malfunction and death of nerve cells, the person suering from Alzheimer’s
disease (AD) slowly and steadily loses their memories, cognitive functions and even their personality. Although
medications may temporarily enhance memory, there are currently no permanent therapies that can halt or cure
this irreversible neurodegenerative process. Nonetheless, fast progress in comprehending the cellular and molec-
ular abnormalities responsible for neuronal degeneration has increased condence in the development of viable
prevention and treatments. All FDA-approved anti-AD medications have merely symptomatic eects and cannot
cure the illness. This necessitates the pursuit of alternate treatments. Accumulating data shows that systemic neu-
roinammation, oxidative stress and associated mitochondrial dysfunction play crucial roles in the etiology of AD
and precede its clinical presentation. Therefore, innovative therapeutic approaches targeting these pathophysio-
logical components of Alzheimer’s disease are being explored aggressively in the present scenario. Phytochemicals
such as resveratrol, curcumin, quercetin, genistein and catechins are prospective therapies owing to their capacity
to alter key AD pathogenetic pathways, such as oxidative stress, neuroinammation, and mitochondrial dysfunc-
tion. The use of new phytochemical delivery strategies would certainly provide the possibility to solve several
issues with standard anti-AD medicines. In this review, the roles of phytophenolic compound-based treatment
strategies for AD are discussed.
1. Introduction
Dementia is a broad spectrum in neurodegenerative disorders char-
acterized by a signicant reduction in cognitive capacity that impairs
daily activities. Alzheimer’s disease (AD) is the most prevalent form of
dementia, related to age. It causes chronic cognitive loss and prevalent
neurodegeneration. The occurrence of genetically determined AD due
to specic mutations is limited to 1-2 % of cases. Although therapeutic
∗ Corresponding authors.
E-mail addresses: ad.shkodina@gmail.com (A. Shkodina), sandeeps.bhu@gmail.com (S.K. Singh) .
1 Equal Contribution
interventions for symptom management are at present accessible, AD re-
mains incurable. An estimated fty million individuals worldwide are af-
icted with AD, and the disease continues to spread. (World Alzheimer’s
Report) [ 1 ]. AD is associated with a gradual decrease in both the
autophagy-lysosomal pathway as well as the ubiquitin-proteasome sys-
tem (UPS), both of which are essential catabolic reactions in eukaryotes.
(ALP) [ 2 ]. Proteostasis is regulated by both the ALP and UPS pathways,
which combine to form a single structure for protein stabilization. An
https://doi.org/10.1016/j.tjpad.2024.100004
Accepted 16 October 2024
Available online 1 January 2025
2274-5807/© 2024 The Authors. Published by Elsevier Masson SAS on behalf of SERDI Publisher. This is an open access article under the CC BY license
( http://creativecommons.org/licenses/by/4.0/ )
R.A. Naik, R. Rajpoot, R.K. Koiri et al. The Journal of Prevention of Alzheimer’s Disease 12 (2025) 100004
accumulation of detrimental proteins within the cells can occur when
the functionality of UPS and ALP is compromised; this, in turn, can
accelerate the development of Alzheimer’s disease [ 2 ]. Dysfunction in
the crucial lysosomal pathway transmembrane protein (TMEM)175 is a
dening characteristic of a number of neurodegenerative disorders, in-
cluding Alzheimer’s disease, Parkinson’s disease, and Huntington’s dis-
ease [ 3 ]. At this time, AD represents a substantial worldwide social and
medical issue. The most prominent pathogenic features of Alzheimer’s
disease (AD) are the deposition of amyloid beta (A 𝛽) in the brain and
the formation of neurobrillary tangles (NFTs), which are distinguished
by the excessive phosphorylation of tau proteins. [ 4 ]. Oxidative stress,
neuroinammation, mitochondrial dysfunction, and biometabolic im-
balance are all potential consequences of the damage induced by A 𝛽
and NFT. These eects can culminate in the dendritic spine reduction,
synaptic loss, and neuronal demise. [ 5 ].
One extensively researched concept pertaining to the initiation and
progression of Alzheimer’s disease (AD) is the cholinergic hypothesis.
This hypothesis, which was the initial idea proposed concerning the
pathogenesis of AD, has garnered signicant attention (Hampel et al.,
2019). In people with Alzheimer’s disease (AD), brain shows various
pathological signs, such as shrinkage, synaptic loss, and reduced central
neurotransmission, as well as the presence of histopathological markers.
There is a general decline in the functioning of basal forebrain neurons
[ 6 ]. At the onset of the illness, there is a decline in the population of
cholinergic neurons located in the basal nucleus and entorhinal cortex.
However, in the later stages of Alzheimer’s disease, over 90 % of the
cholinergic neurons in the basal nucleus experience loss [ 7 ]. Based on
the cholinergic hypothesis, it is suggested that the dysfunctional or im-
paired operation of the cholinergic system might lead to a memory im-
pairment in animal models, resembling Alzheimer’s disease [ 8 ]. Based
on this concept, the degeneration of cholinergic neurons located in the
basal forebrain, together with the subsequent decline in central cholin-
ergic transmission, is believed to be responsible for the manifestation of
both psychological and non-cognitive characteristics observed in indi-
viduals diagnosed with AD. [ 9 ].
Because there are no eective therapies for Alzheimer’s disease, in-
novative prevention techniques are being developed based on dietary
modications, vitamin and mineral supplements, healthy foods, and nat-
ural substances. Lately, there have been instances an increased focus
on natural phytochemicals as potential alternative treatment agents for
Alzheimer’s disease [ 10 ]. The characterization of the therapeutic poten-
tial of natural chemical structures in neurodegenerative illnesses, such
as Alzheimer’s disease (AD), has become increasingly important due to
recent advancements [ 11 ].
Phytochemicals are a potent substance found in plants, which are
classied as secondary metabolites. They include a wide variety of
chemical groups, including polyphenols, avonoids, steroidal saponins,
organosulphur compounds, and vitamins. They play crucial roles in
development of plants, participating in signicant physiological pro-
cesses like as reproduction, symbiotic organizations, and interactions
with other species and the environment. Plants generate phytochemi-
cals (e.g., phenols, terpenes, and organosulfur) promote pigmentation,
smells, and allergens that may protect the plant from internal (e.g.,
metabolic) and exterior (e.g., environmental) threats to its survival, in-
cluding infectious agents, predatory animals, UV rays, as well as ROS
and protein excessive expression, respectively. Humans appear to de-
rive health benets from consuming plants that produce these phyto-
chemicals through the modulation of multiple biological mechanisms
such as inammatory reactions, death of neuronal cells (apoptosis),
growth of neurons, neural communication, and activity of enzymes are
involved [ 12 ]. Possible reasons for these impacts might involve an an-
tioxidant and anti-allergic characteristics and regulation of A 𝛽levels
and toxicity. Various pharmaceutical therapies for Alzheimer’s disease
are originating from conventional herbal treatments. An AChE blocker
referred to as galantamine is obtained from daodil plants, whereas an
anti-inammatory drug called aspirin is produced through the synthe-
sis of salicylic acid, a polyphenol discovered in the outer bark of wil-
low shrubs. Various phytochemicals are being studied over potential use
in alleviating Alzheimer’s disease. [ 13 ]. Furthermore, there has been a
growing interest in investigating the purpose and processes of nutrition
phytochemical compounds with respect to the role of the gastrointesti-
nal microbiome. There is an expanding eld of interest in examining
the correlation between age-related amyloid genesis, proinammatory
microbial activities, and neurodegeneration [ 14 ]. The gastrointestinal
microbiota also has been highly involved in the metabolism and bio-
logical activation of nutritional phytochemicals, in addition to its role
in the pathogenesis of AD. Initial absorption of dietary phytochemicals
has been shown to range from 5 to 10 %. Numerous microbiomes pro-
duced phenolic metabolites, according to recent investigations of their
pharmacokinetic action, attained statistically signicant volumes in the
brain. [ 15 ].
Phytochemicals can be ingested through means other than the diet.
For instance, it was hypothesized that tobacco use might supply a de-
gree of defense against accumulation of A 𝛽and the progress of AD. This
was largely attributable to postmortem examinations of the brains of
Alzheimer’s disease patients, which revealed that smokers had substan-
tially reduced levels of A 𝛽in the entorhinal cortex. [ 16 ]. Conversely,
Smoking is amyloid beta accumulation identied as a predictive fac-
tor for the onset of Alzheimer’s disease (AD). in recent epidemiological
researches [ 17 ]. Consistent consumption of fruits and vegetables con-
taining a signicant amount of bioactive phytochemical substances may
reduce the possibility of acquiring AD in an integrated and synergis-
tic manner, according to prior research. The apparent health-promoting
properties of natural products as therapeutics for AD have been con-
rmed in multiple studies [ 18 ]. Furthermore, a variety of epidemio-
logical studies have provided evidence regarding the correlation be-
tween dietary patterns and the occurrence of neurodegenerative dis-
eases. A notable positive correlation has been proposed between the in-
gestion of foods abundant in polyphenolic phytochemicals and the pre-
vention of specic neurological disorders, such as Alzheimer’s disease.
[ 12 ]. From a variety of natural substances that are gaining attention for
having potential anti-AD characteristics, this study will concentrate on
polyphenolic phytochemicals. These phytochemicals may exhibit anti-
amyloidogenic, anti-oxidative, and anti-inammatory eects, with spe-
cial focus on molecular targets which may be signicant in safeguarding
neurons against AD.
Polyphenols constitute plant-derived compounds that include sev-
eral phenol structural groups. They help plants defend themselves
against pathogen assaults and stress caused by both physical and chem-
ical harm. These compounds provide protection in animals by alter-
ing multiple intracellular mechanisms that take care of neurons [ 19 ].
Polyphenols are a variety of chemical compounds produced naturally
by secondary metabolic processes of plants’, recognized by a number of
aromatic rings having a number of hydroxyl compounds. Flavonoids, the
predominant phenolic compounds in nature, are increasingly acknowl-
edged for their many benets. Flavonoid ingestion has been linked to
enhancing cognition, reducing neurological inammation, as well as de-
creasing oxidative stress in many studies. [ 20 ]. Polyphenols have been
discovered that they exert their impact on stem cells via a dierent way.
Neurological protective eects by polyphenols and promotion of neuro-
genesis are seen at several phases, encompassing the regulation of anti-
apoptotic proteins, activation of intracellular signaling pathways, sup-
pression of oxidative enzymes, and modication related to the function
of mitochondria [ 21 ]. Furthermore, polyphenols have a signicant role
in the suppression of free radical species and the binding of metal ions,
hence regulating the primary protein degradation processes [ 22 , 23 ].
2. Alzheimer’s disease
The two primary pathology characteristics of AD is characterized by
the presence of senile plaques (SPs) as well as neurobrillary tangles
(NFTs). Till date, multiple experimental results have supported the con-
2
R.A. Naik, R. Rajpoot, R.K. Koiri et al. The Journal of Prevention of Alzheimer’s Disease 12 (2025) 100004
cept that oxidative stress is linked to an early onset of Alzheimer’s dis-
ease [ 24 ]. The brains of people with Alzheimer’s disease have character-
istics marked the condition is characterized by a formation of Amyloid- 𝛽
(A 𝛽) peptides, referred to as amyloid plaques, with the degeneration of
neurons due to neurobrillary tangles (NFTs), predominantly made up
of elevated Tau proteins [ 25 ]. The generation of toxic oligomers is es-
sential for the neurotoxic eects of 𝛼-synuclein, especially when coupled
to A 𝛽as well as tau.
2.1. A 𝛽aggregation and toxicity
Brain of patients having Alzheimer’s disease are characterized by
extracellular deposits of A 𝛽aggregates, known as neuritic plaques [ 26 ].
A 𝛽accumulation and formation begin at the cellular level prior to clin-
ical diagnosis of A.D. Furthermore, new research shows that inam-
matory responses may play a substantial role in the development of
Alzheimer’s disease. Deposition of beta-amyloid (A 𝛽) polymers induces
oxidative stress as well as inammatory reactions via activation of sig-
naling pathways involving neuronal membranes. The A 𝛽peptide is a
core component of amyloid plaques and is generated from the process-
ing of its parent protein, the amyloid- 𝛽protein precursor. Further, A 𝛽
plaques may disrupt the neurotransmitter acetylcholine (ACh), aecting
synaptic transmission and stimulating inammatory pathways which
generate reactive oxygen species (ROS) [ 27 ]. Plaques of A 𝛽originate
in the orbitofrontal, temporal, and basal neocortex before metastasiz-
ing to the hippocampus, amygdala, diencephalon, and basal ganglia. In
extreme cases, A 𝛽might be found in the mesencephalon, lower brain
stem, or cerebellar cortex. The buildup of A 𝛽leads to the formation of
𝜏-tangles in the locus coeruleus, trans entorhinal, and entorhinal areas
of the brain. During a critical phase, it reaches the hippocampus and
neocortex [ 28 ].
In the brain, the proteolytic enzymes cleave the APP to form the
A 𝛽peptide, which has 39-43 amino acid sequences. Amyloid precur-
sor protein (APP), an essential protein on the plasma membrane, is rst
alteredly cleaved by 𝛽-secretases (BACE1) and 𝛾-secretases to form in-
soluble A 𝛽brils, which is the beginning of amyloid pathology. A 𝛽then
oligomerizes, diuses into synaptic clefts, and interferes with synap-
tic signaling [ 29 ]. The location where 𝛼-secretase cleaves. is beneath
the amyloid beta sequence in amyloid precursor protein (APP), which
prevents A 𝛽production. The "amyloid genic pathway" processes APP
he processes begins with cleavage by 𝛽-secretase, also referred to as
𝛽-site APP Cleaving Enzyme 1 (BACE-1), followed by cleavage by 𝛾-
secretase, leading to the formation of monomeric A 𝛽components. Fore-
most common species are A 𝛽1-40 and A 𝛽1-42 [ 30 ]. A 𝛽may be cleared
by transporting it into cerebrospinal uid, crossing the blood-brain
barrier (BBB), and being removed by brain macrophages. Besides A 𝛽
plaques and more than 50 % Alzheimer’s patients have 𝛼-synuclein dis-
ease. 𝛼-synuclein is a 140 amino acids long protein found in neuronal
presynaptic terminals. Research indicates that 𝛼-synuclein might serve
a function in the progression of Alzheimer’s disease beginning with the
production of A 𝛽pathology [ 31 ]. Unknown factors may contribute to
the disrupted APP metabolism as well as A 𝛽deposition observed in spo-
radic instances of AD. However, potential contributors involve intra-
cellular ion equilibrium disruptions, age-related increases in oxidative
stress, as well as disrupted energy utilization. Diverse cell types are tar-
geted by the toxicity of A 𝛽1-42 aggregates, which signicantly impacts
an extensive array of cellular functions. Disruption in ionic homeostasis,
oxidative stress, dysfunction of the mitochondria, stimulation of astro-
cytes and microglia, and transmembrane disruption are a few of the
cellular processes that occur subsequent to the assembly and accumula-
tion of A 𝛽1-42 [ 32 ]. All of these events combine into neuronal network
disruption, synaptic disorder, neuroinammation, and neurodegenera-
tion, that eventually result in the serious dementia that is characteristic
of the progressed phases of Alzheimer’s disease. Consequently, the dis-
ruption of ionic balance induced by A 𝛽in astroglial cells might have an
essential role in their pathological transformation. Signicantly, while
it is believed that neuro-glial vascular impairment and after that cere-
brovascular destruction occur prior to and might even lead to the dis-
ruption of A 𝛽balance, dissolve A 𝛽clusters that spread across the brain
have the potential to accumulate in vascular-level deposits that are in-
soluble. This can compromise both the functioning of vessels and the
functioning of the blood-brain barrier (BBB) [ 33 ]. These phytochemi-
cals have the ability to provide therapeutic benets by acting as an-
tioxidants and reducing inammation via the regulation of A 𝛽toxicity.
Aggregated A 𝛽peptides, hydroxyl radicals created by H2O2, and mi-
tochondrial dysfunction caused by APP in Alzheimer’s disease may be
mitigated by pharmaceutical methods including phytochemicals which
maintain mitochondrial dynamics. [ 34 ].
2.2. Hyperphosphorylation of Tau and its toxicity
Tau hyperphosphorylation is the result of a disproportion in the ki-
nase and phosphatase activities in AD. A 𝛽aggregates have been iden-
tied as potential carriers of Excessive phosphorylation of tau by aug-
menting the activity of multiple kinases, such as GSK-3 𝛽and MAPKs.
Furthermore, the stimulation of caspase-3 and calpain-1 is induced by
A 𝛽, resulting in the production of small fragments capable of inducing
neuronal mortality and neurite degeneration at the C-terminus of Tau.
It is noteworthy that the stimulation of the JNK pathway additionally
promotes Tau cleavage by activating caspases. [ 35 ]. A dierence in ki-
nase and phosphatase activity leads to Tau excessive phosphorylation
in Alzheimer’s disease. A 𝛽aggregation may cause Tau hyperphospho-
rylation by increasing the activity of multiple kinases such as GSK-3 𝛽
and MAPKs. Additionally, A 𝛽induces the production of caspase-3 and
calpain-1, leading to the cleavage of Tau at the C-terminus, producing
tiny fragments that may cause neurite degradation as well as neuronal
death. The stimulation of the JNK pathway triggers caspase activity,
which in turn promotes Tau breakdown. [ 36 ].
The role of Tau protein in memory loss is excessively phosphory-
lated, causing damage to microtubules and interfering with many cellu-
lar functions as growth, dierentiation, protein transport, including cell
structure ( Fig. 1 ). Despite the fact that tau toxicity is recognized as an
essential component for neurodegenerative cascade in Alzheimer’s dis-
ease, the molecular processes enabling tau-mediated neuroinammation
remain poorly understood. A second factor contributing to cell mortal-
ity in Alzheimer’s disease is the hyperphosphorylation of the tau pro-
tein, which is responsible for microtubule stabilization. A high degree
of phosphorylation on tau turns it dysfunctional; consequently, the mi-
crotubule disintegrates, and the neurotransmitters as well as neuronal
signals are blocked by the NFTs.
Tau, an exceptionally soluble protein, is prevalent in neurons of the
central nervous system. Its excessive phosphorylation is the result of
a kinase-phosphatase imbalance. NFTs are generated when tau hyper-
phosphorylation transforms the protein from a monomer to an oligomer
and then into pair helical laments (PHFs). In the AD model, the tau
oligomer is regarded as the most toxic form that induces synaptic im-
pairment [ 37 ]. The brain of AD patients contains three distinct groups of
tau: AD tau, which is soluble and hyperphosphorylated; AD Phosphory-
lated tau (AD P-tau), which resembles normal tau and isn’t hyperphos-
phorylated; and associated helical laments (PHFs)-tau, which is both
insoluble and hyperphosphorylated. Tau levels in Alzheimer’s disease
brains are approximately 60 % lower than those in healthy brains. The
biochemical stability of hyperphosphorylated tau facilitates its aggre-
gation, giving rise to its prion-like characteristics. These ndings align
with our own investigations utilizing Alzheimer’s disease-associated in-
creased phosphorylation tau obtained from a study by Alonso et al. in
1996. The structural transmission from AD P-tau to natural tau resem-
bles the behavior of a prion protein.
Tau phosphorylation has become widely researched since it was dis-
covered that abnormally hyperphosphorylated tau is primary compo-
nent of PHFs in Alzheimer’s disease. 2–3 moles for every mole of phos-
phate of tau is contained by healthy brain. To date, more than 40 phos-
3
R.A. Naik, R. Rajpoot, R.K. Koiri et al. The Journal of Prevention of Alzheimer’s Disease 12 (2025) 100004
Fig. 1. Hyper phosphorylated tau. (A) The detachment of microtubules is induced by tau protein excessive phosphorylation. (B) The accumulation as well as
generation of Tau oligomers, that are formed in order to produce tangled neurobrillary cells. (C) Release of tau oligomers into the outer layer of cells and subsequent
neuronal demise.
phorylation sites have been identied in tau protein isolated from AD
brain [ 38 ]. Tau has major role is to promote polymerization of micro
tubules and stability. Microtubules, a component of the cytoskeletal in
all eukaryotes, are made up of heterodimers of 𝛼- and 𝛽-tubulin creating
tubular polymers. Microtubules play a vital role in cytoskeletal integrity
and serve as freeways for the intracellular movement of organelles, vesi-
cles, protein molecules, and signaling compounds. [ 39 ].
2.3. Metal-dependent toxicity of A 𝛽and tau aggregates and
neuroinflammation
Alzheimer’s disease (AD) is a neurodegenerative condition that
causes a signicant deterioration in cognitive abilities and is accom-
panied by pathological changes in the brain. The development of AD
has been linked to a range of biological and environmental variables,
with age being one of the key risk factors. There is a growing body of
data indicating that the development of Alzheimer’s disease (AD), par-
ticularly the accumulation of amyloid and tau proteins, is regulated by
the presence of metal ions [ 40 ]. Biometal ions, despite their physio-
logical signicance, can serve as detrimental cofactors in the etiology of
Alzheimer’s disease (AD) when their equilibrium is disrupted. Moreover,
the widespread presence of environmentally hazardous metal ions and
their capacity for rapid dissemination render them a signicant world-
wide health concern. Although signicant advancements have been
made in elucidating the impact of metal ions on the aggregation of amy-
loid and tau proteins, the precise processes and mechanisms involved in
this process remain very intricate [ 41 ]. Individuals with Alzheimer’s dis-
ease (AD) have impaired metal homeostasis in their brains, resulting in
increased levels of metals that include copper (Cu), zinc (Zn), iron (Fe),
and aluminum (Al). ( Fig. 2 ). These metals have a great anity for the A 𝛽
peptide, causing an increase in toxicity. These metallic ions have been
seen to facilitate the process of aggregation and the subsequent pro-
duction of harmful species. The formation of the A 𝛽metal ion complex
leads to the occurrence of oxidative stress and membrane impairment.
Specically, the A 𝛽-copper complexes intensify the generation of reac-
tive oxygen species (ROS) and provoke biomolecular damage [ 40 ]. The
neurons inside the brain exhibit a high degree of susceptibility towards
free radicals. The occurrence of DNA damage, protein oxidation, lipid
peroxidation, and the formation of advanced glycosylation end products
(AGEs) in the brains of individuals with Alzheimer’s disease (AD) is com-
monly associated with oxidative stress caused by free radical assaults
and disturbances in metal homeostasis. Oxidative stress has been exten-
sively observed in individuals with Alzheimer’s disease (AD) as well as
in animal models. dysfunction, of Metal ion such as iron, calcium, the
metal copper, and zinc, can contribute to oxidative stress. This oxida-
tive stress, in turn, can lead to tau hyperphosphorylation, A 𝛽deposition,
the formation of cross-links between nerve bers, and damage to nerve
cells. These processes are strongly associated with the development and
progression of AD [ 42 ].
2.4. Oxidative stress and mitochondrial dysfunction in AD
Oxidative stress as well as impairment of the mitochondria have been
markers of numerous neurodegenerative disorders, involving AD. An
increase in intracellular reactive oxygen species (ROS) levels prompts
the peroxidation of lipids, breakdown of proteins, as well as damage
to DNA have all been induced in cells of neurons. ROS/microbes target
mitochondria extensively.RNS injuries [ 43 ]. Furthermore, it is worth
noting that ROS and RNS not only involve peroxidation of lipids, pro-
tein the carbonylation process, along with mitochondrial destruction of
DNA. but they also initiate the development of the permeable transi-
tion pore (PTP), a process that enhances the signals generated by free
radicals. ROS (comprising H2O2, OH, and O2) might be the underly-
ing cause of developmental abnormalities in the brain of humans and
defects in mitochondrial respiration that are accompanied by increased
ROS production. Furthermore, they play a role in the dynamic modi-
cations that occur in the brain as AD and aging advance ( Fig. 3 ). The
relationship between oxidative stress (OS) and AD has been extensively
acknowledged as a prodromal factor [ 44 ]. Cellular regulation of OS is
crucial for preserving the equilibrium of the microenvironment, which
is required for numerous biological processes including bioenergetics,
vesicle transport, and post-transcriptional modications. Due to their
membranes being dense with fatty acids that are polyunsaturated and
their typically low antioxidant level, neurons are especially susceptible
to OS [ 45 ]. Age-related oxidative damage signicantly impairs synap-
tic components that are implicated in neuronal plasticity, cytoskeletal
dynamics, and cellular communication etc which are recognized as de-
fective mechanisms in Alzheimer’s disease. A reduction in the concen-
tration of presynaptic high-anity choline transporter 1 (CHT1) was
detected in synaptosomes located in the hippocampus as well as neona-
tal cortex of human with Alzheimer’s disease. In addition, elevated OS
deactivates nAChRs, which results in cholinergic transmission being in-
hibited permanently [ 46 ]. Additionally, ROS can modulate the function
of the BBB by upregulating the expression of a number of metallopro-
teinases, specically isoform 9. MMP9 expression is signicant in the
microvascular environment of the brain because its modications are
linked to an increase in BBB permeability, which promotes the progress
of AD by allowing inammatory factors and reactive oxygen species to
extravasate into the brain [ 47 ]. There is an abundance of polyunsatu-
rated fatty acids in brain tissue. They are susceptible to degradation into
malondialdehyde, a compound that induces cellular harmful stress and
destruction of DNA [ 48 ].
The brain is very susceptible to oxidative stress due to its high
concentrations of redox transition metal ions, rapid oxygen consump-
4
R.A. Naik, R. Rajpoot, R.K. Koiri et al. The Journal of Prevention of Alzheimer’s Disease 12 (2025) 100004
Fig. 2. The toxicity of A 𝛽and tau aggregates in Alzheimer’s disease is inuenced by metal ions and exhibits a complex and multidimensional nature.
Fig. 3. AD develops due to mitochondrial malfunction and oxidative stress in neurons. ROS are often generated by several pathways including ER stress, mitochondrial
failure, neuroinammation, as well as excitotoxicity. High levels of reactive oxygen species (ROS) cause oxidative stress (OS), resulting in mitochondrial malfunction.
Oxidative stress inhibits the breakdown of protein molecules and hinders the removal of misfolded proteins, resulting in an accumulation of proteins that results in
death of neurons and Alzheimer’s disease.
tion, and higher quantities of polyunsaturated fatty acids (which
are easily targeted by free radicals). Additionally, the brain con-
tains an exceptionally low concentration of antioxidants. [ 49 ]. Indeed,
the accumulation of Ab protein induced by reactive oxygen species
(ROS) in Alzheimer’s disease leads to neuronal mortality by caus-
ing lysosome membrane breakdown. The most prevalent mitochon-
drial electron transport chain (ETC) malfunction in Alzheimer’s dis-
ease (AD) involves a cytochrome c oxidase decit which causes an
increase in reactive oxygen species (ROS) manufacturing, a reduction
of stored energy, and a disturbance in the utilization of energy [ 50 ].
In addition, reactive oxygen species (ROS) prevent phosphatase 2A
(PP2A), thereby promoting the stimulation of glycogen synthase ki-
nase (GSK) 3b, which is among the protein kinases implicated in tau
phosphorylation.
5
R.A. Naik, R. Rajpoot, R.K. Koiri et al. The Journal of Prevention of Alzheimer’s Disease 12 (2025) 100004
Fig. 4. Depiction of ROS-triggered mitochondrial irregularities in Alzheimer’s disease.
AD has been associated with oxidative dysregulation and a signi-
cant increase in its byproducts, according to multiple reports. Extensive
research has established that Alzheimer’s disease signicantly amplies
lipid peroxidation, which occurs when reactive oxygen species (ROS)
employ a free radical chain reaction mechanism to attack lipids and gen-
erate lipid peroxidation products [ 51 ]. Progressive mitochondrial dys-
function has also been implicated in aging and Alzheimer’s disease as
the primary source of reactive oxygen species (ROS) production; mito-
chondria are a main target of oxidative damage. As an essential factor
in the pathogenesis of Alzheimer’s disease, mitochondrial dysfunction
resulting from the improper processing of reactive oxygen species has
been documented in numerous studies [ 52 ]. Furthermore, it is critical to
mention that oxidative stress is associated with mitochondrial function-
ing, not only due to the fact that mitochondria produce reactive oxygen
species (ROS), but also for the reason that ROS can induce a decline
in mitochondrial function ( Fig. 4 ). Reducing ROS levels through the
use of antioxidant pharmaceuticals, exercise, and dietary modications
may therefore protect neuronal mitochondria from oxidative injury and
thereby reduce the risk of AD.
When there is either excessive ROS synthesis or a dysfunctional an-
tioxidant system, it leads to an imbalance in cellular redox status, re-
sulting in an overproduction of ROS. Reactive oxygen species produced
during the process of cellular respiration harm mitochondria and impair
neural function. Elevated levels of reactive oxygen species (ROS) lead
to a decrease in mitochondrial membrane potential ( ΔΨm) and adeno-
sine triphosphate (ATP) production by impairing mitochondrial energy
reserves, disrupting energy metabolism, and compromising mitochon-
drial dynamics and mitophagy. ROS also leads to elevated caspase ac-
tivity and triggers apoptosis. Conversely, excessive ROS generation leads
to the suppression of phosphatase 2A (PP2A), resulting in the activation
of glycogen synthase kinase (GSK) 3 𝛽, leading to tau hyperphosphory-
lation as well as the buildup of neurobrillary tangles.
Mitochondria are obligatory organelles in all mammalian cells be-
cause they regulate apoptotic pathways as well as energy metabolism,
both of which are critical for cell survival or demise. However, their
function extends beyond that, as neurons require signicant amounts
of energy, specically for synaptic activity within neurons and for neu-
rotransmission events. [ 53 ]. Under conditions of elevated OS, the sero-
toninergic eciency of mitochondria is compromised due to membrane
permeability and modications in serotoninergic metabolism. Overall,
mitochondrial dysfunction diminishes monoaminergic activity. Dier-
ent in vitro studies have postulated a correlation between increased
levels of A 𝛽, dysfunctional mitochondrial function, and oxidative bur-
den, all of which aid in the development of Alzheimer’s disease. In
Alzheimer’s disease, a reduction in neuronal ATP levels signies mito-
chondrial dysfunction, which is correlated with an excessive generation
of reactive oxygen species (ROS) and suggests mitochondria might be
unable to sustain cellular energy. A considerable quantity of ATP is de-
pleted within the brain as a result of high energy demands of neurons
as well as glia. Signicantly, dysfunction of mitochondria is contribut-
ing to decreased ATP production, Ca2 + dyshomeostasis, and ROS pro-
duction. Early-stage Alzheimer’s disease is characterized by mitophagy
and mitochondrial metabolism alterations, but its root causes remain
inadequately understood. Therefore, research that uncovers the mecha-
nisms underlying mitochondrial dysfunction in Alzheimer’s disease will
contribute to the development of therapeutic approaches that safeguard
synaptic activity and, consequently, cognitive function, thereby enhanc-
ing our knowledge of the disease progression of neurodegenerative dis-
order. Ca2 + is an essential regulator of important neuronal processes,
including production, motility, metabolism, plasticity of synapses, pro-
liferation, expression of genes, and necrosis. Mitochondria are crucial in
maintaining cellular Ca2 + homeostasis. It is widely accepted that dys-
regulation of Ca2 + homeostasis is a crucial factor in the acceleration
of pathology associated with AD. By stimulating the permeability tran-
sition (PT), mitochondrial Ca2 + can easily transform into a toxic fac-
tor. Intracellular Ca2 + maintains numerous neuronal functions; how-
ever, a disruption in its homeostasis may result in neuronal damage
or demise. In fact, elevated cytosolic Ca2 + concentrations may induce
the most signicant damage processes, namely mitochondrial Ca2 +
ac-
cumulation and subsequent dysfunction [ 54 ]. However, an abundance
of results from experiments indicates that mitochondrial dysfunction
as well as oxidative stress both contribute to an upregulation of amy-
loidogenic cleavage of the APP and an abnormal production of A 𝛽.
In fact, research has demonstrated that oxidizing compounds can en-
hance the activity and expression of BACE-1 and the APP [ 55 ]. Fur-
thermore, the A 𝛽peptide has been identied as a target molecule for
metal-catalyzed oxidation in both in vitro and in vivo investigations
[ 56 ]. Nevertheless, the precise mechanism by which A 𝛽oxidation af-
fects its aggregation and/or its anity for plasma membranes is still
unknown.
6
R.A. Naik, R. Rajpoot, R.K. Koiri et al. The Journal of Prevention of Alzheimer’s Disease 12 (2025) 100004
3. Pathogenic mechanism in Alzheimer’s disease
Alzheimer’s disease (AD) is a complex neurodegenerative disorder
that occurs with the passage of time and has numerous etiological fac-
tors. Extracellular amyloid -peptide (A 𝛽) plaques along with intraneu-
ronal neurobrillary tangles (NFTs) composed of tau protein that has
been hyperphosphorylated constitute the most prominent characteristic
of this disorder. Neuronal synapses are subsequently lost, and neuronal
degeneration occurs. As a consequence, critical neurotransmitters expe-
rience a reduction in the amount [ 57 ]. The primary constituent of amy-
loid plaques, A 𝛽, is obtained through proteolytic cleavage of APP. The
hypothesis that APP and A 𝛽play a crucial role in the development and
progression of AD [ 58 ]. NFTs are composed of forms of the microtubule-
associated protein tau that have been hyperphosphorylated. Tau protein
association with microtubules is accountable for cytoskeleton stability in
neurons. Due to its limited binding for microtubules, hyperphosphory-
lated tau remains insoluble, putting microtubule regulation at risk and
consequently leading to synaptic dysfunction and neurodegeneration.
Inammation, oxidative damage, tau kinase increase, and phosphatase
reduction all contribute to tau hyperphosphorylation [ 59 ]. Neurovas-
cular endothelial cells are adversely aected by A 𝛽, which can occur
through direct action or by inducing local inammation. The produc-
tion of A 𝛽in the cerebral microvasculature is induced by inammation,
and this A 𝛽subsequently promotes the secretion of pro-inammatory
mediators [ 60 ]. At the beginning, Alzheimer’s disease (AD) was per-
ceived as a disorder associated with an increase in the production of A 𝛽
and a decrease in its degradation. Concurrently, inadequate approval
is identied as a co-factor. Brains aected by Alzheimer’s disease (AD)
contain A 𝛽plaques that are intimately related to hyperactive microglial
cells as well as reactive astrocytes. These cells display increased levels
of cytokine and acute-phase protein expression. Microglia, which are
mononuclear phagocytes, are found in the brain. Their primary function
is to maintain brain homeostasis and prevent harmful damage to the cen-
tral nervous system. Microglial cells that sustain a neuroprotective role
in healthy individuals through the clearance of A 𝛽plaques [ 61 ]. Addi-
tionally, they exhibit the expression of a variety of neurotrophic factors,
including nerve development factor, brain-derived neurotrophic factor
(IGF)-1, and transformation growth factor- 𝛽. In conditions of systematic
or regional inammation, cellular and molecular constituents transmit
inammatory signals to the brain via distinct pathways. In typical cir-
cumstances, the inammatory response is appropriately regulated in or-
der to prevent uncontrolled injury caused by inammation [ 62 ]. Thus,
rather than addressing these systemic inammatory signals with a pro-
tective response, the damaged microglia evoke an exaggerated reaction
that contributes to the etiology of AD. The microglia that have been "en-
ergized" alter in appearance and secrete numerous cell antigens. Such
cells are called "activated microglia." When microglia are activated, an
array of pro-inammatory substances are secreted. In an experimen-
tal mouse model of Alzheimer’s disease, tau hyperphosphorylation is
caused by chronic inammation and cytokine activation [ 63 ].
Concurrently with periodontal inammations and atherosclerotic
cardiovascular diseases (ACD), inammatory systemic markers such as
interleukins, TNF-, and reactants in the acute phase boost in concentra-
tion. There are two plausible mechanisms by which periodontitis may
contribute to the advancement of Alzheimer’s ( Fig. 5 ):
• Periodontitis preceding systemic inammation/infection
• Bacterial and viral inuence
Pro-inammatory amounts of cytokines are increased by pathogenic
periodontal bacteria as well as the host response, according to the rst
process. A wide range of pro-inammatory substances and cytokines are
secreted into the circulatory system, thereby contributing to the over-
all inammatory stress in the body. Pro-inammatory compounds have
the ability to breach the blood-brain barrier (BBB) as well as inltrate
the cerebral cortex. The second process may include the inltration of
the brain by bacteria and viruses present in the tooth plaque biolm.
This phenomenon could take place either peripherally or directly by
means of cerebral transport facilitated by the circulation [ 64 ]. A sub-
stantial body of research implicates inammatory pathways in the cen-
tral nervous system as the causative agents of memory loss observed in
Alzheimer’s disease. Research conducted on mouse models has demon-
strated the benecial impacts of anti-inammatory agents in reducing
the accumulation of amyloid plaque and neuroinammation. The study
conducted by Yan et al. [ 65 ] identied notable reductions in glial bril-
lary acidic protein and IL-1 𝛽levels, in addition to a substantial eclipse
in plaque burden, in rodents that were administered non-steroidal anti-
inammatory agents. The periodontal plaque spirochetal species exhibit
a diverse array of virulence factors that facilitate their engagement with
the defenses of the host and enhance their capacity to inltrate the pe-
riodontal tissues in the host. [ 66 ]. Peri-periodontitis is characterized by
persistent periodontal inammation, which provides an ongoing supply
of systemic pro-inammatory factors that are elevated. These agents and
their byproducts possess the ability to penetrate the blood-brain barrier
(BBB) and gain access to the brain. Negative eects may be caused by
these compounds either through direct or indirect impact on the brain
through the disruption of vascular integrity [ 67 ]. Spiketal species that
invade the brain are capable of sustaining an ongoing persistent inam-
matory process through the stimulation of innate immune responses,
which involve the involvement of diverse signaling pathways. This ac-
tivation ultimately leads to neuronal degeneration. There is a proposi-
tion that inammation could serve as a mysterious mediator connecting
periodontitis and the development of Alzheimer’s disease. "Undesirable
systemic inammation" can be exacerbated by periodontitis, which can
also increase the systemic the biological burden. It could potentially be
considered one of the risk factors contributing to the progression of neu-
rodegeneration in Alzheimer’s disease.
4. Multi-target therapies and lifestyle intervention strategies in
Alzheimer’s disease
The intricate characteristics of neurological disorders have gener-
ated an urgent requirement for the development of multitarget-directed
ligands capable of targeting the complementary processes implicated
in such conditions. In the development of therapeutics for AD both
cholinesterase as well as 𝛽-secretase enzymes serve as the primary tar-
gets. A potential multitarget agent was identied in 2018 in the form
of a novel pyrimidinylthiourea a byproduct modied with propargy-
lamine. This compound exhibited a strong anity for inhibiting AChE
and MAO-B in the nervous system of mice, and it also mitigated the
cognitive impairment induced by scopolamine in Alzheimer’s disease in
mice [ 68 ]. Iron metabolism alterations are a frequent complication of
neurological disorders. There exists a correlation between the buildup of
iron within the brain of an individual and an excessive production of re-
active oxygen species. This surplus ultimately leads to neuronal degener-
ation and a deterioration in mental abilities. Additionally, prior studies
have demonstrated that iron is essential for inhibiting the development
of amyloid- 𝛽aggregates which are organized, an event that contributes
to neurodegeneration in Alzheimer’s disease. [ 69 ]. Therefore, the main-
tenance of cerebral iron homeostasis is recognized as a promising ther-
apeutic target for conditions associated with aging. M30, a multitarget
neuroprotective material, was synthesized to exhibit dual iron eliminat-
ing capabilities as well as inhibitory eects on MAO-A as well as -B. Mul-
titarget directed ligands (MTDLs) are ecacious agents for addressing
the incomprehensible intricacy of neurological disorders. The capacity
of MTDLs to target dierent pathological cascades of neurodegenerative
diseases is equivalent to their enhanced therapeutic properties in com-
parison to single-target tiny compounds. Consideration has been given
to the multi-target approach to AD developing medicines in recent years,
but it has not yet acquired widespread acceptance or been implemented
by the scientic community. This may be due to the fact that the single-
target approach is the conventional, standard method for developing
traditional drugs, which is also more readily accepted by the FDA ap-
7
R.A. Naik, R. Rajpoot, R.K. Koiri et al. The Journal of Prevention of Alzheimer’s Disease 12 (2025) 100004
Fig. 5. Potential mechanisms underlying the development of Alzheimer’s disease. LPS -lipopolysaccharide; BBB -blood brain barrier; APP -amyloid precursor protein;
A 𝛽-amyloid beta; NFTs-neuroobrillary tangles.
proval process. One possible explanation could be the diculties asso-
ciated with formulating this approach and the intricacy of assessing the
mechanisms underlying the drug’s eects. Develop an initial pharma-
ceutical compound comprising at least two functionally active groups or
targets. Multiple molecular pathways can be targeted by numerous nat-
ural and synthetic compounds that contain multiple functional groups.
In the realm of conventional pharmaceutical development, non-specic
activities encompass anything beyond the intended target activity. Fre-
quently, the greatest potential specicity is desired in a drug choice. If
"non-specic actions" target other mechanisms implicated in AD, how-
ever, less specic drugs may be favored over more specic ones when it
comes to the treatment of multifaceted AD. Apart from vaccines as well
as enzyme inhibitors, various compounds have been developed to exert
a wide range of techniques for action. ALZT-OP1, a Phase III clinical
trial involving a mixture of two pharmaceuticals that eectively pre-
vents A 𝛽aggregation and neuroinammation, is presently taking place
[ 70 ]. Decades have been devoted to the investigation of neurotrophins
(NTs) and receptor-based treatments for Alzheimer’s disease (AD) due
to pleiotropic impacts of NTs and receptor signaling. However, the prac-
tical implementation of NTs is constrained by their inadequate pharma-
cological characteristics, including brief plasma half-lives, inadequate
oral bioavailability and BBB permeability, and restricted diusion into
brain tissue [ 71 ]. The transmission of genes technique has been em-
ployed as an alternative approach to develop therapies for AD based
on NTs. In addition, evaluate organic compounds with numerous pro-
cesses of action against the diverse toxins and mechanisms implicated in
AD. A number of naturally occurring compounds, including derivatives
of resveratrol, chelerythrine, chalcone, coumarin, huprine, curcumin,
rhein, and berberine, have demonstrated progress in search of devel-
oping drugs for AD [ 72 ]. The progression of Alzheimer’s disease (AD)
and dierent molecular pathways are both susceptible to modulation
by specic molecules or elements. An illustration of this is the regu-
lation of neurodevelopment, neural plasticity, neuronal survival, and
neurodegeneration through brain insulin signaling [ 73 ]. Neurodegen-
eration in Alzheimer’s disease (AD) is likely associated with disrupted
brain glucose metabolism, a well-documented metabolic abnormality
that precedes the disease and appears to be inuenced by dysfunctional
insulin signaling in the AD brain. The research of oral medications that
enhance insulin resistance or sublingual treatment with insulin to re-
store brain insulin signaling for the management of Alzheimer’s dis-
ease (AD) is now being implemented [ 74 ]. The diversity of AD patients’
molecular mechanisms, pathologies, and clinical symptoms is predi-
cated on a multifaceted character of the disease. However, active A 𝛽
immunotherapy as a potential preventive measure contrary to AD has
yet to undergo rigorous testing, and numerous safety concerns, includ-
ing the intensity of immune reactions for the vaccine, require additional
investigation.
It appears that lifestyle interventions modulate a variety of molec-
ular mechanisms to minimize morbidity and mortality in aging popu-
lations; thus, they may represent eective non-therapeutic approaches
to address metabolic and aging-related diseases. Innovative approaches
that target a range of cardiovascular and metabolic risk factors-such as a
lack of exercise cigarette smoking, postmenopausal high blood pressure,
midlife being overweight, and diabetes —may be able to reduce the in-
cidence and prevalence of decline in cognition and AD, according to re-
cent studies [ 75 ]. Consequently, dietary and lifestyle modications may
serve the same eective primary prevention approaches for Alzheimer’s
disease. Adiponecteritis and Alzheimer’s disease (AD) may be inuenced
by neuroinammatory processes that are altered by nutritive dietary
components that are healthy and abundant in anti-inammatory and an-
tioxidant qualities. Sultana and Alauddin [ 76 ]. The utilization of these
nutritional supplements and behavioral patterns could potentially serve
as possible strategies to avoid cognitive impairment or postpone the on-
set of Alzheimer’s disease. The functions of various food sources in both
good and bad health have been investigated, including omega-3 fatty
acids, nutraceuticals, minerals, micronutrients, and vitamins. In the
pathophysiology of diabetes, obesity, cardiovascular diseases, cancer,
and so forth, these nutritional strategies are recognized to ameliorate the
condition. Curcumin is extracted from the rhizome of Curcuma longa,
produced primarily in India and China, It is recognized for its signi-
cant contribution to disease prevention via the regulation of diverse bio-
chemical pathways [ 77 ]. It is the primary active constituent of turmeric,
a herbaceous Asian spice. Antioxidant, anticancer, anti-inammatory,
antibacterial, antiviral, and antifungal properties distinguish turmeric
powder from other substances that are traditionally treated with it. Cur-
cumin exhibits neuroprotective, anti-inammatory, and potent antiox-
idant properties, which have been demonstrated in recent research to
confer a protective eect against Ab in AD [ 78 ].
8
R.A. Naik, R. Rajpoot, R.K. Koiri et al. The Journal of Prevention of Alzheimer’s Disease 12 (2025) 100004
Flavonoids, which have a polyphenolic construction, are prevalent in
a variety of natural sources including fruits, vegetables, cereals, foliage,
roots, stems, orals, tea, and wine (Panche and Diwan). Flavonoids are
classied into diverse subclasses based on their chemical makeup, in-
cluding but not limited to avonols, avones, anthocyanins, isoavones,
chalcones, and dihydrochalcones. Flavonoids may possess potent antiox-
idants, antibacterial, anti-mutagenic, and anti-carcinogenic properties,
according to a number of studies. As a result of these characteristics,
avonoids prevent the development of cancer, Alzheimer’s, and cardio-
vascular diseases. [ 79 , 80 ].
Quercetin, a avonoid found in a wide variety of foodstus as well
as vegetation, includes American elder, red wine, scallions, green tea,
pears, cherries, and Ginkgo biloba. Possible upregulation or downregu-
lation of cytokines via the nuclear factors (Nrf2), Paraoxonase-2, c-Jun
N-terminal kinase (JNK), Protein kinase C, Mitogen-activated protein
kinase (MAPK), and PI3K/Akt paths are among molecular processes be-
neath neuroprotective benets of quercetin, as shown in in living cells
and in the laboratory research. [ 81 ].
Abnormalities in the brain of aged APP rodents are reversed and
reduced by caeine. The observed decrease in Ab plaques could poten-
tially be attributed to the upregulation of survival pathways in the brain
and the stimulation of protein kinase A activity, as suggested by Zeitlin
et al., [ 82 ]. This is supported by the elevated levels of phosphor-CREB
and the reduced production of phosphor-JNK as well as phosphor-ERK
in animal models of Alzheimer’s disease.
Resveratrol, a polyphenol found in red wine and grapes, is gain-
ing recognition as a result of its powerful antioxidant and anti-
inammatory properties. The previously mentioned characteristics of
resveratrol are attributable to its molecular form, which permits it
the capacity to form bonds with numerous biomolecules. Resveratrol
has been identied as an activator of the class III HDAC sirtuin 1
(SIRT1), which protects cells from ROS-induced inammation and ox-
idative damage [ 83 ]. Supplementing with resveratrol, which possesses
potent antioxidant, anti-inammatory, and neuroprotective attributes,
could potentially serve as an eective therapeutic approach in address-
ing the increasing incidence of cognitive impairment and Alzheimer’s
disease.
Increased dietary mineral intake protects against a variety of
metabolic diseases, including type 2 diabetes, hypertension, stroke, and
cognitive decline, according to substantial evidence. In cognitive decline
and Alzheimer’s disease, an excess of reactive oxygen species (ROS) is
linked to malfunction of the mitochondria, as evidenced by changes in
biosynthesis and metabolism [ 84 ]. Drugs that target mitochondria may
represent a viable medicinal approach in the treatment of neurological
disorders and aging.
Vitamins may be benecial in preventing the development of
Alzheimer’s disease and preserving cognitive function, as they perform
essential functions in the nervous system [ 85 ]. It has been discovered
that vitamin supplements signicantly reduce the risk of long-term dis-
eases, such as cancer and cardiovascular disease. In numerous diseases,
these dietary changes target molecular mechanisms implicated in dis-
ease pathophysiology, such as calcium homeostasis, inammatory path-
ways, oxidative stress, and mitochondrial dysfunction. Numerous molec-
ular mechanisms implicated in the pathogenesis of Alzheimer’s disease
(AD), mild cognitive impairment (MCI), and aging were modulated in
a recent study, demonstrating the function of vitamins in these condi-
tions. Russell et al. [ 86 ] found that regular exercise improves mitochon-
drial health in the skeletal muscles by stimulating multiple cell signaling
pathways. It is recognized for its ability to regulate blood sugar and body
weight, support blood pressure, diminish dyslipidemia, and enhance the
health of muscles and bones. By enhancing metabolic health, calorie re-
striction (CR) is an additional potentially eective non-pharmacologic
strategy that halts brain aging. Through the neutralization of the detri-
mental eects of ROS and oxidative damage, CR is eective. By target-
ing sirtuins, CR has been demonstrated to prevent the development of
numerous diseases.
5. Role of phytochemicals in the prevention of Alzheimer’s
disease
Phytochemicals, including organosulfur, phenols, terpenes, as well
as terpenes, have been derived from plant compounds that impart col-
oration, smells, and irritating properties. These substances serve as pro-
tective barriers against both internal and external stresses, including
metabolic processes such as free radical reactive oxygen species (ROS)
and expression of proteins as well as hazards from the environment in-
cluding infectious agents, enemies, and UV rays, which are detrimental
to plant survival. Polyphenols (broad assemblages of phenols, which are
compounds consisting of an aromatic ring bonded to a hydroxyl group)
are produced by numerous plant species. Typical phytochemicals such
as stilbenoids, phenolic acids, along with avonoids are included. It
has been demonstrated that a number of phenolic acids regulate neu-
ropathological processes associated with AD. ( Fig. 6 ).
5.1. Role of dietary phytochemicals
Curcumin, a phenolic acid, is present in turmeric, a vibrant yel-
low root spice that is botanically associated with ginger. Morphological
stains thioavin-S and Congo red, that are utilized of illustrating amy-
loid brils in brain tissue, resemble it morphologically. It was stated in
experiments that dietary curcumin can inhibit developing deciencies,
synaptic injury, oxidative stress, and cortical microgliosis in rodents
following intracerebroventricular injection of A 𝛽[ 87 ]. Heme-A 𝛽per-
oxidase harm to muscarinic ACh receptors were also diminished, along
with A 𝛽plaques as well as oxidative stress on APP recombinant rodents.
Furthermore, an investigation involving transgenic mice revealed
elevated levels of DNA damage in comparison to control mice. The
researchers documented that the damage could be substantially mini-
mized through adding supplements to the diet with curcumin [ 88 ]. The
gastrointestinal microbiota is also highly implicated in the metabolism
and fermentation of dietary phytochemicals, in along with its function
in the pathogenesis of AD. Initial absorption of dietary phytochemicals
may have shown to range from 5 to 10 %. Phytochemicals that persist
are transported to the colon, after which they are subjected to thorough
metabolism by microbiota. While the precise pathways of metabolism
and molecular targets remain unknown, it is possible that the bene-
cial properties of dietary polyphenols could be enhanced through the
intestinal microbiome’s degradation of them [ 15 ]. Regular curry con-
sumers are associated with improved cognitive function and a reduced
risk of Alzheimer’s disease; the compound responsible for these bene-
ts was identied as curcumin, which is present in turmeric, an impor-
tant component in curry [ 89 ]. Curcumin is being documented to safe-
guard the digestive system and microbial metabolism through analogous
mechanisms [ 90 ]. These mechanisms include inhibiting oxidative bowel
injury, maintaining equilibrium in gut immune reactions, and promot-
ing intestinal epithelial cells. An estimated 90–95 % of the polyphenols
found in food are retained in the colon, where they are broken down by
the bacteria in the gut into easily absorbed small biological phenol com-
pounds [ 91 ]. This is because of the prohibitive molecular weight of the
polyphenols in the tiny intestines. Curcumin exhibits limited absorption
in the small intestine when administered orally (1 % bioavailability) and
fails to penetrate the blood-brain barrier (BBB), a property similar to its
insolubility. Reduce pathologies associated with microbial metabolites,
which mediate microbe-produced neurotransmitters and and prevent
the transfer of microbial organisms and their products are all functions
of polyphenols in the brain-gut-microbiota system. [ 91 ].
Anthocyanins, including their deglycosylated form anthocyanidins,
are prevalent in fruits, vegetables, certain pigmented cereals, and
legumes. These water-soluble avonoids have shown promise as poten-
tial interventive agents in Alzheimer’s disease. Furthermore, it has been
documented that Mexican blue maize anthocyanins inhibit 𝛼-amylase,
thereby preventing the digestion of starch. Furthermore, the unpro-
cessed starch can serve as a source of energy for gut probiotics (speci-
9
R.A. Naik, R. Rajpoot, R.K. Koiri et al. The Journal of Prevention of Alzheimer’s Disease 12 (2025) 100004
Fig. 6. Chemical structure of some phytochemicals.
cally Lactobacilli along with Bidobacterium) and as precursors for the
metabolism of SCFA-producing microorganisms. [ 92 ].
Tea has been utilized for health benets for numerous centuries on
account of its potent phenolic content. Among these, epigallocatechin
gallate (EGCG), which comprises around 10 % of the dried weight of tea
leaf, is one of the most prevalent compounds [ 93 ]. It was discovered that
EGCG inhibits the development of curli-related proteins, thereby de-
creasing the amount of amyloid generated by gastrointestinal microbes;
this may account for the decreased serum amyloid level. Tea/EGCG in-
take has been associated with ameliorative impacts on neurodegener-
ative impairments such as memory loss and cognitive dysfunction, ac-
cording to a number of clinical trials. As an illustration, epidemiological
investigations have provided evidence that consistent consumption of
green tea mitigates cognitive decline and dementia associated with ag-
ing, with EGCG being identied as the most ecacious compound [ 94 ].
Multiple research studies have suggested that the administration of di-
etary polyphenols, including (− )-epigallocatechin-3-gallate (EGCG) and
curcumin, can mitigate age-related cellular damage through the inhibi-
tion of reactive oxygen species (ROS) production.
Terpenes comprise an extensive array of lipid-soluble substances that
manifest a spectrum of toxicity ranging from lethal to entirely edible.
This, in conjunction with their aesthetically pleasing scents and tints,
aids in their multifaceted ecological functions, which encompass protec-
tion, discouragement, and promotion of pollination [ 13 ]. Advanced ex-
changes with insects are facilitated through direct neural system (CNS)-
to-insect relationships via neurotransmitters, hormones, and cholinergic
systems; these interactions may be applicable to the mammalian CNS
and oer intriguing prospects for the development of therapeutics for
AD.
It was discovered, for instance, that ginsenosides safeguard gas-
trointestinal barrier functions by increasing glucose absorption by in-
testinal epithelial cells, thereby preventing the translocation of micro-
bial cells and byproducts to the central nervous system. Certain mi-
crobes that are upregulated include Bacteroides, Lactobacillus, and Bi-
dobacterium. These microbes have been identied as ginsenoside deg-
lycosylators, which convert ginsenosides into secondary compounds
that enter the systemic circulation more readily and exhibit more po-
tent anti-inammatory eects than the parent compounds [ 95 ]. The
dual mechanism of action exhibited by ginsenosides signicantly am-
plies their neuroprotective properties, rendering them viable can-
didates for incorporation into preventive and therapeutic strategies
targeting AD.
10
R.A. Naik, R. Rajpoot, R.K. Koiri et al. The Journal of Prevention of Alzheimer’s Disease 12 (2025) 100004
A study conducted by Zhou et al. [ 96 ] discovered that xanthocera-
side, which was extracted from the husks of Xanthoceras sorbifolia
Bunge, increased the level of production of BDNF (brain-derived neu-
rotrophic factor), suppressed tau excessive phosphorylation and accu-
mulation, and mitigated oxidative stress, neuroinammation, as well as
synaptic damage while having no impact on AChE activities. By virtue
of its the insoluble nature, xanthoceraside has a dicult time travers-
ing the BBB and entering the circulatory system [ 97 ]. Consequently, the
brain-gut-microbiota axis determines how its bioactivities regarding AD
are manifested in relation to relationships with the gut microorganisms.
An improvement in memory among older people was found to be as-
sociated with particular dietary phytochemicals, including carotenoids,
although no single nutrient stands out. Nevertheless, through meticu-
lous strategizing, research endeavors can be formulated to specically
examine the correlation between age-related cognitive impairments as
well as polyphenolic nutritional supplements; the outcomes may prove
to be more illuminating. However, in order to ascertain that these stud-
ies produce valuable nutritional insights, further preliminary research
employing suitable simulators is necessary to validate the benecial im-
plications that have already been published.
5.2. Antioxidant role of phytochemicals in AD
After plants have been put under adverse conditions, an oxidative
surge may induce an imbalance among the generation and removal of
reactive oxygen species (ROS), which can activate both biochemical
and nonenzymatic reactive antioxidant processes. The initial one per-
tains to alterations in the functionality of enzymes that protect against
free radicals, including peroxidases, catalase, and superoxide dismutase.
Conversely, the non-enzymatic response concerns the production of an-
tioxidants with both moderate and high molecular weights (ascorbic
acid, glutathione, carotenoids, phenolic acids, avonoids, and others;
tannins). Signicant research focus is devoted to examining the antiox-
idant capacity of naturally occurring compounds, also known as phyto-
chemicals.
Carotenoids, which impart a signicant number of the red, orange,
and yellow colors to fruits, foliage, and owers, are eective antioxi-
dants. Their antioxidant activity is predicated on their capacity to scav-
enge peroxyl radicals; they are abundant in fruits and vegetables, where
they are easily accessible [ 98 ]. The eectiveness of reducing is corre-
lated with the total amount of conjugated double bonds present within
these compounds; for instance, U - and 𝛼-carotene, as well as zeaxanthin
as well as cryptoxanthin, are among the set of 1O2 quenchers charac-
terized by their high activity. An illustration of this can be seen in ly-
copene, which is produced as an intermediate in the metabolic process of
carotenoids. It functions as an ally to nitric oxide, lipid peroxyl radicals,
and reactive oxygen species (ROS), and may exert a protective eect
against cancer, atherosclerosis, diabetes, and diseases associated with
inammation [ 99 ]. The extensive range of biological functions exhib-
ited by phenolic compounds and conjugation of side chains to aromatic
rings and the increased quantity of free hydroxyls have been linked to
increased antioxidant activity [ 100 ].
Terpenoids constitute an additional extensive class of secondary
metabolites found in plants. Antioxidant activity was observed in
monoterpenes, sesquiterpenes, as well as diterpenes isolated from plants
with aromatic compounds, according to in vitro tests [ 101 ]. Tiong et al.
[ 102 ] reported on the hypoglycemic and antioxidant properties of vin-
dolinine, vindoline, vindolidine, and vindolicine, all of which were
extracted from the leaves of Catharanthus roseus. Furthermore, vin-
dolicine decreases H2O2-induced oxidative injury to cells from the pan-
creas and exhibits the greatest level of antioxidant activity, suggesting
that it may have possibility as a hypoglycemic agent.
Numerous studies have documented that resveratrol exhibits activ-
ity targeting the central nervous system (CNS). Despite traversing the
blood-brain barrier (BBB), this element exhibits limited availability due
to its rapid metabolism onto glucuronide and sulfate conjugates. Nu-
merous lines of research suggest that in addition to other biologically
signicant antioxidant functions, therapeutic, and protective properties
are also present [ 103 ]. In relation to the radical-scavenging action of
resveratrol, computational and structural analyses indicate that the hy-
droxyl group located at the 4 ′ -position is considerably more susceptible
to oxidation during the antioxidant reaction compared to other hydroxyl
groups. Resveratrol administered intraperitoneally has been found to en-
hance the activity of various indigenous antioxidant enzymes, including
SOD and CAT, thereby inducing neuroprotective eects [ 104 ]. Resver-
atrol administration over an extended period of time ameliorates the
cognitive decline induced by colchicine, decreases levels of MDA and
nitrite, and replenishes depleted GSH.
Curcumin was shown to possess potent neuroprotective properties as
an antioxidant by scavenging reactive oxygen species (ROS) and elimi-
nating free radicals formed by nitric oxide (NO-) [ 105 ]. It is due to the
H abstraction from these groups that curcumin possesses such excep-
tional antioxidant activity. Additionally, carbon-centered radicals and
phenoxyl radicals are generated during the reactions of curcumin with
free radicals at the methylene CH2 group. Further experimental evi-
dence substantiating the antioxidant characteristics of curcumin was
presented by utilizing an AD transgenic mouse model to illustrate how
curcumin diminishes concentrations of proteins that have been oxidized
in the brain that comprise carbonyl groups [ 106 ]. The antioxidant ac-
tivity exhibited by curcumin in vivo might be facilitated by antioxidant
enzymes including glutathione peroxidase (GSH-Px), superoxide dismu-
tase (SOD), and catalase (CAT). It was recently established that cur-
cumin operates as a Michael receiver via its interaction with glutathione
(GSH) in the form of thioredoxin. An imperative marker of oxidative
stress, which has been linked to the development of Alzheimer’s dis-
ease, is a decrease in intracellular GSH concentrations. Additionally, cur-
cumin has been found to augment the activities of antioxidant enzymes
SOD and CAT in the striatum and midbrain of rodents injected with 1-
methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) [ 107 ]. Given the in
vivo the results that peroxynitrite generates hyperphosphorylation, ni-
tration, and formation of Alzheimer’s-like tau, it has been documented
that curcumin functions as a mediator in the direct detoxication of re-
active nitrogen species, including peroxynitrite. As a result, curcumin
exhibits antioxidant properties [ 108 ].
EGCG demonstrates protective eects beyond its anti-inammatory
properties through the regulation of various survival genes as well as
the control of a multitude of antioxidant protecting enzymes. Neu-
ronal toxicity that is linked to various neurodegenerative disorders is
facilitated by sophisticated glycation end-products. By reducing ROS
and MDA, EGCG enhanced SOD activity while safeguarding against
glycation end products-induced neurotoxicity [ 109 ]. EGCG treatment
increased SOD and GSH-Px activity in aged rodents treated with D-
galactose while decreasing MDA levels in the hippocampus.Still, addi-
tional research is necessary to evaluate the risk associated with this
method of administration. In addition, curative applications of cur-
cumin have been assessed in the management of nonalcoholic fatty
liver disorder, colitis with ulcers, chronic discomfort, cancer, premen-
strual syndrome (PMS), as well as infection with Helicobacter pylori.
[ 110 ] .The various disease conditions for which curcumin has been ob-
served to provide benets have been ascribed to its anti-inammatory
and antioxidant qualities [ 111 ].It suppresses the expression of COX-
2 and iNOS, thereby preventing the harm caused by reactive oxygen
and nitrogen species, and inhibits the signaling pathways IL-6, NF- 𝜅B,
and MAPK, thereby decreasing astroglial activation, furthermore, it hin-
ders the accumulation of tau and encourages the disassembly of tau
oligomers in the laboratory [ 112 ]. Curcumin’s prospective applicabil-
ity in the treatment of Alzheimer’s disease has generated considerable
interest due to its antioxidant and anti-amyloid eects. Pomegranate
juice along with extracts have been found to possess noteworthy bioac-
tive properties, such as anti-inammatory and antioxidant eects, in
numerous animal and human studies [ 113 ]. Recent investigations on
mice that analyzed the eects of extracts from pomegranate peels con-
11
R.A. Naik, R. Rajpoot, R.K. Koiri et al. The Journal of Prevention of Alzheimer’s Disease 12 (2025) 100004
sumption revealed a reduction in pro-inammatory cytokine expression,
A 𝛽plaque density, and AChE activity, as well as an increase in neu-
rotrophic factor, which is derived from the brain, expression [ 114 ].
Additionally, conjugated sucrose, fructose, and glucose, which are
present in pomegranates, possess antioxidant eects, according to one
research.
The avonoid group of polyphenols comprises pigment compounds
such as anthocyanidins and anthoxanthins, as well as avans. Antho-
cyanidins, which are water-soluble compounds that are abundant in
fruits like blueberries, possess strong anti-inammatory and antioxi-
dant characteristics [ 115 ]. Previous research has demonstrated that in-
troducing blueberries into the diet of AD mouse models resulted in
notable reductions in learning and memory decits caused by the ef-
fects of oxidative stress and excitotoxicity, neuronal depletion, and
AChE activity inhibition [ 116 ]. Anthoxanthins, comprising avones and
avonols, are an additional category of avonoid pigments. Fruits,
vegetables, and botanicals contain the avone luteolin, which pos-
sesses anti-inammatory, antioxidant, antimicrobial, and neuroprotec-
tive properties, among others. Lutein inhibits the zinc-induced excessive
phosphorylation of the tau protein at Ser262/365, as shown in labora-
tory investigations [ 117 ]. This is due to luteolin’s antioxidant activity as
well as ability to modulate the tau phosphatase/kinase system. Previous
studies have demonstrated that EGb761 enhances dopaminergic trans-
mission in the prefrontal cortex (PFC) of aged rats, stimulates the synthe-
sis of a brain-derived neurotrophic factor, improves in vitro mitochon-
drial respiration, and inhibits the production of lipid peroxidation and
superoxide free radicals in a rodent model of Parkinson’s disorder [ 118 ].
EGb761 functions as an AChE inhibitor in addition to its robust antioxi-
dant characteristics; consequently, many investigations have conducted
comparisons between its clinical eects and those of pharmaceutical
AChE inhibiting agents. The conventional method "anti-dementia treat-
ments" include Ginkgo biloba, and their neuroprotective and antioxidant
properties are highlighted [ 119 ].
5.3. Neuroprotective role of phytochemicals in AD
Flavonoids derived directly from the mulberry plant Morus alba
are present in quercetin. Quercetin has medicinal value in preventing
and treatment of various ailments, such as cardiovascular disease, can-
cer, and neurodegenerative disease, alongside may penetrate the blood-
brain barrier [ 120 ]. In addition, quercetin has demonstrated charac-
teristics that can inhibit the synthesis of histamine and stabilize the
membranes of mast cells. Anti-inammatory, anti-cancer, and anti-
oxidant are some of its properties [ 121 ]. Quercetin has demonstrated
ecacy as an inhibitor of various accumulation proteins, including A 𝛽,
𝛼-synuclein, and tau, in vitro. This is achieved through a direct asso-
ciation with misfolded proteins, which results in the maintenance of
oligomeric species and the suppression of bril development [ 121 ].
HT22 hippocampal neurons pre-treated with quercetin are resistant to
oxidative damage and hyperphosphorylation of tau protein induced by
okadaic acid. In a triple transgenic rodent model of Alzheimer’s disease,
additional research has shown that intraperitoneal administration of
quercetin (25 mg/kg) decreased levels of A 𝛽and NFTs, ameliorated the
neuroinammatory procedure, and improved memory and cognitive im-
pairment. In conclusion, quercetin is an excellent therapeutic agent for
treating Alzheimer’s disease and other neurodegenerative tauopathies,
primarily because of its ability to traverse the blood-brain barrier.
Oxyresveratrol, a stilbenoid, is discovered in the heartwood of Ar-
tocarpus lakoocha, a member of the Moraceae family. Historically, it
was utilized as the medicinal substance "Puag-Haad" [ 122 ]. In the past,
oxyresveratrol was evaluated in relation to its anticancer properties,
inhibitory activity against tyrosinase, and capacity to enhance the im-
mune system. Oxyresveratrol is rapidly transported to tissues and has
an availability of approximately 50 % [ 123 ]. Furthermore, treatment
with oxyresveratrol prevented the phosphorylation of ERK, c-JNK, and
p38 in cortical neuron cells produced with A 𝛽neurotoxicity, thereby
directly inhibiting inammation and apoptosis. Immune along with in-
ammatory responses, in addition to the development and release of
proinammatory cytokines such as interleukin-18 and IL-1 𝛽, are regu-
lated by inammasomes composed of NACHTLRR-PYD-containing pro-
teins 3 (NLRP3). [ 124 ].
Resveratrol (3,5,40-trihydroxy-trans-stilbene) is a stilbenoid, a phy-
toalexin, and polyphenol derivative derived from Vitis vinifera. It is
synthesized by a number of plants in reaction to infections or injury
[ 125 ]. Resveratrol exhibits promising characteristics as a drug candi-
date, including cardioprotective, anti-carcinogenic, anti-inammatory,
and anti-carcinogenic properties [ 126 ]. Additionally, the ability of
resveratrol to prevent hyperphosphorylation of the tau protein and/or
facilitate dephosphorylation has been investigated. It is noteworthy that
tau protein that has undergone hyperphosphorylation can bind resver-
atrol and become stabilized in a comparatively soluble state in a tau
transgenic mouse model [ 127 ], thereby impeding tau aggregation into
tangles. In laboratory models of severe brain injury, resveratrol sup-
plementation immediately following the occurrence of traumatic brain
injury decreases damage volume and oxidative stress. SIRT1, which is
stimulated by resveratrol, reduces amyloid neuropathology in the brains
of Tg2576 rodents and protects cells from A 𝛽-induced ROS production
[ 128 ]. Given that resveratrol is a neuroprotective compound in the con-
text of Alzheimer’s disease, it is plausible to hypothesize that its an-
tioxidant eects and SIRT1 activation may contribute to its ability to
combat A 𝛽toxicity. Given the signicant role that NF-k 𝛽signaling ac-
tivation plays in neurodegeneration, an additional correlation between
Alzheimer’s disease (AD) and the neuroprotective properties of resvera-
trol is its capacity to downregulate the expression of NF-k 𝛽-modulated
genes, including cathepsin, NO, prostaglandin E2 (PGE2), and iNOS.
[ 129 ].
Rosmarinic acid, which is obtained from Melissa ocinalis, has a
long history of utilization due to its antioxidants, neurologically pro-
tective, as well as antioxidant characteristics [ 130 ]. Rosmarinic acid
has the ability to inhibit inammation and allergenic immunoglobu-
lin reactions of polymorph nuclear leukocytes. Signicantly, research
has conclusively demonstrated that rosmarinic acid’s anti-inammatory,
anti-apoptotic, and neuroprotective properties oer therapeutic advan-
tages in the aftermath of brain injury [ 131 ]. Memory retention has also
been observed to be enhanced by rosmarinic acid, possibly as a re-
sult of its experimental eects on increased BDNF levels and decreasing
phospho-tau (p-tau) expression. In vitro studies have demonstrated that
rosmarinic acid inhibits 𝛽-sheet assembly in the tau protein associated
with Alzheimer’s disease and decreases hyperphosphorylation of the tau
protein [ 132 ]. Although rosmarinic acid possesses remarkable proper-
ties, more studies are required to validate its eectiveness against AD
[ 133 ].
Quinic acid possesses anti-inammatory and carcinogenic proper-
ties as well as is a cyclic polyol along with cyclohexane carboxylic acid
[ 134 ]. An essential source of quinic acid derivatives is the Asteraceae
family plant Aster scaber. Aster scaber ameliorates neurite growth by
activating the TrkA signaling pathway, which is recognized as a crucial
neurodegeneration process and whose signicant anti-inammatory ef-
fects in studies on animals make it a possible candidate for Alzheimer’s
disease. [ 135 ].
Curcumin, which is present in the condiment turmeric, originates
from Curcuma longa, which belongs to the Zingiberaceae family of gin-
gers. Curcuminoids, consisting of curcumin, demethoxycurcumin, and
bisdemethoxycurcumin, are bioactive constituents found in turmeric.
Experimental research and clinical research has demonstrated that these
compounds have a multitude of benecial eects [ 136 ]. Certain experts
of healthcare administer turmeric intravenously, purportedly to address
inammatory conditions including psoriasis and joint discomfort. Cur-
cumin, a substance that inhibits GSK-3 𝛽[ 137 ], is known to protect cells
against tau-induced neurotoxicity. GSK-3 𝛽regulation of tau phosphory-
lation is facilitated by this enzyme. In recent studies involving rodents
and rats, the potential of curcumin to mitigate inammation and mito-
12
R.A. Naik, R. Rajpoot, R.K. Koiri et al. The Journal of Prevention of Alzheimer’s Disease 12 (2025) 100004
chondrial dysfunction in models of neurological insult has been inves-
tigated. Curcumin decreased post-injury lesion diameters and inam-
matory biomarkers in brain tissue, and enhanced mitochondrial func-
tion and behavioral outcomes, according to the ndings [ 138 ]. Fur-
thermore, a transgenic mouse study revealed elevated levels of dam-
aging DNA in comparison to the control group of mice, and adding
curcumin to the diet was found to substantially mitigate the damage.
Curcumin exhibits signicant antimicrobial properties that might ex-
ert either direct or indirect impacts on the accumulation of A or other
neuropathological pathways that contribute to the development of AD.
Curcumin’s antioxidant and anti-amyloid properties have sparked con-
siderable interest in its potential therapeutic applications for AD. The
insoluble nature of curcumin in water, nevertheless, has limited its ap-
plication. By synthesizing curcumin molecules that retain their anti-
oxidative attributes, are actually non-cytotoxic, and have the potential
of destroying amyloid aggregates, this limitation may be surmounted,
allowing for an integrated strategy to the prevention of Alzheimer’s
disease
Zingiber ocinale, frequently referred to as ginger, is a member of
the Zingiberaceae family and has been utilized historically for its aro-
matic and condiment properties. 6-Shogaol is the primary active compo-
nent of Zingiber ocinale. Scholarly investigations have demonstrated
that shogaol (6-, 8-, and 10-shogaol) possesses potent anti-inammatory
and anti-oxidant characteristics [ 139 ]. Furthermore, a multitude of in
vitro investigations have substantiated the protective properties of 6-
Shogaol against neurodegenerative disorders, most notably Alzheimer’s
disease, through its ability to improve memory, suppress inammation,
and stimulate the antioxidant system. Furthermore, the 6-shogaol ex-
tract was found to increase BDNF expression and decrease iNOS, NF-kB,
and COX-2 levels, all of which are crucial components of the neurode-
generation process. The phytotherapeutic potential of 6-shagaol in the
treatment of neurodegenerative disorders such as Alzheimer’s disease
was uncovered by these investigations.
Citrus fruits, including oranges (Citrus sinensis) along with grape-
fruit (Cirus paradis) are abundant in the potent antioxidant naringenin
[ 140 ]. The potential of naringenin’s antioxidant, anti-inammatory, as
well as neuroprotective properties to enhance memory function in indi-
viduals with diabetes type 2 and dementia has been extensively docu-
mented [ 141 ]. Naringenin treatment induces a reduction in the expres-
sion of nucleotide oligomerization domain protein 2 (NOD2) and NF-kB
in a rodent model of injury involving serious brain injury.
Delphinidin is an anthocyanidin-class dye that is accessible in water.
Red wine as well as berries, which contain noteworthy pharmacological
activities including anti-inammatory as well as antioxidant qualities,
are profuse in this substance. In relation with the neuroprotective prop-
erties of delphinidin, extant research indicates that it impedes the hy-
perphosphorylation of tau as well as the activation of GSK-3 𝛽in PC12
cells, both of which are induced by A 𝛽[ 142 ]. In a similar manner, it
inhibits calcium levels within cells to avoid neurodegeneration induced
by A 𝛽.
Epigallocatechin-3-gallate (EGCG) is a avonol predominantly
present in green tea leaves. There has antioxidant, antitumoral, antibac-
terial, and neuroprotective properties have garnered signicant atten-
tion in both laboratory settings [ 121 ]. EGCG binds to a partially mis-
folded intermediate, which prevents seeding and rescuing cells from tau-
induced toxicity, in accordance with new research [ 121 ]. Nevertheless,
EGCG is a phytochemical that has the ability to increase the breakdown
of phosphorylated tau molecules in neurons in a selective manner; this
may have substantial implications for preventing the progression of AD.
The pace at which EGCG crosses the BBB is minimal, and its bioavail-
ability was estimated to be around 5 % following oral administration. It
is important to acknowledge that rat hippocampal neurons perished in
response to high doses of EGCG via the mitochondrial-dependent pro-
cess. Furthermore, EGCG exhibits prooxidant and proapoptotic proper-
ties at elevated levels [ 143 ]. Furthermore, the possibility that inhibiting
monoamine oxidase (MAO) activity could provide protection against ox-
idative neurodegeneration is intriguing. The intake of adult rat brains
with EGCG inhibited the activity of MAO-B, thereby preventing physio-
logical peroxidation. In a recombinant AD rodent model, intraperitoneal
EGCG injection reduced brain A 𝛽neuropathology and enhanced cog-
nitive function [ 144 ]. EGCG specically hinders the brillogenesis of
A 𝛽by binding to natively stretched polypeptides and obstructing their
transformation to intermediates of toxic formations.
Morin, a avonol, is found in dyer’s mulberry, guava, and imita-
tion orange, among other fruits and vegetables. It functions as an anti-
inammatory agent, antioxidant, hepatoprotectant, as well as antihy-
pertensive. Morin may prevent GSK3 𝛽-induced tau phosphorylation in
vitro as well as inhibit GSK3 𝛽activity as a neuroprotective agent [ 145 ].
Furthermore, morin administration signicantly reduced tau hyperphos-
phorylation in APPswe/PS1dE9 double transgenic mice by inhibiting
the CDK5 signaling pathway. Meganatural-az (MN) represents a collec-
tion of grape seed-derived polyphenolic formulations. According to a
rodent model of Alzheimer’s disease [ 146 ], it decreases A 𝛽oligomeriza-
tion and enhances memory. Additionally, MN facilitates tau oligomer
breakdown. The polyphenol oleocanthal is extracted from excess vir-
gin olive oil. Its nonsteroidal anti-inammatory activity was found to
be comparable to that of ibuprofen. The polyphenol in question ex-
hibits an inhibitory impact on the brillation of both A 𝛽and tau [ 147 ].
With respect to the oligomerization of tau, oleocanthal inhibits the mis-
folding of tau and preserves its state of unfolded nature. Therefore,
this polyphenol warrants further investigation as a possible substance
to incorporate into innovative treatments for neurodegenerative tau
disorders.
6. Disease modifying therapies of Alzheimer’s disease
The highly anticipated era of disease-modifying medication for
Alzheimer’s disease has already begun and will signicantly inuence
the perception and management of the condition (Ono et al., 2020).
However, these novel therapies will present hurdles in ensuring fair
and equal access. The medications that are most likely to be widely
used in clinical practice are lecanemab and donanemab. Lecanemab re-
ceived complete approval from the FDA on July 6, 2023, making it the
rst medicine for Alzheimer’s disease that can aect the progression of
the illness. Lecanemab is a specic kind of antibody that is designed
to target and bind to amyloid- 𝛽soluble protobrils and oligomers in
humans. It has a strong attraction to these forms of amyloid- 𝛽, but
a less attraction to amyloid- 𝛽monomers and insoluble brils [ 148 ].
The original FDA rapid clearance for donanemab was denied in Jan-
uary 2023, based on the ndings of a phase 2 study. However, on
February 7, 2024, it was subsequently granted permission [ 149 ]. Pa-
tients who suer from moderate cognitive impairment (MCI) or mild
Alzheimer’s disease may benet from these intravenous monoclonal
antibody treatments since they are able to pass the blood–brain bar-
rier and eliminate cerebral amyloid- 𝛽(A 𝛽) [ 150 ]. The introduction of
disease-modifying medications for Alzheimer’s disease might lead to an
increase in the number of persons seeking clinical care. This includes
those already diagnosed with the illness, those with various forms of
dementia, and people who are worried about their chances of getting
dementia [ 151 ]. The diculties associated with planning for the prompt
and fair distribution of disease-modifying medicines for Alzheimer’s dis-
ease are signicant. New therapies are expected to rst be implemented
at specialised facilities. However, as knowledge and expertise are ac-
quired, these medications will need to be made available to all eligi-
ble individuals. These disease-modifying therapies for Alzheimer’s dis-
ease present a signicant challenge, but they also present an unparal-
leled chance to alter the way dementia is understood, enhance clini-
cal pathways and patient care for all patients, and set the stage for
the delivery of the upcoming generation of therapies as they become
available [ 152 ].
13
R.A. Naik, R. Rajpoot, R.K. Koiri et al. The Journal of Prevention of Alzheimer’s Disease 12 (2025) 100004
7. Conclusion and outlook
AD has a multilateral pathogenesis, as well as the development of
novel therapies capable of targeting dierent targets in brain, is neces-
sary for managing its polyetiological origin, cognition and motor dys-
function, melancholy, and neurodegeneration. Phytochemical entities
capable of targeting specic targets implicated in the pathogenesis of
AD are described in this article. Furthermore, while the previously men-
tioned phytocompounds’ neurological protective eects seem promising
due to their diverse biological activities, at the very least, supplemen-
tary long-term research is required to determine whether or not they
delay the progression of AD. In summary, it has been demonstrated
that polyphenols possess signicant potential as protective compounds
within the realm of neuroscience, and this knowledge continues to grow.
In conclusion, pertinent ndings regarding the medical advantages of
phytochemicals in neurodegenerative disease have been discussed in
this review. Further investigation is warranted to ascertain whether
these phytochemicals alleviate symptoms in patients diagnosed with
Alzheimer’s disease (AD), as well as to determine whether the anti-AD,
neuroprotective, and anti-inammatory properties documented in this
study are also associated with a deceleration of the neurodegeneration
process in AS. Further preclinical investigations are warranted to ex-
amine the impact of phytochemicals on neurodegenerative disorders,
with a particular focus on Alzheimer’s disease, so as to increase our un-
derstanding of the protective mechanisms exhibited by phytochemicals
in such conditions. Moreover, it is imperative that scientic investiga-
tions incorporate the therapeutic advantages of natural products, given
the ample body of literature that consistently arms their eectiveness
and safety when employed in lieu of conventional therapies. In-vitro and
in-vivo studies have consistently indicated that phenolic-derived phyto-
chemicals exhibit more potent anti-inammatory properties and target
subsequent signaling pathways, which bodes well for the prevention of
Alzheimer’s disease development.
Author contribution
RAN, RR, RKK, AS and SKS conceptualized and designed the rst
blueprint for the manuscript. RAN, RB, AFA, AKJ, HF, AOB, AH, WFA,
ASA, MA, AA, AS and SKS collaborated on the paper’s composition and
opinion, as well as making important edits and signing o on the nal
version of the manuscript. All authors have read and approved this draft
for publication.
Data Availability Statement: Data sharing does not apply to this ar-
ticle as no new data were created or analyzed in this study.
Declaration of competing interest
The authors state that they have no competing interests in this arti-
cle.
Acknowledgments
RAN and RR would like to express their appreciation to the
Indian Council of Medical Research (ICMR) for the fellowship.
This research was economically supported by the grant from ICMR
New Delhi, India sanctioned to RAN ( 45/44/2019-PHA/BMS ) and
RR ( 45/17/2022/TOXI/BMS ) respectively. Authors are gratefully ac-
knowledged to the Department of Zoology, Dr. Harisingh Gour
Vishwavidyalaya, Sagar and the DST-FIST program (SR/FST/LS-
1/2018/176(C)) for providing infrastructural facilities. SKS highly ac-
knowledges the Indian Scientic Education and Technology Foundation
for support.
References
[1] Calo C, Gonzalez A, Singh SK, Rojo LE, Maccioni RB. The emerging role of nu-
traceuticals and phytochemicals in the prevention and treatment of Alzheimer’s
disease. J Alzheimer’s Dis 2020;77:33–51
.
[2] Nourbakhsh F, Read MI, Barreto GE, Sahebkar A. Boosting the autophagy-lysosomal
pathway by phytochemicals: A potential therapeutic strategy against Alzheimer’s
disease. IUBMB Life 2020;72:2281–360
.
[3] Jinn S, Drolet RE, Cramer PE, Wong AHK, Toolan DM, Gretzula CA, Voleti B, Vas-
sileva G, Disa J, Tadin-Strapps M. TMEM175 deciency impairs lysosomal and
mitochondrial function and increases 𝛼-synuclein aggregation. Proc Natl Acad Sci
2017;114:2389–94
.
[4] Chen XQ, Mobley WC. Exploring the pathogenesis of Alzheimer disease in basal
forebrain cholinergic neurons: converging insights from alternative hypotheses.
Front Neurosci 2019;13:446
.
[5] Androuin A, Potier B, Nägerl UV, Cattaert D, Danglot L, Thierry M, Youssef I,
Triller A, Duyckaerts C, El Hachimi KH. Evidence for altered dendritic spine com-
partmentalization in Alzheimer’s disease and functional eects in a mouse model.
Acta Neuropathol 2018;135:839–54
.
[6] Chen ZR, Huang JB, Yang SL, Hong FF. Role of cholinergic signaling in Alzheimer’s
disease. Molecules 2022;27(6):1816
.
[7] Martinez JL, Zammit MD, West NR, Christian BT, Bhattacharyya A. Basal forebrain
cholinergic neurons: linking down syndrome and Alzheimer’s disease. Front Hum
Neurosci 2021;13:703876
.
[8] Bekdash RA. The cholinergic system, the adrenergic system and the neuropathology
of Alzheimer’s disease. Int J Mol Sci 2021;22(3):1273
.
[9] Ballinger EC, Ananth M, Talmage DA, Role LW. Basal forebrain cholinergic cir-
cuits and signaling in cognition and cognitive decline. Neuron 2016;91(6):1199–
1218 .
[10] Piccialli I, Tedeschi V, Caputo L, D’Errico S, Ciccone R, De Feo V, Sec-
ondo A, Pannaccione A. Exploring the therapeutic potential of phytochemicals in
Alzheimer’s disease: Focus on polyphenols and monoterpenes. Front Pharmacol
2022;13:876614
.
[11] Rahman MH, Bajgai J, Fadriquela A, Sharma S, Trinh TT, Akter R, Jeong YJ,
Goh SH, Kim CS, Lee KJ. Therapeutic potential of natural products in treating
neurodegenerative disorders and their future prospects and challenges. Molecules
2021;26:5327
.
[12] Singh M, Arseneault M, Sanderson T, Murthy V, Ramassamy C. Challenges
for research on polyphenols from foods in Alzheimer’s disease: bioavailabil-
ity, metabolism, and cellular and molecular mechanisms. J Agric Food Chem
2008;56:4855–73 .
[13] Hartman RE, Ross DM. Eects and mechanisms of actions of phytochemicals on
Alzheimer’s disease neuropathology. Front Biosci 2018;10:300–33
.
[14] Petra AI, Panagiotidou S, Hatziagelaki E, Stewart JM, Conti P, Theoharides TC.
Gut-microbiota-brain axis and its eect on neuropsychiatric disorders with sus-
pected immune dysregulation. Clin Ther 2015;37:984–95
.
[15] Gasperotti M, Passamonti S, Tramer F, Masuero D, Guella G, Mattivi F, Vrhovsek U.
Fate of microbial metabolites of dietary polyphenols in rats: is the brain their target
destination? ACS Chem Neurosci 2015;6:1341–52
.
[16] Court J, Johnson M, Religa D, Keverne J, Kalaria R, Jaros E, McKeith I, Perry R,
Naslund J, Perry E. Attenuation of A 𝛽deposition in the entorhinal cortex of normal
elderly individuals associated with tobacco smoking. Neuropathol Appl Neurobiol
2005;31:522–35 .
[17] Farr SA, Nieho ML, Ceddia MA, Herrlinger KA, Lewis BJ, Feng S, Welleford A,
Buttereld DA, Morley JE. Eect of botanical extracts containing carnosic acid
or rosmarinic acid on learning and memory in SAMP8 mice. Physiol Behav
2016;165:328–38
.
[18] Le Bars PL, Katz MM, Berman N, Itil TM, Freedman AM, Schatzberg AF. A place-
bo-controlled, double-blind, randomized trial of an extract of Ginkgo biloba for
dementia. JAMA 1997;278:1327–32
.
[19] Davinelli S, Sapere N, Zella D, Bracale R, Intrieri M, Scapagnini G. Pleiotropic pro-
tective eects of phytochemicals in Alzheimer’s disease. Oxid Med Cell Longev
2012;2012
.
[20] Cichon N, Dziedzic A, Gorniak L, Miller E, Bijak M, Starosta M, Saluk-Bijak J. Un-
usual bioactive compounds with antioxidant properties in adjuvant therapy sup-
porting cognition impairment in age-related neurodegenerative disorders. Int J Mol
Sci 2021;22:10707
.
[21] Ono K, Yoshiike Y, Takashima A, Hasegawa K, Naiki H, Yamada M. Potent an-
ti-amyloidogenic and bril-destabilizing eects of polyphenols in vitro: implica-
tions for the prevention and therapeutics of Alzheimer’s disease. J Neurochem
2003;87:172–81 .
[22] Nabavi SF, Sureda A, Dehpour AR, Shirooie S, Silva AS, Devi KP, Ahmed T,
Ishaq N, Hashim R, Sobarzo-Sanchez E, Daglia M. Regulation of autophagy by
polyphenols: Paving the road for treatment of neurodegeneration. Biotechnol Adv
2018;36(6):1768–78
.
[23] Singh SK, Srivastav S, Yadav AK, Srikrishna S, Perry G. Overview of Alzheimer’s
disease and some therapeutic approaches targeting A 𝛽by using several synthetic
and herbal compounds. Oxid Med Cel Longev 2016:2016
.
[24] Buttereld DA, Grin S, Munch G, Pasinetti GM. Amyloid 𝛽-peptide and amy-
loid pathology are central to the oxidative stress and inammatory cascades under
which Alzheimer’s disease brain exists. J Alzheimer’s Dis 2002;4:193–201
.
[25] Terzo S, Amato A, Mulè F. From obesity to Alzheimer’s disease through insulin
resistance. J Diabetes Complicat 2021;35:108026
.
[26] Ono K. Alzheimer’s disease as oligomeropathy. Neurochem Int 2018;119:57–70 .
[27] Wollen KA. Alzheimer’s disease: the pros and cons of pharmaceutical, nutritional,
botanical, and stimulatory therapies, with a discussion of treatment strategies from
the perspective of patients and practitioners. Altern Med Rev 2010;15:223–44
.
[28] Goedert M. Alzheimer’s and Parkinson’s diseases: The prion concept in relation to
assembled A 𝛽, tau, and 𝛼-synuclein. Science 2015;349
.
[29] Chen JX, Yan SS. Role of mitochondrial amyloid- 𝛽in Alzheimer’s disease. J
Alzheimer’s Dis 2010;20:S569–78
.
14
R.A. Naik, R. Rajpoot, R.K. Koiri et al. The Journal of Prevention of Alzheimer’s Disease 12 (2025) 100004
[30] Seubert P, Oltersdorf T, Lee MG, Barbour R, Blomquist C, Davis DL, Bryant K,
Fritz LC, Galasko D, Thal LJ. Secretion of 𝛽-amyloid precursor protein cleaved at
the amino terminus of the 𝛽-amyloid peptide. Nature 1993;361:260–3
.
[31] Vergallo A, Bun RS, Toschi N, Baldacci F, Zetterberg H, Blennow K, Cavedo E,
Lamari F, Habert MO, Dubois B. Association of cerebrospinal uid 𝛼-synuclein with
total and phospho-tau181 protein concentrations and brain amyloid load in cog-
nitively normal subjective memory complainers stratied by Alzheimer’s disease
biomarkers. Alzheimer’s Dement 2018;14:1623–31
.
[32] Selkoe DJ, Hardy J. The amyloid hypothesis of Alzheimer’s disease at 25 years.
EMBO Mol Med 2016;8:595–608
.
[33] Xu F, Fu Z, Dass S, Kotarba AE, Davis J, Smith SO, Van Nostrand WE. Cerebral
vascular amyloid seeds drive amyloid 𝛽-protein bril assembly with a distinct an-
ti-parallel structure. Nat Commun 2016;7:1–10
.
[34] Kim J, Lee HJ, Lee KW. Naturally occurring phytochemicals for the prevention of
Alzheimer’s disease. J Neurochem 2010;112:1415–30
.
[35] Martin L, Latypova X, Wilson CM, Magnaudeix A, Perrin ML, Yardin C,
Terro F. Tau protein kinases: involvement in Alzheimer’s disease. Ageing Res Rev
2013;12:289–309
.
[36] Sahara N, Murayama M, Lee B, Park JM, Lagalwar S, Binder LI, Takashima A.
Active c-jun N-terminal kinase induces caspase cleavage of tau and additional
phosphorylation by GSK-3 𝛽is required for tau aggregation. Eur J Neurosci
2008;27:2897–906 .
[37] Kabir MT, Suan MA, Uddin M, Begum M, Akhter S, Islam A, Mathew B, Islam M,
Amran M. NMDA receptor antagonists: repositioning of memantine as a multitar-
geting agent for Alzheimer’s therapy. Curr Pharm Des 2019;25:3506–18
.
[38] Gong CX, Liu F, Grundke-Iqbal I, Iqbal K. Post-translational modications of tau
protein in Alzheimer’s disease. J Neural Transm 2005;112:813–38
.
[39] Nogales E. Structural insights into microtubule function. Annu Rev Biochem
2000;69:277–302
.
[40] Ramesh M, Govindaraju T. Multipronged diagnostic and therapeutic strategies for
Alzheimer’s disease. Chem Sci 2022;13(46):13657–89
.
[41] Kim AC, Lim S, Kim YK. Metal ion eects on A 𝛽and tau aggregation. Int J Mol Sci
2018;19(1):128
.
[42] Wang L, Yin YL, Liu XZ, Shen P, Zheng YG, Lan XR, Lu CB, Wang JZ. Current un-
derstanding of metal ions in the pathogenesis of Alzheimer’s disease. Transl Neu-
rodegener 2020;9(1):1–13
.
[43] Hung CHL, Cheng SSY, Cheung YT, Wuwongse S, Zhang NQ, Ho YS, Lee SMY,
Chang RCC. A reciprocal relationship between reactive oxygen species and mito-
chondrial dynamics in neurodegeneration. Redox Biol 2018;14:7–19
.
[44] Llanos-Gonzalez E, Henares-Chavarino AA, Pedrero-Prieto CM, García-Carpin-
tero S, Frontinan-Rubio J, Sancho-Bielsa FJ, Alcain FJ, Peinado JR, Rabanal-Ruíz Y,
Duran-Prado M. Interplay between mitochondrial oxidative disorders and pro-
teostasis in Alzheimer’s disease. Front Neurosci 2020;13:1444
.
[45] Franco R, Vargas MR. Redox biology in neurological function, dysfunction, and
aging. New Rochelle, NY 10801 USA: Mary Ann Liebert, Inc. 140 Huguenot Street;
2018. p. 1583–6. 3rd Floor
.
[46] Campanucci VA, Krishnaswamy A, Cooper E. Mitochondrial reactive oxygen species
inactivate neuronal nicotinic acetylcholine receptors and induce long-term depres-
sion of fast nicotinic synaptic transmission. J Neurosci 2008;28:1733–44
.
[47] Ridnour LA, Dhanapal S, Hoos M, Wilson J, Lee J, Cheng RY, Brueggemann EE,
Hines HB, Wilcock DM, Vitek MP. Nitric oxide-mediated regulation of-amyloid
clearance via alterations of MMP-9/TIMP-1. J Neurochem 2012;123:736–49
.
[48] Marnett LJ. Lipid peroxidation-DNA damage by malondialdehyde. Mutat Res-Fun-
dam Mol Mech Mutagen 1999;424:83–95
.
[49] Cassidy L, Fernandez F, Johnson JB, Naiker M, Owoola AG, Broszczak DA. Ox-
idative stress in alzheimer’s disease: A review on emergent natural polyphenolic
therapeutics. Compl Ther Med 2020;49:102294
.
[50] Rak M, Benit P, Chretien D, Bouchereau J, Schi M, El-Khoury R,
Tzagolo A, Rustin P. Mitochondrial cytochrome c oxidase deciency. Clin
Sci 2016;130:393–407
.
[51] Galbusera C, Facheris M, Magni F, Galimberti G, Sala G, Tremolada L, Isella V,
Guerini FR, Appollonio I, Galli-Kienle M. Increased susceptibility to plasma lipid
peroxidation in Alzheimer disease patients. Curr Alzheimer Res 2004;1:103–9
.
[52] Tobore TO. On the central role of mitochondria dysfunction and oxidative stress in
Alzheimer’s disease. Neurol Sci 2019;40:1527–40
.
[53] Wong KY, Roy J, Fung ML, Heng BC, Zhang C, Lim LW. Relationships between
mitochondrial dysfunction and neurotransmission failure in Alzheimer’s disease.
Aging Dis 2020;11:1291
.
[54] Misrani A, Tabassum S, Yang L. Mitochondrial dysfunction and oxidative stress in
Alzheimer’s disease. Front Aging Neurosci 2021;13:617588
.
[55] McCarty MF, DiNicolantonio JJ, Lerner A. A fundamental role for oxidants and
intracellular calcium signals in Alzheimer’s pathogenesis-and how a comprehen-
sive antioxidant strategy may aid prevention of this disorder. Int J Mol Sci
2021;22:2140
.
[56] Inoue K, Nakagawa A, Hino T, Oka H. Screening assay for metal-catalyzed oxidation
inhibitors using liquid chromatography− mass spectrometry with an n-terminal
𝛽-amyloid peptide. Anal Chem 2009;81:1819–25
.
[57] Zetterberg H, Blennow K, de Leon M. Alzheimer’s disease. Lancet 2006;368:387 .
[58] Galimberti D, Scarpini E. Progress in Alzheimer’s disease. J Neurol
2012;259:201–11
.
[59] Lee YJ, Han SB, Nam SY, Oh KW, Hong JT. Inammation and Alzheimer’s disease.
Arch Pharm Res 2010;33:1539–56
.
[60] Li M, Shang DS, Zhao WD, Tian L, Li B, Fang WG, Zhu L, Man SM, Chen YH. Amyloid
𝛽interaction with receptor for advanced glycation end products up-regulates brain
endothelial CCR5 expression and promotes T cells crossing the blood-brain barrier.
J Immunol 2009;182:5778–88
.
[61] Fetler L, Amigorena S. Brain under surveillance: the microglia patrol. Science
2005;309:392–3
.
[62] Weitz TM, Town T. Microglia in Alzheimer’s disease: it’s all about context. Int J
Alzheimer’s Dis 2012:2012
.
[63] Kitazawa M, Oddo S, Yamasaki TR, Green KN, LaFerla FM. Lipopolysaccha-
ride-induced inammation exacerbates tau pathology by a cyclin-dependent ki-
nase 5-mediated pathway in a transgenic model of Alzheimer’s disease. J Neurosci
2005;25:8843–53 .
[64] Kamer AR, Craig RG, Glodzik-Sobanska L, Dasanayake A, Annam KRC, Corby P,
Bry M, Janal MN, Deepthii G, De Leon MJ. Alzheimer’s disease and peripheral
infections: the possible contribution from periodontal infections, model and hy-
pothesis. Handb Infect Alzheimer’s Dis 2017;5:163
.
[65] Yan Q, Zhang J, Liu H, Babu-Khan S, Vassar R, Biere AL, Citron M, Landreth G.
Anti-inammatory drug therapy alters 𝛽-amyloid processing and deposition in an
animal model of Alzheimer’s disease. J Neurosci 2003;23:7504–9
.
[66] Visser M, Ellen R. New insights into the emerging role of oral spirochaetes in peri-
odontal disease. Clin Microbiol Infect 2011;17:502–12
.
[67] Gurav AN. Alzheimer’s disease and periodontitis-an elusive link. Rev Assoc Med
Bras 2014;60:173–80
.
[68] Xu YX, Wang H, Li XK, Dong SN, Liu WW, Gong Q, Tang Y, Zhu J, Li J, Zhang HY.
Discovery of novel propargylamine-modied 4-aminoalkyl imidazole substituted
pyrimidinylthiourea derivatives as multifunctional agents for the treatment of
Alzheimer’s disease. Eur J Med Chem 2018;143:33–47
.
[69] Liu B, Moloney A, Meehan S, Morris K, Thomas SE, Serpell LC, Hider R,
Marciniak SJ, Lomas DA, Crowther DC. Iron promotes the toxicity of amyloid 𝛽
peptide by impeding its ordered aggregation. J Biol Chem 2011;286:4248–56
.
[70] Bachurin SO, Bovina EV, Ustyugov AA. Drugs in clinical trials for Alzheimer’s dis-
ease: the major trends. Med Res Rev 2017;37:1186–225
.
[71] Pardridge WM. Neurotrophins, neuroprotection and the blood-brain barrier. Curr
Opin Investig Drugs 2002;3:1753–7
.
[72] Gong CX, DAI C, Liu F, Iqbal K. Multi-targets: an unconventional drug development
strategy for Alzheimer’s disease. Front Aging Neurosci 2022:86
.
[73] Chen Y, Deng Y, Zhang B, Gong CX. Deregulation of brain insulin signaling in
Alzheimer’s disease. Neurosci Bull 2014;30:282–94
.
[74] Chen Y, Zhang J, Zhang B, Gong CX. Targeting insulin signaling for the treatment
of Alzheimer’s disease. Curr Top Med Chem 2016;16:485–92
.
[75] Norton S, Matthews F, Barnes D, Yae K, Brayne C. Potential for primary preven-
tion of Alzheimer’s disease: an analysis of population-based data. Lancet Neurol
2014;13:1070 -1070
.
[76] Sultana A, Alauddin M. Exercise-Eating Pattern and Social Inclusion (EES) is an
Eective Modulator of Pathophysiological Hallmarks of Alzheimer’s Disease. Inte-
chOpen 2022
.
[77] Tao YM, Yu C, Wang WS, Hou YY, Xu XJ, Chi ZQ, Ding YQ, Wang YJ, Liu JG.
Heteromers of 𝜇opioid and dopamine D1 receptors modulate opioid-induced
locomotor sensitization in a dopamine-independent manner. Br J Pharmacol
2017;174:2842–61
.
[78] Ono K, Hasegawa K, Naiki H, Yamada M. Curcumin has potent anti-amyloido-
genic eects for Alzheimer’s 𝛽-amyloid brils in vitro. J Neurosci Res 2004;
75:742–50
.
[79] Middleton E, Kandaswami C, Theoharides TC. The eects of plant avonoids on
mammalian cells: implications for inammation, heart disease, and cancer. Phar-
macol Rev 2000;52:673–751
.
[80] Minocha T, Birla H, Obaid AA, Rai V, Sushma P, Shivamallu C, Moustafa M,
Al-Shehri M, Al-Emam A, Tikhonova MA, Yadav SK. Flavonoids as promising neu-
roprotectants and their therapeutic potential against Alzheimer’s disease. Oxidat
Med Cell Longev 2022:2022
.
[81] Zaplatic E, Bule M, Shah SZA, Uddin MS, Niaz K. Molecular mechanisms un-
derlying protective role of quercetin in attenuating Alzheimer’s disease. Life Sci
2019;224:109–19
.
[82] Zeitlin R, Patel S, Burgess S, Arendash GW, Echeverria V. Caeine induces ben-
ecial changes in PKA signaling and JNK and ERK activities in the striatum and
cortex of Alzheimer’s transgenic mice. Brain Res 2011;1417:127–36
.
[83] Whittington AG, Hofmeister AM, Nabelek PI. Temperature-dependent ther-
mal diusivity of the Earth’s crust and implications for magmatism. Nature
2009;458:319–21
.
[84] Calkins MJ, Manczak M, Mao P, Shirendeb U, Reddy PH. Impaired mitochondrial
biogenesis, defective axonal transport of mitochondria, abnormal mitochondrial
dynamics and synaptic degeneration in a mouse model of Alzheimer’s disease. Hum
Mol Genet 2011;20:4515–29
.
[85] McCleery J, Abraham RP, Denton DA, Rutjes AW, Chong LY, Al-Assaf AS, Grif-
th DJ, Rafeeq S, Yaman H, Malik MA. Vitamin and mineral supplementation for
preventing dementia or delaying cognitive decline in people with mild cognitive
impairment. Cochrane Database Syst Rev 2018 .
[86] Russell AP, Foletta VC, Snow RJ, Wadley GD. Skeletal muscle mitochondria: a
major player in exercise, health and disease. Biochim Biophys Acta - Gen Subj
2014;1840:1276–84
.
[87] Abe O, Aoki S, Hayashi N, Yamada H, Kunimatsu A, Mori H, Yoshikawa T, Okubo T,
Ohtomo K. Normal aging in the central nervous system: quantitative MR diu-
sion-tensor analysis. Neurobiol Aging 2002;23:433–41
.
[88] Thomas P, Wang YJ, Zhong JH, Kosaraju S, O’Callaghan NJ, Zhou XF, Fenech M.
Grape seed polyphenols and curcumin reduce genomic instability events in a trans-
genic mouse model for Alzheimer’s disease. Mutat Res - Fundam Mol Mech Mutagen
2009;661:25–34
.
[89] Sanei M, Saberi-Demneh A. Eect of curcumin on memory impairment: A system-
atic review. Phytomedicine 2019;52:98–106
.
15
R.A. Naik, R. Rajpoot, R.K. Koiri et al. The Journal of Prevention of Alzheimer’s Disease 12 (2025) 100004
[90] Lee SA, Lim JY, Kim B-S, Cho SJ, Kim NY, Kim OB, Kim Y. Comparison of the gut
microbiota prole in breast-fed and formula-fed Korean infants using pyrosequenc-
ing. Nutr Res Pract 2015;9:242–8
.
[91] Monagas M, Urpi-Sarda M, Sánchez-Patan F, Llorach R, Garrido I, Gomez-Cor-
doves C, Andres-Lacueva C, Bartolome B. Insights into the metabolism and micro-
bial biotransformation of dietary avan-3-ols and the bioactivity of their metabo-
lites. Food Funct 2010;1:233–53
.
[92] Hidalgo M, Oruna-Concha MJ, Kolida S, Walton GE, Kallithraka S, Spencer JP, de
Pascual-Teresa S. Metabolism of anthocyanins by human gut microora and their
inuence on gut bacterial growth. J Agric Food Chem 2012;60:3882–90
.
[93] Wang Y, Chung FF, Lee SM, Dykes GA. Inhibition of attachment of oral bacteria to
immortalized human gingival broblasts (HGF-1) by tea extracts and tea compo-
nents. BMC Res Notes 2013;6:1–5
.
[94] Cascella M, Bimonte S, Muzio MR, Schiavone V, Cuomo A. The ecacy of Epi-
gallocatechin-3-gallate (green tea) in the treatment of Alzheimer’s disease: An
overview of pre-clinical studies and translational perspectives in clinical practice.
Infect Agents Cancer 2017;12:1–7
.
[95] Wang HY, Qi LW, Wang CZ, Li P. Bioactivity enhancement of herbal supplements by
intestinal microbiota focusing on ginsenosides. Am J Chin Med 2011;39:1103–15
.
[96] Zhou H, Tai J, Xu H, Lu X, Meng D. Xanthoceraside could ameliorate Alzheimer’s
disease symptoms of rats by aecting the gut microbiota composition and modu-
lating the endogenous metabolite levels. Front Pharmacol 2019;10:1035
.
[97] Meng DL, Shang L, Feng XH, Huang XF, Che X. Xanthoceraside hollow gold
nanoparticles, green pharmaceutics preparation for poorly water-soluble natural
anti-AD medicine. Int J Pharm 2016;506:184–90
.
[98] Jomova K, Valko M. Health protective eects of carotenoids and their interactions
with other biological antioxidants. Eur J Med Chem 2013;70:102–10
.
[99] Petyaev IM. Lycopene deciency in ageing and cardiovascular disease. Oxid Med
Cell Longev 2016:2016
.
[100] Moran JF, Klucas RV, Grayer RJ, Abian J, Becana M. Complexes of iron with phe-
nolic compounds from soybean nodules and other legume tissues: prooxidant and
antioxidant properties. Free Radic. Biol Med 1997;22:861–70
.
[101] Baratta MT, Dorman HD, Deans SG, Biondi DM, Ruberto G. Chemical composition,
antimicrobial and antioxidative activity of laurel, sage, rosemary, oregano and co-
riander essential oils. J Essent Oil Res 1998;10:618–27
.
[102] Tiong SH, Looi CY, Hazni H, Arya A, Paydar M, Wong WF, Cheah S-C, Mustafa MR,
Awang K. Antidiabetic and antioxidant properties of alkaloids from Catharanthus
roseus (L.) G. Don. Molecules 2013;18:9770–84
.
[103] Von Bergen M, Barghorn S, Müller SA, Pickhardt M, Biernat J, Mandelkow E-M,
Davies P, Aebi U, Mandelkow E. The core of tau-paired helical laments studied by
scanning transmission electron microscopy and limited proteolysis. Biochemistry
2006;45:6446–57
.
[104] Su J, Cummings B, Cotman C. Localization of heparan sulfate glycosaminoglycan
and proteoglycan core protein in aged brain and Alzheimer’s disease. Neuroscience
1992;51:801–13
.
[105] Rao M. Nitric oxide scavenging by curcuminoids. J Pharm Pharmacol
1997;49:105–7
.
[106] Lim GP, Chu T, Yang F, Beech W, Frautschy SA, Cole GM. The curry spice cur-
cumin reduces oxidative damage and amyloid pathology in an Alzheimer trans-
genic mouse. J Neurosci 2001;21:8370–7
.
[107] Rajeswari A. Curcumin protects mouse brain from oxidative stress caused by
1-methyl-4-phenyl-1, 2, 3, 6-tetrahydro pyridine. Eur Rev Med Pharmacol Sci
2006;10:157
.
[108] Iwunze M, McEwan D. Peroxynitrite interaction with curcumin solubilized in
ethanolic solution. Cell Mol Biol 2004;50:749–52
.
[109] Gotz JR, Chen F, Barmettler R, Nitsch RM. Tau lament formation in transgenic
mice expressing P301L tau. J Biol Chem 2001;276:529–34
.
[110] Abbas Momtazi A, Sahebkar A. Diuorinated curcumin: a promising curcumin ana-
logue with improved anti-tumor activity and pharmacokinetic prole. Curr Pharm
Des 2016;22:4386–97
.
[111] Mollazadeh H, Cicero AF, Blesso CN, Pirro M, Majeed M, Sahebkar A. Immune
modulation by curcumin: The role of interleukin-10. Crit Rev Food Sci Nutr
2019;59:89–101
.
[112] Morales I, Cerda-Troncoso C, Andrade V, Maccioni RB. The natural product cur-
cumin as a potential coadjuvant in Alzheimer’s treatment. J Alzheimer’s Dis
2017;60:451–60
.
[113] Al-Kuraishy HM, Al-Gareeb AI. Potential eects of pomegranate on lipid peroxida-
tion and pro-inammatory changes in daunorubicin-induced cardiotoxicity in rats.
Int J Prev Med 2016;7
.
[114] Everett JA. The 12 item social and economic conservatism scale (SECS). PloS One
2013;8:e82131
.
[115] Giacalone M, Di Sacco F, Traupe I, Pagnucci N, Forfori F, Giunta F. Blueberry
polyphenols and neuroprotection, Bioactive nutraceuticals and dietary supple-
ments in neurological and brain disease. Elsevier; 2015. p. 17–28
.
[116] Papandreou MA, Dimakopoulou A, Linardaki ZI, Cordopatis P, Klimis-Zacas D, Mar-
garity M, Lamari FN. Eect of a polyphenol-rich wild blueberry extract on cognitive
performance of mice, brain antioxidant markers and acetylcholinesterase activity.
Behav Brain Res 2009;198:352–8
.
[117] Zhou F, Chen S, Xiong J, Li Y, Qu L. Luteolin reduces zinc-induced tau phospho-
rylation at Ser262/356 in an ROS-dependent manner in SH-SY5Y cells. Biol Trace
Elem Res 2012;149:273–9
.
[118] Belviranl ı M, Okudan N. The eects of Ginkgo biloba extract on cognitive functions
in aged female rats: the role of oxidative stress and brain-derived neurotrophic
factor. Behav Brain Res 2015;278:453–61
.
[119] Singh SK, Srivastav S, Castellani RJ, Plascencia-Villa G, Perry G. Neuroprotective
and antioxidant eect of Ginkgo biloba extract against AD and other neurological
disorders. Neurotherapeutics 2019;16:666–74
.
[120] Tota S, Awasthi H, Kamat PK, Nath C, Hanif K. Protective eect of quercetin against
intracerebral streptozotocin induced reduction in cerebral blood ow and impair-
ment of memory in mice. Behav Brain Res 2010;209:73–9
.
[121] Dhouai Z, Cuanalo-Contreras K, Hayouni EA, Mays CE, Soto C, Moreno-Gonzalez I.
Inhibition of protein misfolding and aggregation by natural phenolic compounds.
Cell Mol Life Sci 2018;75:3521–38
.
[122] Kim YM, Yun J, Lee CK, Lee H, Min KR, Kim Y. Oxyresveratrol and hydroxystilbene
compounds: inhibitory eect on tyrosinase and mechanism of action. J Biol Chem
2002;277:16340–4
.
[123] Wang JH, Feng J, Lu W. Associative memory cells are recruited to encode triple
sensory signals via synapse formation. Biophys J 2017;112:443a–4a
.
[124] Gao X, Lin S, Zhu Y. NACHT-LRR-PYD-containing proteins 3 inammasome and
nonalcoholic fatty liver disease. Chin J Hepatol 2016;24:956–60
.
[125] Yazir Y, Utkan T, Gacar N, Aricioglu F. Resveratrol exerts anti-inammatory and
neuroprotective eects to prevent memory decits in rats exposed to chronic un-
predictable mild stress. Physiol Behav 2015;138:297–304
.
[126] De La Lastra CA, Villegas I. Resveratrol as an anti-inammatory and anti-aging
agent: mechanisms and clinical implications. Mol Nutr Food Res 2005;49:405–30
.
[127] Yu KC, Kwan P, Cheung SK, Ho A, Baum L. Eects of resveratrol and morin on
insoluble tau in tau transgenic mice. Transl Neurosci 2018;9:54–60
.
[128] Kelsey NA, Wilkins HM, Linseman DA. Nutraceutical antioxidants as novel, neuro-
protective agents. Molecules 2010;15:7792–814
.
[129] Candelario-Jalil E, de Oliveira ACP, Graf S, Bhatia HS, Hüll M, Munoz E,
Fiebich BL. Resveratrol potently reduces prostaglandin E2production and free rad-
ical formation in lipopolysaccharide-activated primary rat microglia. J Neuroin
2007;4:1–12
.
[130] Fonteles AA, de Souza CM, de Sousa Neves JC, Menezes APF, do Carmo MRS, Fer-
nandes FDP, de Araujo PR, de Andrade GM. Rosmarinic acid prevents against mem-
ory decits in ischemic mice. Behav Brain Res 2016;297:91–103
.
[131] Mahboubi M. Melissa ocinalis and rosmarinic acid in management of memory
functions and Alzheimer disease. Asian Pac J Trop Biomed 2019;9:47
.
[132] Andrade S, Ramalho MJ, Loureiro JA, Pereira MdC. Natural compounds for
Alzheimer’s disease therapy: a systematic review of preclinical and clinical studies.
Int J Mol Sci 2019;20:2313
.
[133] Mao XY, Yu J, Liu ZQ, Zhou HH. Apigenin attenuates diabetes-associated cognitive
decline in rats via suppressing oxidative stress and nitric oxide synthase pathway.
Int J Clin Exp Med 2015;8:15506
.
[134] Lee SY, Moon E, Kim SY, Lee KR. Quinic acid derivatives from Pimpinella brachy-
carpa exert anti-neuroinammatory activity in lipopolysaccharide-induced mi-
croglia. Bioorg Med Chem Lett 2013;23:2140–4
.
[135] Xiao HB, Cao X, Wang L, Run XQ, Su Y, Tian C, Sun SG, Liang ZH. 1, 5-dicaf-
feoylquinic acid protects primary neurons from amyloid 𝛽1-42-induced apoptosis
via PI3K/Akt signaling pathway. Chin Med J 2011;124:2628–35
.
[136] Momtazi AA, Derosa G, Maoli P, Banach M, Sahebkar A. Role of microRNAs
in the therapeutic eects of curcumin in non-cancer diseases. Mol Diagn Ther
2016;20:335–45
.
[137] Di Martino RMC, De Simone A, Andrisano V, Bisignano P, Bisi A, Gobbi S,
Rampa A, Fato R, Bergamini C, Perez DI. Versatility of the curcumin scaold: dis-
covery of potent and balanced dual BACE-1 and GSK-3 𝛽inhibitors. J Med Chem
2016;59:531–44
.
[138] Redfearn DP, Trim GM, Skanes AC, Petrellis B, Krahn AD, Yee R, Klein GJ.
Esophageal temperature monitoring during radiofrequency ablation of atrial b-
rillation. J Cardiovasc Electrophysiol 2005;16:589–93
.
[139] Palatty PL, Haniadka R, Valder B, Arora R, Baliga MS. Ginger in the prevention of
nausea and vomiting: a review. Crit Rev Food Sci Nutr 2013;53:659–69
.
[140] Haniadka R, Rajeev AG, Palatty PL, Arora R, Baliga MS. Zingiber ocinale (ginger)
as an anti-emetic in cancer chemotherapy: a review. J Altern Complement Med
2012;18:440–4
.
[141] Bai X, Zhang X, Chen L, Zhang J, Zhang L, Zhao X, Zhao T, Zhao Y. Protec-
tive eect of naringenin in experimental ischemic stroke: down-regulated NOD2,
RIP2, NF- 𝜅B, MMP-9 and up-regulated claudin-5 expression. Neurochem Res
2014;39:1405–15 .
[142] Kim HS, Sul D, Lim JY, Lee D, Joo SS, Hwang KW, Park SY. Delphinidin amelio-
rates beta-amyloid-induced neurotoxicity by inhibiting calcium inux and tau hy-
perphosphorylation. Biosci Biotechnol Biochem 2009 0906221517-0906221517
.
[143] Reed LA, Wszolek ZK, Hutton M. Phenotypic correlations in FTDP-17. Neurobiol
Aging 2001;22:89–107
.
[144] Kampers T, Friedho P, Biernat J, Mandelkow E-M, Mandelkow E. RNA stimulates
aggregation of microtubule-associated protein tau into Alzheimer-like paired heli-
cal laments. FEBS Lett 1996;399:344–9
.
[145] Gong EJ, Park HR, Kim ME, Piao S, Lee E, Jo DG, Chung HY, Ha NC, Mattson MP,
Lee J. Morin attenuates tau hyperphosphorylation by inhibiting GSK3 𝛽. Neurobiol
Dis 2011;44:223–30
.
[146] Wang J, Ho L, Zhao W, Ono K, Rosensweig C, Chen L, Humala N, Teplow DB,
Pasinetti GM. Grape-derived polyphenolics prevent A 𝛽oligomerization and atten-
uate cognitive deterioration in a mouse model of Alzheimer’s disease. J Neurosci
2008;28:6388–92
.
[147] Li W, Sperry JB, Crowe A, Trojanowski JQ, Smith III AB, Lee VMY. Inhibition of
tau brillization by oleocanthal via reaction with the amino groups of tau. J Neu-
rochem 2009;110:1339–51
.
[148] Noguchi-Shinohara M, Ono K. The mechanisms of the roles of 𝛼-synuclein,
amyloid- 𝛽, and tau protein in the lewy body diseases: pathogenesis, early detection,
and therapeutics. Int J Mol Sci 2023;24:10215
.
16
R.A. Naik, R. Rajpoot, R.K. Koiri et al. The Journal of Prevention of Alzheimer’s Disease 12 (2025) 100004
[149] Espay AJ, Kepp KP, Herrup K. Lecanemab and Donanemab as therapies for
Alzheimer’s disease: an illustrated perspective on the data. eNeuro 2024;11(7):1–6
.
[150] Cummings J, Osse AML, Cammann D, Powell J, Chen J. Anti-amyloid monoclonal
antibodies for the treatment of Alzheimer’s disease. BioDrugs 2024;38(1):5–22
.
[151] Arafah A, Khatoon S, Rasool I, Khan A, Rather MA, Abujabal KA, Faqih YAH,
Rashid H, Rashid SM, Bilal Ahmad S, Alexiou A. The future of precision medicine
in the cure of Alzheimer’s disease. Biomedicines 2023;11(2):335
.
[152] Golde TE. Disease-modifying therapies for Alzheimer’s disease: more questions than
answers. Neurotherapeutics 2023;19(1):209–27
.
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