Molecular Neurobiology

https://doi.org/10.1007/s12035-020-02065-3

Emerging Therapeutic Promise of Ketogenic Diet to Attenuate

Neuropathological Alterations in Alzheimer’s Disease
Md. Sahab Uddin 1,2 & Md. Tanvir Kabir 3 & Devesh Tewari 4 & Abdullah Al Mamun 1,2 & George E. Barreto 5,6 &
Simona G. Bungau 7 & May N. Bin-Jumah 8 & Mohamed M. Abdel-Daim 9,10 & Ghulam Md Ashraf 11,12

Received: 1 May 2020 / Accepted: 7 August 2020

# Springer Science+Business Media, LLC, part of Springer Nature 2020

Abstract
Alzheimer’s disease (AD) is a multifactorial and chronic neurodegenerative disorder that interferes with memory, thinking, and
behavior. The consumption of dietary fat has been considered a vital factor for AD as this disease is related to blood-brain barrier
function and cholesterol signaling. The ε4 allele of apolipoprotein E (APOE4) is a primary genetic risk factor that encodes one of
many proteins accountable for the transport of cholesterol and it is deemed as the leading cholesterol transport proteins in the
brain. In case of AD development, the causative factor is the high level of serum/plasma cholesterol. However, this statement is
arguable and, in the meantime, the levels of brain cholesterol in individuals with AD are extremely inconstant and levels of
cholesterol in the brain and serum/plasma of AD individuals do not reflect cholesterol as a risk factor. In fact, APOE4 is neither
fundamental nor sufficient for the advancement of AD; it just acts as a synergistic and increases the danger of AD. Another
noticeable characteristic of AD is area-specific decreases in the metabolism of brain glucose. It has been found that the brain cells
cannot efficiently metabolize fats; hence, they totally rely upon glucose as a vitality substrate. Thus, suppression of glucose
metabolism can possess an intense effect on brain actions. Hypometabolism is frequently found in AD and has quite recently
achieved impressive consideration as a plausible target for interfering in the progression of the disease. One promising approach
is to keep up the normal supply of glucose to the brain with ketone bodies from the ketogenic diet signifies a potential therapeutic
agent for AD. Therefore, this review represents the role of ketogenic diets to combat AD pathogenesis by considering the
influence of APOE.

Keywords Ketogenic diets . APOE4 . Alzheimer’s disease . Hypometabolism . Lipids

Abbreviations KBs Ketone bodies

AD Alzheimer’s disease BHB β-Hydroxybutyrate
KD Ketogenic diet ApoE Apolipoprotein E

* Md. Sahab Uddin 6

Instituto de Ciencias Biomédicas, Universidad Autónoma de Chile,
msu-neuropharma@hotmail.com; msu_neuropharma@hotmail.com Santiago, Chile
* George E. Barreto 7
Department of Pharmacy, Faculty of Medicine and Pharmacy,
George.Barreto@ul.ie University of Oradea, Oradea, Romania
* Ghulam Md Ashraf 8
Department of Biology, College of Science, Princess Nourah bint
ashraf.gm@gmail.com; gashraf@kau.edu.sa Abdulrahman University, Riyadh 11474, Saudi Arabia
9
1 Department of Zoology, College of Science, King Saud University,
Department of Pharmacy, Southeast University, Dhaka, Bangladesh P.O. Box 2455, Riyadh 11451, Saudi Arabia
2
Pharmakon Neuroscience Research Network, Dhaka, Bangladesh 10
Pharmacology Department, Faculty of Veterinary Medicine, Suez
3
Department of Pharmacy, Brac University, Dhaka, Bangladesh Canal University, Ismailia 41522, Egypt
4 11
School of Pharmaceutical Sciences, Lovely Professional University, King Fahd Medical Research Center, King Abdulaziz University,
Phagwara, Punjab, India Jeddah, Saudi Arabia
5 12
Department of Biological Sciences, University of Limerick, Department of Medical Laboratory Technology, Faculty of Applied
Limerick, Ireland Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia

Introduction
Alzheimer’s disease (AD) is the most predominant cause of
dementia in people more than 60 years old, affecting about 44
million individuals globally [1–3]. The most well-known ge-
netic risk factor for AD is the possession of the ε4 allele of
apolipoprotein E (APOE4) [4–6]. Although about 70% of the
risk factor is supposed to be genetic [7], non-genetic risk fac-
tors have also been associated with AD, including lifestyle-
related factors of exercise, eating routine, and weight, and
these factors may represent up to around 33% of AD cases
[8, 9]. In fact, with the concurrence of both the aging people
and increasingly obese and overweight society, comprehen-
sion regarding the crossing point of eating regimen, genotype,
and cognitive impairment is very important. APOE4 acts as a
predominant, dose-dependent mode; one copy of APOE4 in-
creases the risk of developing AD approximately 3-fold,
whereas two copies increase the risk around 10-fold [10,
11]. AD is clinically featured by the chronic deterioration in
memory as well as language, and pathologically by aggrega-
tion of neurofibrillary tangles and senile plaques [12–15].
Regional cerebral hypometabolism is another noticeable
characteristic of AD. On the other hand, low cerebral meta-
bolic rates of glucose utilization in probable AD individuals
were uncovered by early imaging investigations [16], and this
is currently accepted as a common characteristic of the disease
[17]. It is known that the most generally affected regions in
Alzheimer’s are parietal, posterior cingulate, prefrontal, and
temporal regions [18]. Indeed, these impairments can be iden-
tified in pre-symptomatic, in individuals who are at risk, for
example, E4 carriers, as young adults. Interestingly, such al-
terations have been identified in cognitively normal individ-
uals well before there is extensive loss of neurons or antici-
pated deposition of plaque, which further recommends that
low cerebral metabolic rates of glucose (CMRglc) use are an
early event in the disease [19].
Numerous studies have investigated the impact of alter-
ation in lifestyle-related factors in improving AD and their
interaction with APOE genotype [20–23]. For instance, taking
part in regular exercise enhances cognitive functions and re-
lated cognitive impairments in AD patients and diminishes
amyloid in the brain [24], and APOE4 carriers experience
more noteworthy positive advantages of exercise engagement
[25]. Like exercise, a Western diet introduction and related
weight gain to a nation correspond with an increased occur-
rence of AD in that country [26], while consumption of a
Mediterranean diet is found to be linked with lesser AD risk
and mild cognitive impairment (MCI) [27]. Nevertheless,
rather than exercise, dietary intervention seems to be less ef-
fective in APOE4 carriers [28].
The reason for the hypometabolism remains obscure and
might be owing to the loss of dendritic fields or neurons.
Hypometabolism has been ascribed to the activity of AD-
Mol Neurobiol
related aspects. For the dysregulation of the mitochondrial
function, both amyloid beta (Aβ) [29, 30] and the ApoE4
protein fragmentation have been implicated [11, 31].
Additionally, many studies have suggested alterations in insu-
lin signaling as an effective supporter of the progression of
hypometabolism [32–34]. Despite its cause, treatments that
focused on the correction of cellular metabolism may demon-
strate usefulness to individuals with AD [35].
Induction of ketosis is one of such auspicious therapies
[36]. Glucose is the principal energy substrate for the brain,
under normal conditions [37]. However, in some cases, for
example during prolonged fasting, the liver generates ketone
bodies (KBs) in order to be used by extrahepatic tissues, such
as the brain. Acetone, acetoacetate (ACA), and β-
hydroxybutyrate (BHB) are generally regarded as KBs; for
cells, they serve as an efficient fuel [38, 39] as shown in
Fig. 1. Interestingly, through adherence to a high-fat, low-
carbohydrate ketogenic diet (KD), levels of circulating KBs
can be elevated. AD patients are often found to undergo alter-
ations in food choice toward sweet and carbohydrate-rich
foods [40, 41]. It is well-known that induction of the hepatic
production of KBs can be instigated by the diets that contain a
great amount of fat content and very low carbohydrate [42]. A
number of studies have confirmed that KDs have neuropro-
tective effects and improve cognitive functions [42–45].
Analysis to explore the therapeutic potentiality of KB and
ketosis can be regarded as a new auspicious area of
Alzheimer’s research [36, 46]. In this review, we represent
the therapeutic potential of KBs in AD.
Glucose Metabolism in Alzheimer’s Disease
A conspicuous characteristic of AD is chronic and area-spe-
cific, and decreases in the CMRglc. On the other hand, in
CMRglc across the whole brain, previous investigations com-
paring AD patients with normal controls observed a 17 to 24%
decline. Furthermore, noticeable associations were found
among cognitive function and CMRglc, such that the low rate
of CMRglc is linked with low cognitive scores [16].
Subsequently, a number of imaging studies have validated
these justifications. In the AD brain, unusually low CMRglc
rates are observed in a characteristic arrangement, predomi-
nantly in the areas of posterior cingulate, parietal, temporal,
and prefrontal cortex. In addition, as a diagnostic tool for AD,
this arrangement is found to be reproducible and has been
recommended [18, 47]. Fascinatingly, brain regions
exhibiting hypometabolism markedly overlap with areas de-
tected in the default network. In addition, it has been recom-
mended that the utilization of elevated concentrations of glu-
cose in these areas might be beneficial to the forthcoming
development of cell atrophy, deposition of plaque, and
hypometabolism that describes AD [48].
Mol Neurobiol
Fig. 1 The schematic representation of ketogenic metabolism and typical
oxidative glucose metabolism that lead to the formation of energy. During
fasting, in ketogenic metabolism, lipids are metabolized by β-oxidation
to generated ketone bodies (i.e. acetoacetate, β-hydroxybutyrate, and
acetone). Later by multi-step pathways, acetoacetate and β-
In AD, a decrease in the regional CMRglc levels might be
owing to the decrease in the activity or density of glial cells or
terminal neuronal fields, a metabolic defect observed within
glia or neurons, or a mixture of these factors [19]. In a study,
Reiman et al. [19] observed the beginning of hypometabolism
in non-demented subjects at risk for developing AD. The same
research also observed, in an early experiment, screened indi-
viduals within the ages of 50 and 65 years of age with a family
history of AD and who were homozygous for the E4 allele,
and thus at greater risk of AD development [18]. On the other
hand, 11 E4/E4 subjects (mean age was 55.4) were selected
and subsequently compared with 22 matched controls (mean
age was 56.3). Interestingly, in any cognitive test, the controls
and homozygotes did not vary; however, the E4/E4 homozy-
gotes exhibited declines in the metabolism of glucose in the
same areas detected in AD individuals [18]. Then 12 E4 car-
riers (E4/E3) were compared with E4 non-carriers by Reiman
et al. [19] in a follow-up study investigating young adults.
hydroxybutyrate are converted to acetyl-CoA. On the other hand, in typ-
ical oxidative glucose metabolism, glucose is metabolized to acetyl-CoA
via glycolysis. The generated acetyl-CoA then entered into Krebs Cycle
and ETC to engender ATP. ETC, electron transport chain; ATP, adeno-
sine triphosphate
Like the aforementioned study, in spite of exhibiting no signs
of weakened cognitive function, E4 carriers had low CMRglc
bilaterally in the posterior cingulate and prefrontal, temporal,
and parietal cortices. It was found that 30.7 years was the
mean age of the E4 carriers [19]. Henceforth, in the disease
process, a low level of regional CMRglc seems to be a very
early event, well before any medical signs of dementia are
obvious, and well before deposition of plaque or loss of cell
is expected to have happened.
The low level of regional CMRglc is not specific for E4
carriers. In another study, Corder et al. [49] studied 46 patients
in a memory disorder clinic. Among them, 31 subjects were
diagnosed with possible AD; in addition, 4 of them were E2/
E3, 11 were E3/E3, and 16 were E3/E4. In the frontal area,
these 31 individuals showed a mean 11% decline in the level
of CMRglc. In contrast, in the temporoparietal areas of the
cortex, 27 to 31% decrease was observed. Furthermore, each
genotype was studied to determine the variations in the level

of CMRglc, and none were observed. In a different study
involving 83 individuals with probable AD, yet again, no
variations were observed based on the absence or presence
of the E4 allele [50]. Nonetheless, some variations among
E4(−) and E4(+) participants have been identified via studies
involving more advanced voxel-based methods. Since low
rates were identified in other regions of the brain not observed
in E4(−) individuals, E4(+) individuals might possess more
global declines in the level of CMRglc [51]. Henceforth, cer-
tain variations might be present among E4 carriers in other
areas of the brain or in the advancement of the CMRglc de-
cline [52].
The exact molecular cause of hypometabolism is still
obscure. The lower level of CMRglc might be owing to
the changes in the processing of either the ApoE4 protein
or amyloid precursor protein (APP). On the other hand,
ApoE4 protein fragments avoid the normal secretory
mechanism and move in the mitochondria, suggested by
Mahley and Huang [31]. The E4 fragments might bind
with F1-ATPase subunits within the mitochondria; there-
fore, they can cause a reduction in the production of cellu-
lar energy [31]. It has been recommended by other re-
searchers that the Aβ peptide produced from the APP pro-
tein cleavage [53, 54] binds heme and can lead to complex
IV activity loss [55]. However, some other researchers still
suggest that Aβ peptide–stimulated activity of glycogen
synthase kinase 3β (GSK3β) can lead to a decrease in
energy metabolism and phosphorylation of pyruvate dehy-
drogenase [56] as given in Fig. 2. In other researches, it has
been suggested that the impairments in energy metabolism
might be owing to the low level of expression of energy
metabolism genes in affected regions of the brain, for
example posterior cingulate neurons [57].
Low CMRglc rates are found in the early stage of the dis-
ease, before greater amounts of Aβ are anticipated to exist,
and in the AD individuals who are E4(−). Henceforth, several
researchers studied whether disruptions in energy metabolism
precede changes in the processing of APP. Interestingly, it has
been found that a decrease in the production of energy via
treating cells with sodium azide can lead to an 80-times in-
crease in the production of C-terminal fragment of APP as
well as aggregation of APP in the secretory pathway [58].
This increase in fragmentation of APP might be owing to
the increased activity of β-secretase (BACE), which is con-
sidered the rate-limiting step for Aβ production. On the other
hand, a long-term increase in the levels of BACE1 enzyme
was noticed when acute energy deprivation inducing agents
(i.e. 2-deoxyglucose and insulin) were used to treat wild-type
mice. In addition, following treatment, it was observed that
increased BACE1 levels were long-lasting and lasted at least
1 week. Moreover, it was observed that such treatments
caused a two-times increase in the levels of Aβ1–40, 1 week
after treatment [59].
Mol Neurobiol
Another postulate is that the signs of a more general distur-
bance are altered APP processing and low rate of CMRglc.
One likely culprit has changed the metabolism of lipid/
glucose-stimulated either by several factors of environment,
for instance, genetic predisposition, or by diet, for example,
APOE4 allele possession, or both. In addition, changes in the
level of lipid metabolism that cause low levels of circulating
docosahexaenoic acid (DHA) might elevate the risk of AD
development [60]. Incorrect APP cleavage and weakened ac-
tions of other sensitive proteins (for example glucose trans-
porters) may be caused by the disruptions in the metabolism of
lipid. The changes might be apparent in the production of
reactive oxygen species, amyloid accumulation, and
hypometabolism. In reality, possibly the changes in the me-
tabolism of lipids are due to the modern style of diet consump-
tion and evolutionarily acrimonious diets; all of these are cru-
cial to the AD etiology [34, 36].
APOE in Lipid and Glucose Metabolism
APOE assumes a key part in the process of lipid metabolism in
the brain through ApoE receptor-mediated uptake of the lipo-
protein [61]. ApoE4 allies especially with triglyceride-rich
very-low-density lipoprotein (VLDL) particles whereas
ApoE2 and ApoE3 have an inclination for small,
phospholipid-rich high-density lipoprotein (HDL) in the plas-
ma [184]. The only lipoprotein particle in the brain is HDL-
like size particles. Currently, it has been demonstrated that the
sizes of ApoE particles in the cerebrospinal fluid (CSF) of
moderately aged non-demented individuals follow the
pattern of ApoE 2/3 > ApoE3/3 > ApoE3/4 > ApoE 4/4
[62]. In aged adults, the sizes of the CSF ApoE complex
follow the pattern of ApoE4-negative > ApoE4-positive.
Though, there is no distinction among non-demented and per-
sons with the mildest dementia in the sizes of CSF ApoE
lipoprotein particles.
To examine the impacts of ApoE in the brain metabolome,
Lee et al. [63] examined metabolites of young low-density
lipoprotein receptor (LDLR) knockout and ApoE knockout
mice. The serum cholesterol was dramatically increased in
the absence of LDLR or ApoE while having extremely subtle
consequences on the lipid metabolism or fatty acids in the
brain [63]. It was concluded by the researchers that either
LDLR or ApoE alone may not play an essential role in these
mouse models at an initial stage, however, it rather require the
combined impact from various pathways that prompt dysfunc-
tion at a considerably later phase of life. In another study
conducted by Zhu et al. [64], it was found that brain
phosphoinositol biphosphate (PIP2) was regulated by ApoE3
through suppression of the levels of a PIP2-degrading enzyme,
phosphoinositol phosphatase synaptojanin 1, whereas ApoE4
is non-functional during this process.
Mol Neurobiol
Fig. 2 The regulation of glucose metabolism by Aβ in nerve cells. Aβ
peptide by reducing the efficiency of oxidative phosphorylation in
mitochondria increases the production of ROS. Aβ causes
phosphorylation of pyruvate dehydrogenase by stimulating GSK3β and
blocks the formation of acetyl-CoA from pyruvate as well as exert
deleterious effects on ETC by inhibiting mitochondrial redox carriers.
Type 2 diabetes is also related to AD in spite of the fact that
it is as yet uncertain whether it is a cause or outcome of AD
[65–68]. The APOE genotype alters the response to insulin
treatment in humans. The connection between insulin resis-
tance and Aβ is also controlled by APOE [69]. An investiga-
tion was done to show the interaction among insulin, Aβ, and
APOE isoforms through an APP mouse model that expressed
human APOE isoforms [70, 71]. The Aβ-induced disability of
insulin signaling was upgraded by ApoE4 and quickened the
cognitive defects that were hippocampal-dependent as com-
pared with ApoE3 [71]. It was also reported that insulin re-
ceptors that were co-immunoprecipitated with ApoE in the
brain lysates of APP/ApoE4 mice were lesser with ApoE in
comparison with APP/ApoE3 mice which suggested that there
was a feebler interaction between the insulin receptor and
ApoE4 when compared with ApoE3 [70]. Since amyloid
plaque load is higher in the ApoE4 mice compared with
ApoE3 mice, it is difficult to rule out if the higher amount of
Aβ in the APP/ApoE4 mice really advocates the insulin
resistance.
Seneff et al. [72] suggested that modern diets, which are
low in fats and rich in carbohydrates, produce high blood
sugar levels after meals, which in turn impair vital proteins,
such as the ApoE protein. ApoE proteins are predominantly
As a result, the formation of ATP is reduced that activates AMPK
which stimulates β-oxidation of fatty acid and reduces protein,
glycogen synthesis as well as stimulate autophagy. ROS, reactive
oxygen species; GSK3β, glycogen synthase kinase 3β; ETC, electron
transport chain; AMPK, AMP-activated protein kinase; ATP, adenosine
triphosphate
vulnerable to glycation and play a pivotal role in converting
them into advanced glycation end products (AGEs). In the
brains and cerebrospinal fluid of AD patients, AGEs are ob-
served in large amounts [73]. This glycation damage is ac-
countable for the impairment of ApoE that hampers its capa-
bility to carry lipids to astrocytes, eventually contributing to
inadequate levels of vital fats like cholesterol in neurons.
Regarding this, there is a cascade effect of neuronal dysfunc-
tion, mitochondrial dysfunction, and oxidative stress, conse-
quently leading to neuronal cell death [72, 74, 75]. The eluci-
dation of the pathogenesis events of AD [72] could strengthen
numerous research outcomes that were explained earlier. For
example, the relationship between AD and diabetes can be
owing to the resistance of insulin as well as the excess blood
glucose level raising the glycation of ApoE proteins.
Moreover, ApoE proteins transcribed and translated by
the E4 isoform of the gene are 3 times more AGE-binding
compared with those of other APOE isoforms [76]. This
recommends ApoE4-positive people may be more vulner-
able to the cascade effect suggested by Seneff et al. [72],
which might clarify why they are considered the most risk
factors for the development of AD. In addition, this finding
might also elucidate why Henderson et al. [77] observed a
noteworthy enhancement in ApoE4-negative but not in
 Mol Neurobiol

ApoE4-positive people, as the research participants were Hypometabolism as a Therapeutic Target

allowed to eat carbohydrates. Ultimately, lipidated ApoE
levels are responsible for the increase or decrease of the
levels of Aβ levels, which indicates that the deficiency of
lipidated ApoE may contribute to the increase of Aβ,
whereas copiousness of lipidated ApoE possibly improves
the removal of Aβ [78, 79]. Furthermore, a study found
decreased Aβ levels in mice model that ate KDs, as the
KDs potentially lessen glycation via dropping blood glu-
cose levels, but also increase the availability of lipids, and
both effects may contribute to increased lipidated ApoE
[80]. Additionally, this increase in existing lipidated
ApoE may supply astrocytes with vital facts that are sig-
nificant for the growth as well as the function of neurons,
possibly stopping the cascade effect suggested by Seneff
et al. [72] as shown in Fig. 3. These mounting proofs rec-
ommend that glycation of the ApoE protein and the resul-
tant downstream effects may elucidate factors of the AD
pathogenesis, as well as KDs, which may improve damage
through the stabilization of blood glucose level and in-
crease the availability of vital fats such as cholesterol.
Irrespective of the cause, energy deprivation can be harmful to
neurons. Furthermore, this deprivation may play a pivotal role
in progressing AD [81, 82]. Thus, enhancing the overall cere-
bral metabolic rate might be beneficial for individuals with
AD. Indeed, one way to overcome this problem is to study
how the body typically survives with situations of low glucose
availability and if such circumstances may be exogenously
used to AD. Extended starvation or fasting can be a simple
way to study the response toward low glucose availability. In
classic studies investigating brain metabolism during fasting,
Owen et al. [83] studied the utilization of substrate when
obese participants went through 5 to 6 weeks of complete
starvation. Participants of that study were limited to the intake
of 1.5-l water, 17 mEq of sodium chloride, and one multivi-
tamin capsule per day during the period of starvation. In ad-
dition, glucose synthesis rates were also calculated during the
starvation period. Glucose is mainly generated under such
circumstances from the catabolism of proteins, lactate from
glycolytic tissues, or glycerol from fat stores. It was

Fig. 3 The role of high

carbohydrate diets in the
pathogenesis of Alzheimer’s
disease. ApoE protein modulates
the biosynthesis of lipoproteins.
Thus, generated ApoE-labeled li-
poproteins are transported intact
across the endothelium of the
blood-brain barrier and taken up
by astrocytes and finally trans-
ferred to neurons for neuronal
metabolism. On the other hand,
high carbohydrate diets cause
glycation of ApoE and block the
formation of lipoproteins which
in turn starves neuron and causes
neurodegeneration reported in
AD. ApoE, apolipoprotein E
Mol Neurobiol
determined based on rates of nitrogen excretion and other
factors that total glucose synthesis and availability to the body
during starvation was around 33 g glucose/day, and this was
below the brain’s normal oxidation of 110 g/day. The brain
will obtain most of its required energy from the oxidation of
KBs under such fasting conditions. On the other hand, during
the period of starvation, the concentration of the major
KB, BHB was within the range of 4–8 mM, 10- to 20-times
over normal fasting values. Furthermore, it is evaluated that
approximately 60% of the brain’s energy requirements are
provided by the supply of KBs under such scenarios [83].
Amino acids are the main sources of de novo synthesized
glucose. A considerable tissue (mainly muscle) breakdown is
required for the brain in order to provide high glucose levels. It
has been observed that such lean body mass loss during pe-
riods of food insufficiency would likely be maladaptive. As an
alternative, the use of KBs permits for the tapping of abundant
fat stores [83].
Ketogenic Diet and Alzheimer’s Hallmarks
The capability of KBs to enhance the mitochondria efficacy
and glucose supplementation makes them alluring compounds
for the treatment of AD [84]. A ketosis condition can be ac-
tuated via enhanced levels of free fatty acid (FFA) circulation
and encouraging oxidation of fatty acid. This can be accom-
plished through adherence to KDs. The KDs gained attention
when it developed to decrease seizure incidence in epileptics.
These diets are effectively utilized for a long time for the
treatment of refractive childhood epilepsy. The KDs have
likewise been utilized effectively to moderate the manifesta-
tions of glucose deprivation, for example those that happen in
glucose transporter type 1 deficiency syndrome [85].
Including AD, KDs have exhibited potential in the treat-
ment of many neurological conditions like amyotrophic hori-
zontal sclerosis [86], traumatic brain injury [87], and
Parkinson’s disease [194]. In a study, Van der Auwera et al.
[80] directly assessed a KD in an AD animal model. In addi-
tion to this, this investigation utilized a transgenic line of mice
that were expressing mutation of APP (V717I) that was driven
via THY1 promoter. It has been observed that these animals
demonstrate noteworthy levels of soluble Aβ in as little as
3 months, and widespread deposition of plaque by 12 to
14 months of age [88]. In this study, either standard chow or
ketogenic chow (i.e. composed mainly of lard and butterfat,
mainly saturated fat and lesser carbohydrate) was feed for
43 days to 3-month-old, sixteen female mice. During the treat-
ment time, the levels of KBs were substantially enhanced in
the range of 2–9 mM, and finally, it was found that there was a
decrease of 25% in the levels of Aβ40 and Aβ42 [80].
Initially, this outcome may appear inconsistent with prior ex-
aminations that ascribed a high-fat diet to enhance Aβ loads
[89, 90]; nonetheless, in these prior investigations, fat was
introduced to the eating regimen without a marked reduction
in the content of carbohydrate. It is dubious these animals
generated KB. In these study designs, the distinctions feature
the remark that not all high-fat diets are high-fat diets [91].
Animal models have been used by the researchers for a
better understanding of how ketosis may provide protection
to the human brain against neurodegeneration. Yin et al. [92]
elucidated the relationship between the metabolic benefits of
ketones, lower Aβ, and enhanced cognitive function. Indeed,
a novel neuroprotective pathway has been discovered by this
study in which they blocked the entry of Aβ1–42 into neurons.
It was found that inhibition of intracellular Aβ1–42 accumula-
tion ameliorated synaptic plasticity, decreased oxidative
stress, and rescued mitochondrial complex I effects. In the
symptomatic AD mouse model, it was also revealed by this
study that peripheral administration of ketones caused a
marked reduction of Aβ burden and also significantly en-
hanced memory and learning ability [92]. Collectively, these
findings provide a better understanding and also can help to
establish a novel therapeutic use of ketones for AD treatment.
Therapeutic Potential of Ketogenic Diet
to Combat Alzheimer’s Pathology
The capacity of the brain in glucose utilization seems to be
pathologically decreased in AD [93, 94]. Neurobiological
proofs revealed that the KBs are successful elective energy
substrate for the brain [95, 96]. Increase in the levels of plasma
KBs by medium chain triglycerides (MCTs) oral dose might
enhance cognitive function in adult people with memory dis-
orders. It has been confirmed by several studies that KDs are
effective in treating AD as given in Table 1 and Table 2.
Reduced levels of blood glucose and increased KB concentra-
tion are the key features of the neuroprotective effects of KD
(Fig. 4). Additionally, KBs increased the action of brain-
specific uncoupling proteins (UCP), which decrease the gen-
eration of reactive oxygen species (ROS) through mitochon-
drial complex I, moderate neuron dysfunction, and neurode-
generation [97, 98]. The expression of UCP is induced by
ketosis and it also upregulates many genes associated with
the energy metabolism of oxidation through the nuclear tran-
scription factor peroxisome proliferator-activated receptor-α
(PPARα) and peroxisome proliferator-activated receptor γ
coactivator-1 (PGC-1α) [97, 98]. Ketosis is reported to stim-
ulate the mitochondrial biogenesis, hence produces higher
adenosine triphosphate (ATP) and also increases energy re-
serves, which are recognized to stabilize the synaptic activity.
Perhaps, the ratio of increased phosphocreatine to creatinine
(PCr:Cr) energy reserve might potentiate GABAergic output,
which is most probably linked with the enhanced γ-
aminobutyric acid (GABA) synthesis triggered by ketosis
 Mol Neurobiol

Table 1 Promising preclinical

studies regarding the Species/ Experimental model Outcomes References
neuroprotective effect of studied
ketogenic diet against material
neurodegeneration
Mice Alzheimer’s disease Reduced Aβ levels [80]
(AD)
Cell culture AD Increased cell survival [100]
Rats Hypoxia ischemia Neuroprotection [101]
Cell culture Glutamate toxicity Increased mitochondrial efficiency [102]
Cell culture Glutamate toxicity Neuroprotection [103]
Cell culture Hypoxia Increased cell survival [104]
Rats Glutamate toxicity Neuroprotection and reduced lipid peroxidation [105]
Cell culture Glutamate toxicity Increased cell survival [106]
Mice Hypoxia Maintained adenosine triphosphate ) and low lactate [107]
Mice Ischemia Decreased cerebral edema formation and infarct area [108]
Mice Ketogenic diet Enhanced mitochondrial function, reduced reactive [46]
treatment oxygen species generation, and elevated levels of
cerebral ATP
Rats Ketogenic diet Decreased levels of insulin, phosphorylation of S6 and [109]
treatment protein kinase B, and reduced activation of
mammalian target of rapamycin
Mice Hypercholesterolemia Elevated transcriptional activity of peroxisome [110]
proliferator-activated receptor γ and suppressed his-
tone deacetylases
Mice AD Decreased Aβ deposition, and enhanced energy [111–114]
metabolism and motor function
Mice AD Improved tau and Aβ pathology, and enhanced [115]
cognitive performance

Table 2 Promising clinical studies regarding the neuroprotective effect of ketogenic diet against Alzheimer’s disease

Type of study Participants Disease condition Duration Outcomes References

of the participants

Randomized, double-blind,
placebo-controlled,
parallel-group study
Longitudinal, open-label study
Randomized study
Single-arm, pilot clinical study
Randomized placebo-controlled
study
Double-blind, placebo-controlled 20
study
Prospective, open-label,
observational study
Singe-patient case study
152 Mild to moderate 90 days AC-1202 rapidly elevated serum ketone bodies [77]
Alzheimer’s (β-hydroxybutyrate) that resulted in noticeably en-
disease (AD) hanced ADAS-Cog score as compared to placebo
20 Mild-to-moderate 12 weeks Medium-chain triglyceride (MCT)-based ketogenic diet [116]
AD improved cognitive performance, verbal memory,
and processing speed
23 Mild cognitive 6 weeks Very low-carbohydrate consumption, even in the short [117]
impairment term, can improve memory function
(MCI)
15 Mild-to-moderate 3 months MCT supplemented ketogenic diet enhanced the [118]
AD ADAS-Cog score
6 MCI 24 weeks MCT supplementation increased serum ketone bodies [119]
and improved memory as compared to placebo
AD or MCI 90 min MCT-based ketogenic diet significantly increased level [120]
of β-hydroxybutyrate (i.e. higher in case of ApoE4(+
) as compared to APOE4(−));
Enhanced cognitive function and memory in the
participants; APOE4(+) carriers were less responsive
to ketogenic diet as compared to APOE4(−)
22 Mild-to-moderate 90 days Axona did not improve cognitive function [121]
AD
1 Early-onset AD 20 months Ketone monoester noticeably enhanced the daily [122]
activities, self-care, and mood;
Enhanced cognitive function in APOE4(+) patient
Mol Neurobiol

[97–99]. Augmented acetone levels are linked with KB effect
and this might activate K2P channels that limit neuronal excit-
ability and hyperpolarize neurons [97, 99]. The change in the
metabolism of glutamate and GABA in the brain is also af-
fected by KBs.
In a study conducted by Reger et al. [123], it was found that
on different days, 20 individuals with MCI or AD were ad-
ministered a drink comprising emulsified MCTs or placebo.
There was a significant increase in levels of KB, BHB after
90 min of treatment when administered the subjective tests,
and the moderation of BHB increases was directed through
APOE.
In the case of ε4+ individuals, levels of BHB kept on as-
cending between the 90- and 120-min blood draws in the
treatment condition, while the levels of BHB of ε4− individ-
uals held consistently. On the other hand, in the case of cog-
nition test, MCTs treatment encouraged execution on the AD
Assessment Scale-Cognitive Subscale (ADAS-Cog) for ε4−
subjects, yet not for ε4+ individuals. It has been found that
higher ketone was related to the more noteworthy change in
memory enhancements (passage recall) with MCTs treatment
with respect to placebo overall individuals. Further research is
justified to decide the impact of MCTs for AD patients and
how APOE4 might intervene in the BHB effect.
Henderson et al. [77] later on followed up these short-term,
initial results through the use of AC-1202 (i.e. an oral keto-
genic compound) among 152 people (with possible AD) for
the duration of 90 days. It has been observed that as compared
with placebo, AC-1202 markedly increased the level of a se-
rum BHB following 2 h of its administration. It was observed
in each of the population groups that there was a noticeable
difference between AC-1202 and placebo in terms of mean
change from baseline in ADAS-Cog score on the 45th day. On
the other hand, it was found among the individuals who did
not contain the APOE4 allele (E4(−)) that there was a marked
difference between AC-1202 and placebo in terms of mean
alteration from baseline in ADAS-Cog score on the 45th and
90th day. In case of intention-to-treat population, it was

Fig. 4 Possible neuroprotective

effects of the ketogenic diet to
combat Alzheimer’s disease.
Ketogenic diet induces metabolic
shifts by increasing fatty acids
and reducing glucose levels.
Elevated fatty acids are suggested
to induce ketosis and finally
causes a reduction of neuronal
excitability and vesicular
glutamate transporters that lead to
the stabilization of synaptic
activity. On the other hand,
accompanying decreased glucose
availability increased oxidative
phosphorylation of ATP thus
enhanced energy reserves that
stabilize synaptic activity and
finally increased GABAergic
output. Ketogenic diets also
increase the activity of
uncoupling proteins that lead to
the reduction of ROS and
stimulate mitochondrial
biogenesis thus leading to
enhanced energy reserves that
stabilize synaptic activity and
finally potentiate GABAergic
output. ATP, adenosine
triphosphate; ROS, reactive
oxygen species

observed that when AC-1202 was administered in E4(−) par-
ticipants (N = 55), a marked 4.77 point difference was ob-
served in mean change from baseline in ADAS-Cog scores
on the 45th day and a 3.36 point difference on the 90th day in
comparison with placebo. Interestingly, it has been observed
in the case of per-protocol (PP) population that when AC-
1202 was administered to E4(−) subjects (N = 37), there was
a 5.73 point difference on 45th day and a 4.39 point difference
on the 90th day. On the other hand, in the case of dosage
compliant population, it was observed that when AC-1202
was administered to E4(−) subjects (N = 38), there was a
6.26 point difference on 45th day and a 5.33 point difference
on the 90th day (N = 35). In addition to this, in E4(−) subjects,
a noteworthy pharmacologic response was detected between
change in ADAS-Cog scores and the levels of serum BHB on
the 90th day [77]. It was observed that adverse events were
more prevalent among the participants who received AC-
1202. Nevertheless, those adverse events were limited to the
gastrointestinal system and were largely mild to moderate in
severity and transient in nature.
As stated earlier, multiple AD risk factors include lifestyle
and genetic. Lifestyle risk factors include exercise and diet,
while genetic risk factors include possession of APOE4 over
risk-neutral APOE3. However, the connection of these risk
factors with the disease is poorly understood. In a study,
Lane-Donovan et al. [124] demonstrated the effect of diet on
ApoE levels by feeding wild-type and ApoE3- and ApoE4-
targeted replacement mice with chow, ketogenic (i.e. very
low-carbohydrate, high-fat), or high-fat diets. Moreover, they
also observed that the high-fat diet has an impact on both
hippocampal and plasma levels of ApoE in an isoform-
dependent mode. In addition to this, a high-fat diet can cause
a marked decrease in the hippocampal levels of ApoE in
ApoE3 targeted replacement mice. In contrast, it was observed
that KDs has no effect on the hippocampal levels of ApoE
[124]. Collectively, these results recommend that APOE ge-
notypes should be taken into account while using the dietary
interventions in order to slow the AD progression.
These promising findings of ketogenic compounds suggest
that dietary interventions might be beneficial for brain health.
In a study, Krikorian et al. [117] randomly assigned MCI
containing 23 older adults to either a high or very low
carbohydrate-containing diet. Interestingly, after 6-week inter-
vention period, it was found in the low-carbohydrate subjects
that there was an improvement in the verbal memory perfor-
mance along with a decrease in fasting insulin, fasting glu-
cose, waist circumference, and weight. However, symptoms
of depression were found to be not affected in that study.
Interestingly, for the entire sample, alterations in weight, in-
sulin level, and calorie intake were not linked with memory
performance, even though it was observed within the low-
carbohydrate group that there was a trend toward a moderate
relationship between memory and insulin. In a positive
Mol Neurobiol
manner, ketone levels were correlated with memory perfor-
mance [117]. Collectively, these results denote that, even in
the short term, consumption of very low carbohydrate can lead
to an improvement in the memory function in older people
who are at increased risk for AD. This observation might be
due to the ability to correct hyperinsulinemia and other pro-
cesses linked with ketosis, for example increased energy me-
tabolism and decreased inflammation might also be able to
contribute to the improvement of neurocognitive function. In
the context of early neurodegeneration, more studies are re-
quired in order to assess its mechanisms of action and preven-
tive potential.
Established approaches in order to induce therapeutic
hyperketonemia have entailed adherence to KDs [125] and/
or repetitive medium-chain triglyceride (MCTG) administra-
tion [77]. In caregivers and patients, the strong drive is re-
quired in order to successfully adhere to the classical KDs
containing very low carbohydrate and very high fat.
However, liberalized versions might offer clinical benefits at
lower concentrations of plasma ketone [125]. Chronic intake
of KDs might also elevate the atherogenic lipid levels and
generate other adverse effects [77, 125]. It has been observed
that following the consumption of a very-low-carbohydrate
diet for 8 weeks, a group of MCI containing elderly people
showed enhanced verbal memory performance [117].
MCTG-administering individuals can also increase con-
centrations of plasma ketone while they are on their usual diet.
Individuals with AD and MCI were given 20 g of MCTG per
day in a cohort study; it was observed that concentrations of
BHB increased from ~ 0.09 mM (pre-dose) to 0.3– 0.4 mM
(i.e. 2 h post-dose). However, only among the individuals who
are APOE4-negative did marked improvements in their cog-
nitive performances during hyperketonemia exhibit [77].
Indeed, the highest levels of KBs were found to possess the
most benefit. Due to the minor gastrointestinal side effects,
around 12.5% of the individuals discontinued their
participation.
In fact, high concentrations of plasma KBs (6–8 mM) can
be maintained for an indefinite period when ketone monoester
(KME) is consumed at 3–4-h intervals, which might increase
concerns regarding the long-term safety of this extent of
hyperketonemia. Indeed, strict adherence to a very-low-
carbohydrate and very-high-fat KDs or prolonged fasting
was the only way to achieve comparable elevations of plasma
KBs before KME became available [83]. Nevertheless, these
approaches contain various metabolic side effects including
amenorrhea, marked weight changes, urate nephrolithiasis,
and dehydration [126]. Furthermore, these methods cannot
play a key role as a satisfactory test in order to determine the
long-term safety of hyperketonemia induced by KME.
Interestingly, while going through 5–6 weeks of starvation
for weight loss, 3 severely obese participants (i.e. who
sustained mean concentrations of KB at ~ 8 mM) did not show
Mol Neurobiol
any adverse clinical effects which can be attributed to the
prolonged hyperketonemia [83].
In rare cases, it has been observed that in hyperketonemia,
plasma concentrations of uric acid can get increased due to the
decreased renal clearance of uric acid, which can further cause
precipitation of a flare in gout-susceptible people [127]. This
complication can be prevented by the drugs which can inhibit
uric acid synthesis. Presently, there is no strong proof that
chronic hyperketonemia (i.e. at concentrations of ~ 8 mM)
might be clinically unsafe. Nevertheless, if valid safety con-
cerns are increased, then they should be regarded in the light
of a probable beneficial action of KME on devastating disor-
ders like AD, and on disabling convulsions in children and
infants who are refractory to anti-seizure drugs [128].
In a study, Henderson et al. [77] reported that APOE4-
positive participants failed to exhibit statistically significant
and enhanced ADAS-Cog scores in response to the treatment
with MCTG. Indeed, the patient (although APOE4-positive)
showed clear enhancement in their behavior and cognitive
functions, while consuming larger or equivalent amounts of
ketogenic, medium-chain fatty acids. However, the results of
Henderson et al. [77] do not exclude the chance that APOE4
allele carriers may exhibit improvements in their cognitive
functions if higher MCTG doses are given and/or studied for
longer periods of time.
In formal clinical trials, the therapeutic potential of the
ketosis has not been robustly studied. However, Newport
et al. [122] in their recent study revealed a surprising thera-
peutic target in order to control AD. Interestingly, in that
study, an elderly person (i.e. aged 63 years) with sporadic,
younger onset AD was administered 35 ml of coconut oil
(CO) on a daily basis. It has been found that CO contains ~
15% ketogenic medium-chain fatty acids (MCFA). MCTG
was introduced after several months and elevated progressive-
ly to a 4:3 mixture with CO, ultimately reaching 165 ml/day
divided into 3 to 4 servings. After 2.5 months, rapid improve-
ment in the score of Mini-Mental State Examination (MMSE)
from 12 to 20 was observed due to the use of CO/MCTG
mixtures as dietary supplements. In addition to this, gradual
amelioration has also occurred in the recall of recent events,
word-finding, social participation, and gait. Therefore, during
treatment with MCFA for 20 months, it was observed that the
patient’s activities of daily living increased to 14 points and
the ADAS-Cog score was increased to 6 points, followed by
stabilization. No further brain atrophy was observed in the
patient’s magnetic resonance imaging. Subsequently, KME
was introduced in the diet of the patient. Henceforth, improve-
ments were observed in cognitive function, living functions,
and behaviors of the patient. Following 6 to 8 weeks of con-
sumption of 28.7 g KME three times a day, the participant
started to show amelioration in memory retrieval, spontane-
ously discussing events that took place up to 7 days earlier.
Moreover, in order to estimate the dose-response relationships
between KME and plasma BHB, concentrations of plasma
BHB were estimated before and during treatment with
KME. Interestingly, significant alterations were observed only
in the case of certain plasma lipids. It was noticed that a total
cholesterol level dropped from a pre-KME mean (n = 2) of
244 to 163 mg/dl. In contrast, low-density lipoprotein (LDL)
cholesterol dropped from 145 to 81 mg/dl and HDL choles-
terol from 85 to 68 mg/dl. It needs to be noted that the partic-
ipant was an APOE4 carrier; therefore, the researchers con-
cluded that ketosis can be substantially beneficial for the
APOE4 carriers, although former studies revealed that ketosis
is even more beneficial for the individuals with this risk factor
[122].
In addition, MCT-supplemented ≥ 1:1 ratio KD was ad-
ministered for 3 months in 15 mild-to-moderate AD patients
in a single-arm pilot trial [118]. In that study, improvement in
cognitive functions was observed in 9 out of 10 individuals
who successfully finished the study and achieved ketosis
[118]. Furthermore, MCT-supplemented KD was given to
15 AD individuals (around 70% of energy as fat) in a different
study named Ketogenic Diet Retention and Feasibility Trial.
ADAS-Cog test was considerably ameliorated during the KD,
once the ketosis was attained [118]. In a study, MCT was
provided to 20 Japanese mild-to-moderate AD individuals
for more than 12 weeks [116]. Following 120 min of admin-
istration, the level of KBs was elevated; then, following
8 weeks, the individuals showed a marked enhancement in
their delayed and immediate memory tests in comparison with
their baseline score [116].
Currently, several randomized clinical trials by the
University of British Columbia [129], Universite de
Sherbrooke [130], Wake Forest University [131–133], and
Johns Hopkins University [134] are conducted to explore
more evidence about the effect of KD on AD [135].
Participants in these studies with mild AD, subjective memory
impairment, and/or healthy controls were utilized to assess the
influence of 6–18 weeks of the modified ketogenic-
Mediterranean diet to a low-fat diet; 12 weeks of the modified
Atkins diet in comparison with the recommended diet for
seniors to attain a healthy eating index; 1-month treatment
with the two different MCTs oil emulsions (C8 oil or 40–60
oil), or 10 days, two times a day, and administration of a
lactose-free skim milk drink containing either 10–50 g/day
of placebo (high-oleic sunflower oil) or 10–50 g/day of
MCT oil.
Another probable effect of KD on the progression of AD
has also been revealed. Studies have suggested that an elevat-
ed dietary supply of unsaturated fatty acids (particularly ome-
ga 3 and polyunsaturated fatty acids) might lower the risk of
this condition [136–138]. Possibly, the useful effect of KD on
the improvement of AD is linked with an increased supply of
unsaturated fatty acids versus a high or normal-carbohydrate
diet [42].

Adverse Effects of the Ketogenic Diet
Limited data is available on adverse effects of KD in adults;
however, some predictable effects are hypoglycemia and de-
hydration. Other adverse effects are generally less common
and present following long-term intake. Previously, KBs were
considered toxic which is an outcome of the association of
therapeutic ketosis with diabetic ketoacidosis, which leads to
higher ketone concentrations over 20 mM, and can be re-
versed by administration of insulin [139]. It is notable that in
severe cases, hyperketonemia developed by insulin deficiency
may cause severe acidosis, sometimes death [139, 140]. Some
adverse effects on KD like weight loss, gastrointestinal ef-
fects, and transient hyperlipidemia were reported frequently
by patients with epilepsy [141]. The side effects related to
gastrointestinal are nausea, vomiting, constipation, and lower
appetite [141, 142]. Moreover, lipid profile change like tri-
glycerides, fasting total serum cholesterol, and LDL choles-
terol is initially increased during KD treatment and normalizes
after ~ 1 year [143]. Apart from these, hepatitis, dehydration,
hypoglycemia, hyperuricemia, pancreatitis, hypomagnesemia,
hypertransaminemia, and hyponatremia are some of the major
adverse effects of the KD [142, 144]. On the prolonged KD
treatment, it may increase cardiomyopathy, anemia,
nephrolithiasis, atherosclerosis, neuropathy of the optic nerve,
impaired hepatic functions, decrease of mineral bone density,
and also the deficits of vitamins and minerals [99, 144].
Chronic treatment with KD might lead to disturbances in
catabolism and decreased production of functional proteins.
Bearing in mind the lower organoleptic attractiveness and loss
of appetite, it is likely to be problematic to attain a proper
supply of energy and protein in individuals on the KD, since
an inadequate intake of protein or any energetic deficiency
might result in severe consequences for health [118, 144].
Interestingly, when KD was provided for 24 weeks, no note-
worthy adverse effects were seen in 83 obese individuals
[145]. Furthermore, in AD individuals, KD might consider-
ably influence food intake through disturbances in the senses
of taste and smell; neurological symptoms, for instance, be-
havioral disturbances; dysphagia; and apraxia disturbances
during eating [144].
Conclusion
The auspicious effect of KBs gives a new way to combat AD
pathogenesis by a dietary intervention. For the effective AD
treatment, if ketosis becomes avowed, further studies are vital
to establishing the best possible mode of administration, since
MCFA, diets containing high-fat, ketogenic compounds, or
MCT supplements might be individually effective.
Additionally, patient compliance could also indicate chal-
lenges due to the administration of a strict diet or supplements.
Mol Neurobiol
Furthermore, the identification of maximum and minimum
effective dose is imperative to settle the Alzheimer’s treatment
regimen. Notwithstanding these questions, the therapeutic
promise of KDs recommends a great weapon against AD
pathogenesis.
Author Contributions MSU conceived the original idea and designed the
outlines of the study. MSU, MTK, DT, and AAM wrote the draft of the
manuscript. MSU prepared the figures for the manuscript. GEB, SGB,
MNB-J, MMA-D, and GMA revised and improved the manuscript. All
authors have read and approved the final manuscript.
Acknowledgments This work was funded by Deanship of Scientific
Research at Princess Nourah bint Abdulrahman University through the
Fast-Track Research Funding Program. This work was supported by
King Saud University, Deanship of Scientific Research, College of
Science Research Center.
Compliance with Ethical Standards
Competing Interests The authors declare that they have no competing
interests.
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