Apple Cider Vinegar (ACV) and their Pharmacological Approach towards Alzheimer's Disease (AD): A Review

Abstract

Alzheimer's disease (AD) is a neurological degenerative condition described by a progressive decline in memory and associated with dementia. This disease arises usually after 65 years in individuals. Oxidative stress is the major cause of dementia connected with Alzheimer's disease. Here there is an imbalance between the creation and clearance of amyloid β protein, which leads to accumulation of amyloid β plaque in the brain and produces neuronal cell death. Anti-Alzheimer's medications help to cover the symptoms of disease but do not cure the cause of disease. Confirmatory studies suggest that a healthy diet of fruits and green vegetables containing phenolic combinations may reduce the risk of Alzheimer's disease (AD). Apple cider vinegar (ACV) contains phenolic compounds like catechin, caffeic acid, gallic acid, chlorogenic acids and p-coumaric acid having high antioxidant potential. Phenolic compounds are not essential for survival but it can protect against various chronic diseases. Various researches showed that phenolic compounds cure β amyloid and tau protein correlated problems associated with AD. Regular consumption of these healthy substances in the diet may prevent the neuronal cells from oxidative stress which leads to AD. The purpose of this review is to highlight the health benefit role, functional property and therapeutic uses of Apple Cider Vinegar.

Full text

Indian Journal of Pharmaceutical Education and Research | Vol 54 | Issue 2 (Suppl) | Apr-Jun, 2020 S67
Review Arcle
www.ijper.org
Apple Cider Vinegar (ACV) and their Pharmacological
Approach towards Alzheimer’s Disease (AD):
A Review
Smriti Tripathi, Papiya Mitra Mazumder*
Department of Pharmaceutical Sciences and Technology, Birla Institute of Technology-Mesra, Ranchi, Jharkhand, INDIA.
ABSTRACT
Alzheimer's disease (AD) is a neurological degenerative condition described by a
progressive decline in memory and associated with dementia. This disease arises usually
after 65 years in individuals. Oxidative stress is the major cause of dementia connected
with Alzheimer's disease. Here there is an imbalance between the creation and clearance
of amyloid β protein, which leads to accumulation of amyloid β plaque in the brain and
produces neuronal cell death. Anti-Alzheimer's medications help to cover the symptoms
of disease but do not cure the cause of disease. Conrmatory studies suggest that
a healthy diet of fruits and green vegetables containing phenolic combinations may
reduce the risk of Alzheimer's disease (AD). Apple cider vinegar (ACV) contains phenolic
compounds like catechin, caffeic acid, gallic acid, chlorogenic acids and p-coumaric acid
having high antioxidant potential. Phenolic compounds are not essential for survival but
it can protect against various chronic diseases. Various researches showed that phenolic
compounds cure β amyloid and tau protein correlated problems associated with AD.
Regular consumption of these healthy substances in the diet may prevent the neuronal
cells from oxidative stress which leads to AD. The purpose of this review is to highlight
the health benet role, functional property and therapeutic uses of Apple Cider Vinegar.
Key words: Apple Cider Vinegar, Alzheimer’s disease, Oxidative stress, Phenolic
compounds, Aβ aggregation, Pharmacological activities.
DOI: 10.5530/ijper.54.2s.62
Correspondence:
Dr. Papiya Mitra Mazumder
Professor, Department of
Pharmaceutical Sciences
and Technology, Birla Insti-
tute of Technology, Mesra
Ranchi-835215, Jharkhand,
INDIA.
Phone: +91 9431327044
E-mail: pmitramazumder@
bitmesra.ac.in
Submission Date: 01-11-2019;
Revision Date: 06-02-2020;
Accepted Date: 12-03-2020
INTRODUCTION
The lifestyle of humans is mostly connected
with the developing of numerous
complicated neurological conditions
associated with aging. These conditions
include intellectual abilities, language
problems and memory loss. The prolonged
state of these symptoms together develops
intellectual decits in the elderly and is
commonly mentioned as dementia. It is
predicted that 46.8 million people in this
world have dementia and incidences are
expected to grow every year and it would be
131.5 million in 2050.1,2
Alzheimer’s disease (AD) is the most
predominant neural condition associated
with dementia. The most troubling
complication associated with AD is forgetting
daily routine functions. Although the
mechanism behind this neurodegeneration
is completely unknown but several genetic
and environmental factors, together with
vascular pathology have recently shown
the growth and progression of Alzheimer’s
disease.3
In Alzheimer’s disease (AD), an individual
may seem to be t but has more and
more distress making sense. The problem
associated with AD includes memory loss,
poor judgment for making decisions, loss of
spontaneity, time taking normal daily activity,
repeating questions, mood and personality
changes and anxiety and aggression. The
major cause of AD is due to amyloid
β protein (amyloid plaque) aggregation
outside the neuronal cells and intracellular
Tau protein hyper-phosphorylation

Tripathi, et al.: Apple Cider Vinegar (ACV): A New Therapeutic Target for Alzheimer’s Disease
S68 Indian Journal of Pharmaceutical Education and Research | Vol 54 | Issue 2 (Suppl) | Apr-Jun, 2020
composed of neurobrillary tangles (NFTs) and loss of
cholinergic system functions4 shown in Figure 1.
Occurrence of Alzheimer’s disease
In 2005, Alzheimer’s disease Inter national Commissioned
group spread consensus on dementia and created an
epidemiological document acquired over recent years.
The outcomes showed that 24.2 million people suffered
with dementia and 4.6 million new patients arising every
year.5
Expected growth rate of dementia incidence from
2001 to 2040 is 172% and 102% in Western Europe
and North America higher prevalence of dementia
(172% and 102%), China more than 300%, Latin
America 400%, North Africa and Middle Eastern
Crescent 385%. The annual incidence rates increased
exponentially with age after 65 years.6 There is nearly
a 15-fold increase in the frequency of dementia,
predominately Alzheimer’s disease between the ages of
65 to 85 years5,6 (Figure 2).
Mechanism of Alzheimer’s disease
Alzheimer’s disease (AD) persuaded dementia is typically
represented with synaptic injuries and loss of neurons
through propagation of microglial cells.7-9 Based on
new studies, neurodegeneration of the hippocampal
neurons, cortex and limbic region of brain is a probable
mechanism involved in AD.9 Alzheimer’s disease is
characterized by the two major hallmarks: extracellular
aggregation of β-amyloid (Aβ) and intracellular
accumulation of tau protein. Both of these complexes
are insoluble in nature. Aβ is the main factor of senile
plaques and tau phosphorylation forms neurobrillary
tangles.
Amyloid β protein is composed of 36 to 43 amino
acids which are a part of APP (amyloid precursor
protein). APP is a trans membrane protein, produced
by neurons and other brain cells. This protein is present
in extraneuronal tissues. The Aβ is the part of the
trans membrane domain of APP and is derived by the
cleavage of APP with β and γ-secretase enzymes. An
imbalance between the production and metabolism
of amyloid β protein produces toxicity in neurons
synapses. Formation of Aβ protein is typically mediated
by the activity of enzyme including γ-secretase and
BACE-1 metabolism of Aβ protein is produced by an
active proteolytic enzyme ApoE (chaperone) besides
lysosomal and non-lysosomal pathways.10-12 These
Aβ monomers are polymerized into insoluble Aβ42
oligomers, which participate in amyloid accumulation.
These Aβ residues produced microglial inltration,
formation of ROS (reactive oxygen species), synaptic
damage, neurotoxicity and neurodegeneration.
Additionally Aβ aggregations also initiate hyper-
phosphorylation of tau protein and their cleavage
(Figure 3). This phosphorylation and cleavage is induced
by Aβ activated enzyme such as CDK5, GSK-3β and
caspases. These enzymes induce tau phosphorylation
and formation of intracellular neurobrillary tangles
which are insoluble inclusions.13-15 Tau accumulates as
a pair of bers which are twisted around one another
and formed paired helical laments structure (PHFs)
(Figure 3).
Risk Factors Associated With Alzheimer’s
Numerous features have been associated with AD.
Diabetes, cardiovascular complications, obesity,
dyslipidemia and smoking has found to increase the
risk of Alzheimer’s disease in old age16 (Table 1, Figure
4). Remarkably cerebrovascular disease including large
cortical infarcts, cerebral hemorrhage, hypoperfusion
and other effects produces dementia which is associated
with Alzheimer’s disease.17-23
Existing Anti-Alzheimer’s Medication
Prescriptions which prescribe to control the
improvement of AD indications become comparatively
less effective after some time as Alzheimer’s turns out
to be worse. Specialists are searching for new strategies
to treat Alzheimer’s disease (AD). There are various
clinical medications produced by pharmaceutical
companies for the treatment of Alzheimer’s disease.24
Rivastigmine, Galantamine and Donepezil mostly act
on acetyl cholinesterase and prevent the hydrolysis
of acetylcholine, resulting higher concentration of
acetylcholine in cerebrum which produces better
communication between the neurons. Anti-Alzheimer’s
medication found in market shown in Table 2.25
Efficacy of Dietary Nutrients in Preventing
Alzheimer’s disease
Fatty acids
Several examinations have explored the properties
of polyunsaturated fatty acids (PUFAs) in avoiding
or preventing AD. The PUFAs are the important
component of cell membrane and maintain the uidity
of membrane which is signicant for synaptic vesicle
fusion followed by neurotransmitter communication.
The PUFAs contain eicosapentaenoic acid (EPA),
omega-3 fatty acids and decosahexaenoic acid (DHA).
So PUFAs show a signicant dietary involvement in
preventing the neuronal loss and improving learning
and memory.26

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Indian Journal of Pharmaceutical Education and Research | Vol 54 | Issue 2 (Suppl) | Apr-Jun, 2020 S69
Vitamins
Vitamins have high antioxidants potential and scavenge
free radicals effectively. Free radical generation in the
brain contributes to progressive failure of cognitive
abilities and induces dementia. Clinical trials on vitamin E
supplementation carried out for patients with moderate
AD conrmed that vitamin E reduces the progression
of infection.27,28 Other vitamins like Vitamin A and B
were found to be lower in the plasma and serum of the
geriatric patients with psychological defects.29,30 In vitro
studies have shown a direct correlation of the presence
of Vitamin A and β- carotene in case of AD concerning
improvement in brain health.31
Phenolic compounds
Dietary phenolic compounds have been prescribed as a
potential functional food to prevent memory decline.32
Phenolic compounds are regular substances present in
plants, natural products, vegetables and fruits. Some
polyphenols like 4-O-methyl honokiol, resveratrol,
epigallocatechin-3-gallate (EGCG) have been potential
to provide protection against Alzheimer’s disease.33
Their property might be because of antioxidant and
anti-inammatory properties as well as a variety of
chemical enzymatic reactions and intracellular signaling
pathways. The neuronal signaling changes with aging
by acting on CREB/ERK pathway explain synaptic
plasticity and long-term potential effects, rening
memory in humans.34-37
Phenolic Compounds Found in Different Type of
Vinegar
Polyphenolic compounds of different groups are
found in vegetables and fruits. Their biochemical
deviations include thousands of combinations from
phenolic acids to avonoids compound. Phenolic
compounds have different health benecial effects, like
strong antimicrobial, anticarcinogenic and antioxidant
properties which are already reported.38 The interest is
focused on these compounds due to uniformly higher
benecial tness properties. Fruits and vegetables
also possess health-promoting bers, phenolic acids,
Figure 1: Causes of Alzheimer’s disease (AD).
Figure 2: Predictive percentage increase of dementia in
developed and developing regions.
Figure 3: Steps involved in the generation of Alzheimer's
disease (AD).
Figure 4: Mechanisms linking vascular risk factors and Alz-
heimer’s disease (AD).

Tripathi, et al.: Apple Cider Vinegar (ACV): A New Therapeutic Target for Alzheimer’s Disease
S70 Indian Journal of Pharmaceutical Education and Research | Vol 54 | Issue 2 (Suppl) | Apr-Jun, 2020
vitamins, minerals and avonoids. Phenolic compounds
are not a fundamental element for survival but can
provide long term protection against a number of
chronic diseases.39 there are various phenolic compounds
present in different vinegar shown in Table 3.40-43
Apple Cider Vinegar
Apples are essential resources of antioxidants that
prevent free radical generation. The apples have high
nutritive value and their products are a good source
of phenolic compounds, vitamins, minerals, calcium,
potassium, phosphorus which are useful in various
chronic diseases. Apple cider vinegar is made up from
renewed pressed apples, similar to apple juice, treated
in the same way but it is not ltered. ACV is formed
from Cider that has undergone acetous bioconversion
and contains low acetic acid (less than 5%), avonoids,
phenolic compounds, organic acids, minerals and
vitamins.44
Pharmacological Activities of Apple Cider Vinegar
ACV act as anticancer
In 2001 Abe et al.45 assessed the antitumor substance of
apple cider vinegar against Meth-A brosarcoma using
female Balb/c mice. In 2005 Barth et al.46 used a well-
established rodent model for persuading colon damage
associated with colon cancer by 1,2-dimethylhydrazine
and found that cloudy apple juice reduced the DNA
damage, hyperproliferation and act as cancer-preventing
agent. Pelingo apple juice suppressed the proliferation
of breast cancer cells and made cell accumulation in the
cell cycle G2/M phase. In addition the apple juice also
inhibited 12-o-tetra-decanoylphorbol-13-acetate (TPA)
induced tumor genesis of different cell lines.47
Apple polyphenols contain procyanidins, avonoids,
epicatechin, catechin which signicantly suppressed
Table 1: Factors linked with Alzheimer’s disease
(AD).16
Features Direction Mechanisms
Obesity Increased Diabetes inammation
Smoking Increased Cardiovascular defects,
Oxidative stress
Hypertension Increased
and
Decreased
Microvascular disease
Type II Diabetes Increased Cerebrovascular effects,
Insulin and Aβ compete for
clearance
Cardiovascular
Complications
Increased Parenchymal destruction
In brain, leads to increases
Aβ deposition
Traumatic Head
injury
Increased Neuronal Cell death
associated with Aβ
Deposition
Leisure activity Decreased Improves lipid metabolism,
mental stimulation
Mediterranean
diet
Decreased Anti-inammatory and
Antioxidant
Table 2: Popular Medications for the treatment of AD.
Popular
Medications
Phase of
treatment
Targeted
Pathway
References
Donepezil Effective in all
phases
AChE Inhibitor 25
Galantamine Mild to
moderate
AChE Inhibitor 25
Memantine Moderate to
severe
N-Methyl-D
aspartate
Receptor
25
Rivastigmine Mild to
moderate
AChE Inhibitor 25
Tacrine Mild to
moderate
AChE Inhibitor 25
Table 3: Vinegars containing phenolic compounds.
Types of different
Vinegar
Phenolic compounds References
Apple Cider
Vinegar
Gallic acid, catechin,
caffeic acid, epicatechin,
chlorogenic acid and
p-coumaric acid
40
Grape Vinegar Catechin, Gallic acid,
chlorogenic acid, syringic
acid and ferulic acid
41
Sherry Vinegar Protocatechuic
and Gallic acid,
protocatechualdehyde,
tyrosol, p-OH- benzoic
acid, catechin, p-OH-
benzaldehyde, siringic
acid, vanillin, caftaric
acid, cis-p-coutaric
acid, trans-p-coutaric
acid, fertaric acid, cis-
p-coumaric acid, trans-
p-coumaric acid, ferulic
acid.
42
Traditional
Balsamic Vinegar
Gallic acid, Furan-
2-carboxylic acid,
5- hydroxyfuran-
2-carboxylic acid,
4-hydroxybenzoic
acid, vanillic acid,
protocatechuic acid,
syringic acid, isoferulic
acid, p-coumaric acid,
ferulic acid and caffeic
acid
43

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Indian Journal of Pharmaceutical Education and Research | Vol 54 | Issue 2 (Suppl) | Apr-Jun, 2020 S71
colon cancer cells.48 Polyphenols present in apple cider
vinegar has cytotoxicity effects in human urinary bladder
cancer cells (TSGH-8301) associated with apoptosis
and oxidative stress.49 In 2008 Clarissa Gerhauser50 has
written a review article on Cancer chemoprotective
potential of apple components and apple juice. This
review enclosed in vivo animal data, as well as clinical
data, showed a targeted mechanism of apple products
towards cancer.
ACV act as Anti diabetic
Apple cider vinegar (ACV) that is made from
fermentation of Apple juice has been used as a folk
medicine for diabetes. Diabetes is the metabolic disorder
characterized by the hyperglycemic effect. In 2008,
studies of shishehbor et al.51 showed the protective
effect of ACV on lipid prole in normal and diabetic
rats model. Apple derived products modulate the gut
microbiota and improved high fat diet-induced body
weight gain, hyperglycemia, hyperinsulinemia and other
metabolic disorders in rodent models.52
The metabolic disorders caused by high fat diet were
improved by ACV, which proved antihyperlipidemic
effect and prevented the atherogenic effects.53 Apple
cider vinegar (ACV) produced antihyperglycemic effect
by the reduction of inammatory response, reduced
the oxidative stress-related markers and normalized the
lipid proles in the complication of Diabetes.54 In 2016,
studies of Morgan et al.55 observed the protective effect
of ACV on type II diabetes management.
Based on the Meta analysis, it has been reported that
apple products consumption (apple juice, sauce) was
connected with a lower prevalence of obesity.56 In 2016
Fathy and Drees57 performed a study of cloudy apple
juice and apple peel extract on rat pancreas. The apple
juice induced antihyperglycemic effects by the reduction
of inammation, modication of the oxidative stress
and reduced the lipid prole, proposing a useful target
for diabetes mellitus.
ACV act as Anti-inflammatory
In 2014 Nazıroglu et al.58 showed that ACV modied
serum lipid prole, erythrocyte and liver membrane
oxidative stress in mice. Dietary avonoids isolated
from apples reduced the inammation related markers
like interleukin-11, interleukin-2 in intestinal tissue of
mice.59 Apple polyphenolic compounds reduced the
inammatory response of kidney via decrease the
expression and activity of COX-2 in rodent model.60
Apple cider vinegar has a number of avonoids and
highly effective polyphenolic compounds (Yang et al.
2010; Budak et al. 2011; Denis et al. 2013),61-63 which
elucidate the antioxidant potential against oxidative
stress, free radical generation in tissues and erythrocytes.
In 2011 Budak et al.62 determined the cholesterol lowering
effect of apple vinegar in rats fed on high fat diets and
estimated the serum triglyceride levels, total cholesterol,
lipoproteins (HDL, LDL, VLDL) of different groups.
ACV act as Hepatoprotective
Extract of apple polyphenolic compounds reduced
the noxious effect of Aluminum in the liver of rodent
species.64 Polyphenolic compounds improved the SOD
(Superoxide dismutase) and catalase activity associated
with ATP synthesis. In 2015 Kuzniak et al.65 observed
the effect of apple juice on hepatocarcinogenic activity
induced in rats. These results indicated that apple juice
protects liver damage. In 2015 Moura et al.66 conducted
a study on rats that exhibited that apple juice was able
to prevent genotoxicity and oxidative stress persuaded
by Cadmium.
ACV act as the reduction in cardiotoxicity
Atherosclerosis is a chronic disease connected with
inammatory stimulation and oxidative stress which
generates the cardio vascular diseases. In 2018 Wu67
proposed a study and results showed that cardiovascular
health products produced potential effects with apple
cider vinegar to improve atherogenesis, ameliorate
inammation and reduced triacylglycerol in mice serum.
Polyphenolic compounds in apple peel extract reduced
arsenic trioxide induced cardiotoxicity in H9c2 cells. The
extract altered the activity of SOD, catalase, glutathione,
GSH (Glutathione reductase) and caspase 3.68
Apple intake was associated with lower risk of all chronic
diseases.69 In 1994 Laranjinha et al.70 observed that
Polyphenolic compounds like chlorogenic acid found
in apple cider vinegar which reduced the oxidation
of lipoproteins (especially LDLs) and prevented
cardiovascular complications.
ACV act as Antioxidants, Antimicrobial and
Antifungal
It was found that ACV consumption increased
antioxidants enzymes including SOD and glutathione
peroxidase. In 2000 Lu and Foo71 carried out a study
that showed the antioxidant and free radical scavenging
activity of apple cider vinegar containing polyphenolic
compounds. In 2016 Seydim et al.72 made an experimental
model on rats for evaluation of the antioxidant
potential of apple cider vinegar and grape vinegar. In
2018 Yagnik et al.73 observed the antimicrobial activity
of ACV against various bacteria like E. coli, Staphylococcus
aureus and Candida albicans and also checked microbial
protein expression.

Tripathi, et al.: Apple Cider Vinegar (ACV): A New Therapeutic Target for Alzheimer’s Disease
S72 Indian Journal of Pharmaceutical Education and Research | Vol 54 | Issue 2 (Suppl) | Apr-Jun, 2020
Apple cider vinegar (ACV) also has antifungal activity
against candida species involved in denture stomatitis.74
In 2011 Hyson wrote a comprehensive review on apples
and apples constituents followed by a connective link
between the apple products with different chronic
diseases and their relationship with human health.75 This
review contained various in vitro studies and clinical data
analysis supported to apple products.
ACV act as the reduction in Cognitive impairments,
Immunomodulator
A number of studies from the Shea et al.76-82 produced
valuable results of apple juice focused on Alzheimer’s
disease linked with ageing. In this study aging showed
impaired memory functions and oxidative markers in
the mice brain. When aged mice received the dilute
form of apple cider vinegar in drinking water, there was
a signicant improvement in cognitive functions and
increased antioxidant activity.76
Memory impairment, oxidative stress and reduction
of acetyl choline signaling are the major symbols of
Alzheimer’s disease. Apple juice also prevents the
reduction of acetylcholine depletion connected with
aging and oxidative stress and maintains the neuronal
communications.79 In 2017 Safari et al.83 performed a
study to investigate the Immunomodulatory potency
of ACV and found ACV more effective, act as an
immunomodulator on the systemic and mucosal
immune response.
CONCLUSION
ACV (Apple cider vinegar) is a natural health-
promoting food which includes various potential health
benets. Due to the existence of various polyphenolic
compounds, it has high antioxidant, anti-inammatory
action, hepatoprotective and anti-cancer action. The
antioxidant mechanism dened essential suggestions
for a protective effect of ACV not only cancer but also
cardiovascular diseases, asthma and potentially diabetes.
Similarly, oxidative stress and mutation in gene coding
amyloid precursor protein (APP) and aging are the
main origins of Alzheimer’s disease. However, research
data signifying that antioxidant effects are imperative,
including the suppression of neurotoxic mediators in
Alzheimer’s diseases. So regular consumption of ACV
as a part of a healthy diet may prevent the oxidative
effect of cells which is the main cause of Alzheimer’s
disease and it could be an economical and recurrent
source of dietary antioxidant. Ongoing work continues
to dene mechanisms behind this followed by in vivo and
in vitro experiment.
ACKNOWLEDGEMENT
This work was supported by Department of
pharmaceutical Sciences and Technology, Birla Institute
of Technology, Mesra for providing research support.
Authors are also gratefully acknowledged to AICTE-
QIP (All India Council for Technical Education-Quality
improvement programme) for providing nancial
support.
CONFLICT OF INTEREST
The authors declare no conict of interest.
ABBREVIATIONS
AD: Alzheimer’s Disease; ACV: Apple Cider vinegar;
NFTs: Neurobrillary tangles; Aβ: β-amyloid; APP:
Amyloid precursor protein; BACE 1: Beta-secretase 1;
GSK3β: Glycogen synthase kinase 3β; CDK5: Cyclin-
dependent kinase 5; PHFs: Paired helical laments
structure; PUFs: Polyunsaturated fatty acids; ERK:
Extracellular-signal regulated kinase; CREB: Cyclic
AMP response element binding protein; COX-2:
Cyclooxygenase-2; LDL: Low density lipoprotein;
HDL: High density lipoprotein; VLDL: Very low
density lipoprotein.
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Cite this article: Tripathi S, Mazumder PM. Apple Cider Vinegar (ACV) and their Pharmacological Approach towards
Alzheimer’s Disease (AD): A Review. Indian J of Pharmaceutical Education and Research. 2020;54(2s):s67-s74.