International Journal of
Molecular Sciences
Review
Ketogenic Diet in Alzheimer’s Disease
Marta Rusek 1,2 , Ryszard Pluta 3, * , Marzena Ułamek-Kozioł 3,4 and Stanisław J. Czuczwar 1
1
2
3
4
*
Department of Pathophysiology, Medical University of Lublin, 20-090 Lublin, Poland
Department of Dermatology, Venereology and Pediatric Dermatology, Laboratory for Immunology of Skin
Diseases, Medical University of Lublin, 20-080 Lublin, Poland
Laboratory of Ischemic and Neurodegenerative Brain Research, Mossakowski Medical Research Centre,
Polish Academy of Sciences, 02-106 Warsaw, Poland
First Department of Neurology, Institute of Psychiatry and Neurology, 02-957 Warsaw, Poland
Correspondence: pluta@imdik.pan.pl; Tel.: 48-22-6086-540/6086-469; Fax: 48-22-6086-627/668-55-32
Received: 21 July 2019; Accepted: 7 August 2019; Published: 9 August 2019
Abstract: At present, the prevalence of Alzheimer’s disease, a devastating neurodegenerative
disorder, is increasing. Although the mechanism of the underlying pathology is not fully
uncovered, in the last years, there has been significant progress in its understanding. This includes:
Progressive deposition of amyloid β-peptides in amyloid plaques and hyperphosphorylated tau
protein in intracellular as neurofibrillary tangles; neuronal loss; and impaired glucose metabolism.
Due to a lack of effective prevention and treatment strategy, emerging evidence suggests that
dietary and metabolic interventions could potentially target these issues. The ketogenic diet is
a very high-fat, low-carbohydrate diet, which has a fasting-like effect bringing the body into
a state of ketosis. The presence of ketone bodies has a neuroprotective impact on aging brain
cells. Moreover, their production may enhance mitochondrial function, reduce the expression of
inflammatory and apoptotic mediators. Thus, it has gained interest as a potential therapy for
neurodegenerative disorders like Alzheimer’s disease. This review aims to examine the role of the
ketogenic diet in Alzheimer’s disease progression and to outline specific aspects of the nutritional
profile providing a rationale for the implementation of dietary interventions as a therapeutic strategy
for Alzheimer’s disease.
Keywords: Alzheimer’s disease; ketogenic diet; amyloid; tau protein; neuroinflammation; dementia;
ketone bodies therapy
1. Introduction
Alzheimer’s disease (AD) is the most significant cause of dementia that affects around 50 million
people worldwide [1]. It is a heterogeneous and multifactorial disorder, characterized by cognitive
impairment with a progressive decline in memory, disorientation, impaired self-care, and personality
changes [2,3]. The most common symptom present at the beginning of AD is associated with short term
memory deficit, which affects daily activities [3]. Cognitive deficits, resulting from the loss of neurons,
are susceptible to neurofibrillary degeneration located in the limbic system, subcortical structures,
archicortex and neocortex, and progressive synaptic dysfunction [4]. Pathologically, AD involves
progressive deposition of amyloid β-peptide (Aβ) as amyloid plaques, hyperphosphorylated tau
protein intracellularly as neurofibrillary tangles (NFTs) and neuronal loss in the hippocampus [2].
Moreover, patients with AD present mitochondrial dysfunction and metabolic changes, such as
impaired glucose utilization in the brain (glucose hypometabolism) [5].
Mitochondrial dysfunction and a decline in respiratory chain function alter amyloid precursor
protein (APP) processing, which leads to the production of the pathogenic amyloid-β fragments [6,7].
On the other hand, the reduced glucose uptake and inefficient glycolysis have been strongly associated
Int. J. Mol. Sci. 2019, 20, 3892; doi:10.3390/ijms20163892
www.mdpi.com/journal/ijms
Int. J. Mol. Sci. 2019, 20, 3892
2 of 19
with progressive cognitive deficiency [8], due to the downregulation of the glucose transporter GLUT1
in the brain of patients with AD [9]. Clinical studies have demonstrated an association between
a high-glycemic diet and increased cerebral amyloid deposition in mice [10–14] and humans [15],
suggesting that insulin resistance of brain tissue may contribute to the development of AD [16].
To date, there are only a few FDA approved drugs, such as acetylcholinesterase inhibitors
and memantine. Drugs that regulate the activity of the neurotransmitters and partly ameliorate
behavioral symptoms [17]. Another treatment option includes active and passive immunization,
anti-aggregation drugs, γ- and β-secretases inhibitors [18]. Currently, there is no effective treatment
to prevent the risk of AD development or modify its progress. Therefore, emerging results from
preclinical and clinical studies show that change in dietary and lifestyle modifications may have
a potential interest in the treatment of AD [19]. These recommendations include minimizing the
intake of trans fat and saturated fats, dairy products and increased consumptions of vegetables, fruits,
legumes (beans, peas, and lentils), and whole grains [19,20]. Moreover, various dietary patterns are
suggested in order to reduce the neuropathological hallmarks of AD, including ketogenic diet (KD),
caloric restriction (CR), the Mediterranean diet (MedDi), Dietary Approaches to Stop Hypertension
(DASH), and Mediterranean-DASH diet Intervention for Neurological Delay (MIND) [20].
The ketogenic diet was initially established in the 1920s to be used in refractory epilepsy
therapy [21,22]. To date, there are pieces of evidence showing that it has gained interest as a potential
therapy for neurodegenerative disorders, such as AD [10,23], Parkinson’s disease [24], amyotrophic
lateral sclerosis [25], and insulin resistance in type 2 diabetes [26]. Moreover, because of altered
glucose metabolism, it may have anti-tumor effects, as well as, for example, in glaucoma [27], or gastric
cancer [28]. Despite the growing number of evidence that dietary treatment works, the exact mechanism
of its protective activity remains unknown.
This review summarizes the experimental and clinical data, which suggest that the ketogenic diet
could be a potential therapy option for AD, due to its neuroprotective properties.
2. Etiopathogenesis of Alzheimer’s Disease
The etiology of AD remains not fully explained, but both genetic and environmental risk
factors have been proposed to be involved. Thus, the etiopathogenesis of AD has been linked to
hypometabolism [29,30], mitochondrial dysfunction [31], inflammation [32,33], and oxidative stress [21].
Some more cellular events associated with AD neuropathogenesis include impairment of calcium
homeostasis and disturbed autophagy [32]. On the brain tissue level, neurons loss, brain atrophy,
and cerebral amyloid angiopathy have to be mentioned [32]. In addition, the systems-level characteristic
for AD involves the blood-brain barrier (BBB) abnormalities, brain arteries atherosclerosis, and brain
hypoperfusion [32]. Moreover, genome-wide association studies (GWAS) have revealed that more
than 20 genetic loci may be implicated with the risk of AD development [34]. The primary gene is the
apolipoprotein E (ApoE), and the epsilon 4 (E4) variant of ApoE was found to increase the risk for AD
generation [34]. Insulin resistance and type 2 diabetes mellitus are the essential risk factors of AD [3].
The neuropathological features of the AD brain include extracellular diffuse and senile amyloid
plaques and intracellular neurofibrillary tangles. Amyloid plaques contain amyloid β peptides
consisting of 38 to 43 amino acids generated by cleavage of neuronal cell membrane glycoprotein
(APP) by β- and γ-secretases [32]. The main isoforms of Aβ have been distinguished: Aβ1-40
(90%) and Aβ1-42 (10%) [35]. β-secretase by cleaving the extracellular domain of APP and releasing
the soluble N-terminal of APP into the extracellular space initiates the amyloidogenic pathway.
Subsequently, the C-terminal of APP is cleaved by γ-secretase eventually yielding Aβ and APP
intracellular domain (AICD) [35]. As a matter of fact, the non-amyloidogenic processing does not
result in the production of Aβ, due to the cleavage of APP by α-secretase, leading to the release into
the extracellular space of a soluble neuroprotective protein—sAPPα. Finally, γ-secretase cleaves the
remaining the C-terminal fragment C83, yielding P3 and AICD. The increase in the concentration of
Aβ leads to neurotoxicity and neurons loss. Interestingly, Aβ at brain lower concentrations seems
Int. J. Mol. Sci. 2019, 20, 3892
3 of 19
to promote neurogenesis and plasticity, exert neurotrophic functions, influence calcium homeostasis,
antioxidative processes, and redox sequestration of metal ions. Elevated generation of Aβ accompanied
by its reduced clearance clearly results in the accumulation of Aβ and its subsequent neurotoxicity.
The accumulated Aβ1-42 can undergo aggregation, which eventually leads to the formation of insoluble
oligomers and fibrillary arrangement, the final step being senile amyloid plaques [36].
NFTs are composed of abnormally hyperphosphorylated tau protein, located within neurons [36].
The assembly and stabilization of microtubules requires tau protein, being crucial for cytoskeleton
and transport of vesicles and organelles along the axons. Moreover, they play a role in the regulation
of synaptic plasticity and synaptic function [37]. Under physiologic conditions, phosphorylation
of tau protein by kinases is balanced by dephosphorylation by phosphatases, but the change in
structure is observed when tau protein is hyperphosphorylated. The development of paired helical
filaments (PHFs) and/or NFTs, causing destabilization of microtubules, as well as synaptic and neuronal
injury [36].
3. Ketogenic Diet
The ketogenic diet assumes a very high-fat and low-carbohydrate diet, reducing carbohydrate to
≤10% of consumed energy. This restriction triggers a systemic shift from glucose metabolism toward
the metabolism of fatty acids (FAs) yielding ketone bodies (KBs), such as acetoacetate (AcAc) and
β-hydroxybutyrate (β-OHB) as substrates for energy [38]. Approximately 20% of basal metabolism for
the adult brain is provided by the oxidation of 100–120 g of glucose over 24 h [39]. The KD provides
sufficient protein for growth and development, but insufficient amounts of carbohydrates for the
metabolic requirements [40]. Thus, energy is mostly derived from fat delivered in the diet and by the
utilization of body fat [40]. The ketogenic diet is a biochemical model of fasting [41], which promotes
organs to utilize KBs as the dominant fuel source to replace glucose for the central nervous system
(CNS) [42].
Within hours of starting the diet, changes in plasma KBs, glucose, insulin, glucagon, and FAs
levels are observed [43], which results in a drop in blood glucose concentration, as well as the
insulin-to-glucagon ratio. An increased glucagon concentration is associated with the mobilization
of glucose from its liver resources. Thus, the inhibition of glycogenesis and glucose reserves become
insufficient for the fat oxidation process [44]. After 2–3 days of fasting, the primary source of energy
is KBs, produced in the mitochondrial matrix of hepatocytes [45]. The higher level of KBs in the
blood and their elimination via urine cause ketonemia and ketonuria [45]. Under physiological
conditions, the blood concentration of KBs ranges from <0.3 mM, compared to glucose concentration
~4 mM, to 6 mM during prolonged fasting [46]. When KBs achieve concentrations above 4 mM,
they become a source of energy for the CNS. In diabetic ketoacidosis, KBs may reach the level of
25 mM [39], resulting from an insulin deficiency with an increased glucose concentration (>300 mg/dL)
and decreased blood pH (pH < 7.3), which may cause the death of the patient [45].
The KD allows ~90% of total calorie income from fat and much lower from protein (6%) and
carbohydrate (4%) [21]. This may be achieved, due to a macronutrient ratio of 4:1 (4 g fat to every 1 g
protein and carbohydrates) [21]. Thus, it includes replacing carbohydrates by fats in daily meals [41].
The most common KD form contains mainly long-chain fatty acids, although KD requires changes
in eating habits, which is challenging to maintain, especially from a long-term perspective [44].
Therefore, a new form of KD was proposed. A diet based on medium-chain triglycerides (MCT) leads
to similar effects by increasing the concentration of KBs in the blood, even if carbohydrates were
present in the diet [44,47]. Another version of KD is the Atkins diet, in which carbohydrates are limited
to 5% of energy in the diet [44].
As already mentioned, due to the restriction of glucose metabolism, KD requires to obtain energy
from FAs of adipose tissue. Remarkably, the brain, due to its reduced ability to utilize FAs as an
energy source, has to use KBs instead. KBs, through the mitochondrial β-oxidation of FAs yielding
acetyl-CoA, are synthesized in the liver [7,48]. Some acetyl-CoA molecules remaining may be utilized
Int. J. Mol. Sci. 2019, 20, 3892
4 of 19
in the Krebs cycle or to produce AcAc, further being converted spontaneously to acetone or β-OHB by
β-OHB dehydrogenase (BDH) [7,48–50]. Later on, KBs enter the bloodstream and are available for
brain, muscle, and heart, where they generate energy for cells in mitochondria [51]. β-OHB and AcAc
can cross the BBB through proton-linked, monocarboxylic acid transporters, and provide an alternative
substrate for the brain. Their expression is related to the level of ketosis [52]. During the long period of
starvation, KBs may provide up to 70% of cerebral energy requirements [46]. When KBs are present at
sufficient concentrations,
they can maintain the basal
or β OHB by β
– (non-signaling) neuronal energy needs and up to
~50% of the activity-dependent oxidative neuronal requirements [53].
β
Research
studies evoked that KBs provide a more efficient energy source compared to glucose.
They are metabolized faster than glucose and are able to bypass the glycolytic pathway by directly
entering the Krebs cycle, whereas glucose needs to undergo glycolysis [7,46,54]. Because it leads to
fatty acid-mediated activation of peroxisome proliferator-activated receptor α (PPARα), the glycolysis
and FA are inhibited [50,55]. Thus, KBs reduce glycolytic ATP production and elevate ATP generation
by mitochondrial oxidation [50], which enhances oxidative mitochondrial metabolism resulting in
beneficial downstream metabolic changes. It includes the ketosis, higher serum fat levels, and lower
activated loss
receptor
α (PPARα), and
the necrosis.
serum glucose levels contributing to protection against neuronal
by apoptosis
Bough et al. [56] found that KD modulates the upregulation of hippocampal genes, which encode
mitochondrial and energy metabolism enzymes [56]. Consequently, therapeutic ketosis can be
considered as a form of metabolic therapy by providing alternative energy substrates. Through these
metabolic changes, brain metabolism is improved, and ATP production in mitochondria is restored.
Moreover, decreased reactive oxygen species (ROS) production, antioxidant effects, lower inflammatory
response, and increased activity of neurotrophic factors are observed [7]. Another impact includes
stabilization of the synaptic activity between neurons through increased levels of Krebs cycle
intermediates, increased GABA-to-glutamate ratio, and activation of ATP-sensitive potassium
channels [7]. Probable mechanisms underlying the beneficial influence of KD on AD development are
presented in Figure 1.
Alzheimer’s
disease
Figure 1. Hypothesized mechanisms through which ketogenic diet (KD) influence
Alzheimer’s
disease
↓—
↑—
(AD) development. ↓—decreased; ↑—increased. Based on Reference [7].
Int. J. Mol. Sci. 2019, 20, 3892
5 of 19
3.1. The Impact of the Ketogenic Diet on Amyloid and Tau Protein
Defects in mitochondrial and respiratory chain function may alter APP processing, resulting in
production neurotoxic Aβ [57]. The ketogenic diet could alleviate the effects of impaired
glucose metabolism [8,58] by providing ketones as alternative metabolic substrates for the brain.
Besides, this diet may help to reduce the deposition of amyloid plaques by reversing the Aβ(1–42)
toxicity [58,59]. Studies suggest that KD may affect neuropathological and biochemical changes
observed in AD. Rodents treated with the KD, exogenous β-OHB, and MCT display reduced brain
Aβ levels, protection from amyloid-β toxicity, and improved mitochondrial function [10,30]. In the
transgenic mice model of AD, it was observed that KD made soluble Aβ deposits level in their brain 25%
less after only 40 days [60]. Also, in humans, this process may be determined by the presence or absence
of the ApoE4 genotype; however, the presence of which is a risk factor for AD development [23,47].
Evidently, AD neuropathology is associated with aberrant hyperphosphorylation of tau protein.
Mitochondrial dysfunction and decreased neuronal and glial mitochondrial metabolism follow in
older people. The mitochondrial dysfunction results in diminished energy generation from the
oxidation of glucose/pyruvate, and it can also increase Aβ accumulation and tau protein dysfunction.
Consequently, the abnormal mitochondria could be characterized by an increased superoxide generation
with subsequent oxidative injury, a decrease in oxidative phosphorylation, and finally resulting
impairment of the mitochondrial electron transport chain [61].
3.2. The Impact of the Ketogenic Diet on Inflammation
Inflammation and oxidative stress are two essential factors recognized in the neuropathology
of AD, underlying neurotoxic mechanisms leading to neuronal loss, which is present in the brain
regions responsible for memory and cognitive processes [21,62]. It involves releasing proinflammatory
cytokines, NO, and inhibition of neurotrophins, resulting in damage to surrounding tissues [62].
Because a great proportion of cells in the immune system (e.g., macrophages or monocytes) express
abundant GPR109A, KD may actually affect neuroinflammatory mechanisms [63]. GPR109A, which was
found in the brain tissue is, in fact, a G protein-coupled receptor known as hydroxy-carboxylic acid
receptor 2 (HCA2) [63]. Moreover, the β-OHB may directly bind to HCA2, which is expressed on
microglia [63], dendritic cells, and macrophages [64]. Its activation induces the neuroprotective subset
of macrophages, which depend on PGD2 production by COX1 [64]. Consequently, neuroinflammation
is reduced [63].
KD has also been proved to exert effects on inflammatory processes [65] by inhibiting the
activation of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB). It results
in the downregulation of COX2, and inducible nitric oxide synthase expression, associated with
increased immune response [55]. Moreover, the activity of cytokines, such as IL-1b, IL-6, CCL2/MCP-1,
TNF-α, is diminished [66]. Besides, peroxisome proliferator-activated receptor γ (PPARγ) can reduce
the expression of NF-kB, therefore alleviating the neuronal damage caused by excitotoxicity of
N-methyl-D-aspartate (NMDA) [67,68].
Moreover, the KD diet influences the anti-inflammatory action via activation of microglial
cells [69], pro-apoptotic properties, and elevated concentrations of neuroprotective mediators,
including neurotrophins {neurotrophin-3 (NT-3), brain-derived neurotrophic factor (BDNF) and
glial cell line-derived neurotrophic factor (GDNF)}, and molecular chaperones (proteins preventing
aggregation of polypeptides into potentially toxic molecules) [44,70].
Another mechanism of KD is the inhibition of histone deacetylases (HDACs), which play a role in
altering chromatin structure, and accessibility [21]. β-OHB inhibits HDACs 1, 3, and 4 (class I and IIa)
in vitro, leading to memory function improvement and synaptic plasticity [56,71]. Besides, ketones are
able to inhibit the innate immune sensor NOD-like receptor 3 (NLRP3) inflammasome, which controls
the activation of caspase-1, and the release of proinflammatory cytokines, such as IL-1β and IL-18 by
limiting the K+ efflux from cells [42,50,72].
Int. J. Mol. Sci. 2019, 20, 3892
6 of 19
Also, it has been observed that β-OHB may revert the increased expression of inflammatory
cytokines [73]. Lee et al. [74] have observed an elevated expression of cytokine interferon
γ in the hippocampus of rats, which leads to protecting cells against excitotoxicity [74].
Ultimately, reducing inflammation could be one of the most crucial AD modifying effects of a KD.
3.3. The Impact of the Ketogenic Diet on Dementia
The main symptom of some neurodegenerative disorders is dementia, and it includes thinking
difficulties, loss of memory, and obstacles in problem-solving. Progressive impairment of cognitive
functions in AD patients was associated with a reduction in glucose uptake and metabolism [8],
especially if genetic risk factors for AD or positive family history are present. Another possible
mechanism is that lower glucose uptake in the brain may contribute to the development of AD
neuropathology [45]. The study of Vanitallie [75] shows that an early disturbance in brain glucose
metabolism can be detected before any measurable cognitive decline [75]. Moreover, it correlates
with the downregulation of glucose transporter GLUT1 in people with AD [76]. It is observed
that a high-glycemic diet is associated with increased insulin resistance and a higher risk of AD
development [15]. Few studies have demonstrated that supplementation with MCT and KD improves
cognitive performance [23,47,77–82].
The hypometabolism in brain tissue has been referred to indicate a risk for the development of
dementia in the future [83], following chronic brain energy deprivation, then impairment of neuronal
function, and in later stages decline in glucose demand along with the progression difficulties of
cognitive performance [84]. In addition, progressive dementia was correlated with reduced blood flow
and oxygen consumption in the brain [84].
The altered glucose metabolism and mitochondrial function may result from the accumulation
of advanced glycation end products (AGEs) [85]. Although the presence of AGEs in cells and
tissues is a characteristic feature of the aging process, it may be enhanced in AD pathology.
Also, AGEs molecules can be found in amyloid plaques and neurofibrillary tangles resulting from
oxidative stress, protein crosslinking, and neurons cell loss. To sum up, the reduced glycemia could
advance these pathophysiological features in AD [45].
3.4. The Impact of the Ketogenic Diet on Neurodegeneration
AD is associated with energy imbalance caused by impaired glucose transport and metabolism
and mitochondrial dysfunction. Energy deficiency may be observed in different brain structures,
especially in the hippocampus [29]. Within the AD neuropathology, there is a shift in brain metabolism,
which results in diminished cerebral glucose utilization [86]. On the other hand, increased ketogenesis
is observed during the aging process [86].
Mitochondrial dysfunction and oxidative stress play a significant role in neurodegeneration.
Both processes are known to generate higher concentrations of ROS, which are harmful to all
cellular macromolecules, including nucleic acid, lipid, and protein damage [87]. Therefore, KD may
provide neuroprotective benefit by improving mitochondrial function through biochemical changes
resulting from glycolysis inhibition and increased KBs formation. It is observed that metabolic
ketosis may decrease ROS production improving mitochondrial respiration and bypassing complex 1
dysfunction [48].
Moreover, KD modulates the ratio between the oxidized and reduced forms of nicotinamide
adenine dinucleotide (NAD+/NADH). An increased NAD+/NADH ratio plays a role in protection
against ROS and improves redox reactions, mitochondrial biogenesis, and cellular respiration,
which stabilizes synaptic action [56,88]. A significant increase in the NAD+/NADH ratio was
found in the brain cortex and hippocampus of KD-fed rats after two days [54]. After all, it induces the
gene expression via sirtuin 1 (SIRT1), a type 3 histone deacetylase [89], involved in different processes
related to deacetylating histone and non-histone targets [21,90]. Also, SIRT1 may limit the oxidative
stress by improving the synthesis of heat shock proteins [91], promoting DNA repairing activity of
Int. J. Mol. Sci. 2019, 20, 3892
7 of 19
forkhead transcription factor (FOXO) and protein p53 [92], and deacetylation of nuclear factor erythroid
2-related factor 2 (Nrf2), the primary inducer of detoxification genes [93]. In addition, the increased
activation of Nrf2 results from the increased production of hydrogen peroxide in the mitochondria,
and elevated level of lipid peroxidation product—4-hydroxy-2-nonenal (4-HNE) [94]. In addition,
Nrf2 is capable of inducing glutathione reductase, peroxiredoxin and thioredoxin, the primary enzymes
responsible for the regeneration of the active form of endogenous antioxidant agents [95], followed by
the expression of heme oxygenase-1 (HO-1), an antioxidant protein considered to be one of the key
molecules in neuroprotection against oxidative stress [67].
Therefore, KD increases the efficiency of the electron transport chain through the increased
expression of uncoupling proteins (UCP), and their activity in the hippocampus [96] by blocking
voltage-gated sodium and calcium channels, and regulates the membrane receptors in neurons [97].
Thus, mitochondrial energy reserves may be increased [70,96]. UCP moderates the mitochondrial
membrane potential and declines the production of ROS and reactive nitrogen species (RNS) [98].
Moreover, KD increases levels of superoxide dismutase 2 (SOD2), mitochondrial mass,
and regulators, such as SIRT1 and mitochondrial fission 1 protein (FIS1); thus, appears to upregulate
γ-aminobutyric acid (GABA) A receptor subunits α1, and downregulate NMDA receptor subunits
NR2A/B [87].
In addition, KBs may regulate the homeostatic status of mitochondria by changing the
calcium-induced membrane permeability transition (mPT) and inhibit opening the pores [42,99].
Also, the selected polyunsaturated fatty acids (PUFAs), such as eicosapentaenoic acid, arachidonic
acid, or docosahexaenoic acid may promote excitability of neuron-cell membranes by suppressed
ROS production, decreased inflammatory mediators, and blocking voltage-gated sodium and calcium
channels [100]. In addition, KD increases glutathione levels and glutathione peroxidase (GSH-Px)
activity in the hippocampus [101], which is the main enzyme affecting the formation of ROS [97].
The potential mechanism of action may be through modulation of intracellular signaling
pathways, including the mammalian target of rapamycin (mTOR). Studies show that KD decreases
insulin levels and reduces the phosphorylation of Akt and S6, which results in diminished mTOR
activation [42,102]. KD also leads to elevated brain ATP and phosphocreatine concentrations,
and stimulates mitochondrial biogenesis, which may be interpreted in terms of enhanced metabolic
efficiency [56]. Finally, neuronal cells can be considered to have improved resistance and adaptability
to stress and metabolic challenges [50,56].
3.5. Adverse Effects of the Ketogenic Diet
Data on the adverse effects of KD administration is limited in the adult population, but some
effects are predictable, such as hypoglycemia and dehydration. Other side effects are less common and
present following long-term treatment.
Previously, KBs were considered toxic resulting from the association of therapeutic ketosis with
diabetic ketoacidosis, which results in ketone concentrations higher than 20 mM, which can be reversed
with insulin administration [103]. Hyperketonemia resulting from insulin deficiency, in severe cases,
may lead to severe acidosis, and even death of the individuals [45,104].
The adverse effects frequently reported by patients with epilepsy on KD are gastrointestinal
effects, weight loss, and transient hyperlipidemia [42]. Gastrointestinal side effects can include
constipation, nausea, vomiting, and lower appetite [42,105]. Weight loss may be a welcomed effect,
especially in an obese patient, but it should be regulated and monitored. In addition, the change in
lipid profile, such as fasting total serum cholesterol, triglycerides, and low-density lipoprotein (LDL)
cholesterol is increased at the beginning of the KD treatment then it normalizes (after ~1 year) [106].
Moreover, dehydration, hepatitis, pancreatitis, hypoglycemia, hyperuricemia, hypertransaminemia,
hypomagnesemia, and hyponatremia are among the adverse effects of the KD [44,105]. On the
other hand, prolonged KD may cause enhanced atherosclerosis, cardiomyopathy, nephrolithiasis,
Int. J. Mol. Sci. 2019, 20, 3892
8 of 19
impaired hepatic functions, neuropathy of the optic nerve, anemia, reduction of mineral bone density,
and deficiencies of vitamins and mineral components [44].
Chronic KD treatment may cause disturbances in catabolism and reduced synthesis of functional
proteins (membrane proteins, enzymes, etc.). Considering the loss of appetite and lower organoleptic
attractiveness, it would be difficult to achieve an appropriate supply of protein and energy in patients
on the KD, because any energetic deficiency or insufficient protein intake may have severe consequences
for health [44,81]. Any significant adverse effects were not observed in 83 obese patients when the KD
was administered for 24 weeks [107]. Additionally, in patients with AD, KD may significantly affect
food consumption via disturbances in the senses of smell and taste, neurological symptoms, such as
apraxia, dysphagia, and behavioral disturbances during eating [44].
4. The Mechanism of Neuroprotective Action of the Ketogenic Diet
The mechanism of neuroprotective action of KD (Figure 2) remains not fully understood, but several
studies show that KBs influence neurons loss at three different levels, such as (i) metabolic level;
(ii) signaling level; (iii) epigenetic level. Numerous mechanisms have been established through
which the KD may contribute to the neuroprotective activity. The effectiveness of KD was checked in
a limited number of clinical trials. However, there are studies in vitro or in animal models assessing
the underlying biological mechanisms. The main goal of AD treatment is primary the prevention
of specific neuropathological damages, associated with amyloid plaques and neurofibrillary tangles
accumulation. Another focus of research includes brain metabolism dysregulation, neuronal signaling,
and mitochondrial homeostasis. The activity of the ketogenic diet is associated with the decrease of
the inflammatory response and the oxidative damage. Reduced blood glucose level and elevated
concentration of KBs are the main characteristic features of KD treatment.
treatment.
Figure 2. Hypothetical pathways leading to the neuroprotective action of KD (based on
—[50,108]). FA—fatty—γ
— PCr:Cr—phosphocreatine:creatine
References
acids; GABA—γ-aminobutyric acid;
—
— UCP—uncoupling proteins; increase
↑
↓ —(↓)—arrows
ratio;
ROS—reactive oxygen species;
(↑) or decrease
indicate the direction of the relationship between variables.
The effects of KBs are associated with an increased level of acetone, which may activate K2P
channels to hyperpolarize neurons and limit neuronal excitability [50,108]. Also, KBs affect the altering
metabolism of neurotransmitters, such as glutamate and GABA in the brain. Moreover, the activity
of brain-specific UCPs is increased, which reduces ROS generation by mitochondrial complex I,
modulates dysfunction of neurons, and aftereffect neurodegeneration [50,108]. Ketosis would induce
via the nuclear transcription factor PPARα and its
activated receptor γ coactivator
1α)
Int. J. Mol. Sci. 2019, 20, 3892
9 of 19
the expression of UCPs and coordinately upregulate several dozen genes related to oxidative energy
metabolism by acting via the nuclear transcription factor PPARα and its co-activator peroxisome
proliferator-activated receptor γ coactivator-1 (PGC-1α) [50,108]. Ketosis has been shown to stimulate
mitochondrial biogenesis, thus leading to increased generation of ATP and enhanced energy reserves,
which is known to stabilize synaptic activity. Probably, the elevated phosphocreatine:creatine (PCr:Cr)
energy-reserve ratio may potentiate GABAergic output, very likely associated with the ketosis-triggered
increased GABA synthesis [50,108]. During KD, the decreased glucose availability, with accompanying
elevated FAs, is suggested to reduce glycolytic flux. Consequently, it would further be feedback
inhibited by elevated concentrations of ATP and citrate formed during KD treatment. Thus, K2P channels
would be activated [50,108]. Moreover, KD involves changes in microbiome followed by involvement
of the gut-brain axis [109]. Olson et al. [109] present that KD alters the gut microbiota required for
protection against several kinds of seizures [109].
5. Preclinical and Clinical Studies
Epidemiological observations provides evidence that a diet rich in saturated fatty acids may elevate
the risk of AD [19]. Also, transgenic mice fed with a fat-rich diet may exhibit accelerated cognitive
disturbances, due to enhanced oxidative stress, systemic inflammation, and increased neuronal death,
due to apoptosis [110,111]. At the same time, the increasing number of animal studies and clinical
trials on humans show the benefits of KD treatment in AD. The summary of the preclinical and clinical
studies with their main findings is presented in Tables 1 and 2.
Table 1. Main preclinical evaluations of KD treatment in AD.
Preclinical Studies
Model
Main Findings
Ref.
• Hippocampi of juvenile mice
• Improvement of mitochondrial function
• Decreased ROS production
• Increased cerebral ATP concentrations
[96]
• KD in rats
• Reduced insulin levels
• Reduced phosphorylation of Akt and S6
• Decreased mTOR activation
[102]
• KD in rats
• Increased lipid peroxidation product
4-hydroxy-2-nonenal (4-HNE) levels
• Increased activation of Nrf2
[112]
• In vitro models
• Inhibition of histone deacetylases
(HDACs)
• Increased transcriptional activity of
PPAR-γ
[113]
• KD in the APP/V717I transgenic
mouse model of AD
• Better mitochondrial function
• Reduced oxidative stress
• Reduced Aβ deposition
[10]
• KD in the APP/PS1 mouse model
of AD
• Improvement of motor function
• Improvement in energy metabolism
• Reduced Aβ deposition
[11]
[12]
• KD in the Tg4510 mouse model
of AD
• Improvement of motor function
• Improvement in energy metabolism
• Reduced Aβ deposition
[13]
[14]
• Administration of ketone ester in
middle-aged mice (8.5 months old)
over eight months
• Improvement of cognitive function
• Ameliorated Aβ and tau protein
pathology
[30]
AD—Alzheimer’s disease; APP—amyloid precursor protein; Aβ—amyloid β-peptide; KD—ketogenic diet;
PPAR-γ—peroxisome proliferator-activated receptor γ; PS1—presenilin 1; ROS—reactive oxygen species;
β-OHB—β-hydroxybutyrate.
Int. J. Mol. Sci. 2019, 20, 3892
10 of 19
Table 2. Main clinical evaluations of KD treatment in AD.
Clinical Evaluation
Type of Study
Protocol
Main Findings
Ref.
Double-blind
placebo-controlled
trial
• 20 adult patients
with AD or MCI
• Administration of MCT
• Significant increases in β-OHB
levels moderated by ApoE4
genotype (greater for ApoE4(+)
compared to ApoE4(−))
• Improvement of memory and
cognitive function in the ADAS-cog
test compared to placebo
• Patients ApoE4(+) were less
responsive to KD compared to
ApoE4(−)
[23]
Randomized,
Double-blind,
Placebo-controlled
multicenter trial
• 152 adult patients
with mild to moderate
AD
• Administration of
AC-1202 over 90 days
• AC-1202 significantly increases
a β-OHB level resulted in
• Significant improvement in the
ADAS-cog test compared to placebo
after 45 and 90 days of treatment
• Reduced response to AC-1202 in
ApoE4(+) patients compared to
ApoE4(−)
[47]
Other clinical
study
• 23 adult patients with
MCI
• Administration of high
carbohydrate or very low
carbohydrate diet over
six weeks
• Significant improvement in verbal
memory performance for the low
carbohydrate subjects
• Reductions in weight, waist
circumference, fasting glucose,
and insulin in the low carbohydrate
group
• KBs levels positively correlated
with memory performance
[77]
Singe-patient
case study
• One adult patient with
early-onset AD
• Administration of
KME over 20 months
• Improved markedly in mood,
affect, self-care, and daily activities
• Improved cognitive performance
• KME-induced hyperketonemia
seems robust, convenient, and safe
[78]
Pilot and feasibility, randomized,
double-blind placebo-controlled
parallel trial
• Six adult patients with
MCI
• Administration of 56
g/day of MCT over 24
weeks
• Increased β-OHB levels
• Improvement of memory in mild
AD and ApoE4(−)
[79]
Prospective, open-label,
observational study
• 22 adult patients with
mild-to-moderate AD
• Administration of
a ketogenic meal
“Axona” (40 g of powder
containing
20 g of caprylic
triglycerides) over 90
days
• No improvement in cognitive
performance, even in ApoE4(−)
patients
[80]
Single-arm pilot trial
Ketogenic Diet Retention and
Feasibility Trial (KDRAFT)
• Fifteen adult patients
with mild-to-moderate
AD using an
MCT-supplemented ≥1:1
ratio KD for three
months (a very high-fat
ketogenic diet
(VHF-KD))
• Increased β-OHB levels
• Improvement in ADAS-cog in 9
out of 10 patients who completed
the study and achieved ketosis
[81]
Other clinical
study
• 19 adult patients
• Administration of
MCT-supplemented
ketogenic meal
(Ketonformula® )
containing 20 g of MCT
• Increased β-OHB levels
•Improvement of cognitive
performance
• Positive effects on visual attention,
working memory, and performing
tasks in non-demented patients
[82]
Double-blinded,
placebo-controlled, randomized
clinical trial
• 16 adult patients with
mild-to-moderate AD
• Administration of
caprylidene over 45 days
• Increased cerebral blood flow in
patients ApoE4(−)
[114]
AD—Alzheimer’s disease;
ADAS-cog—Alzheimer’s Disease Assessment Scale-Cognitive Subscale;
ApoE4—apolipoprotein E4; KBs—ketone bodies; KD—ketogenic diet; KME—ketone monoester; MCI—mild
cognitive impairment; MCT—medium-chain triglycerides; β-OHB—β-hydroxybutyrate.
Int. J. Mol. Sci. 2019, 20, 3892
11 of 19
5.1. Preclinical Studies
In the transgenic model of AD, mice fed with a KD exhibited better mitochondrial function,
decreased Aβ accumulation, and oxidative stress when compared to healthy controls [10].
Auwera et al. [10] reported that KD low in carbohydrates and rich in saturated fats reduced the
level of Aβ in transgenic mice, expressing a human APP gene with London mutation (APP/V717I).
This particular mutation results in significant levels of soluble brain Aβ (as early as three months
of age) and extensive plaque formation by 12–14 months [10,115]. Moreover, in transgenic mouse
models, high-fat diets increase the deposition of Aβ peptides [116,117]. Exposure to a KD for 43 days
resulted in a 25% reduction in soluble Aβ(1–40) and Aβ(1–42) in brain homogenates, but did not affect
performance on the object recognition task [10]. Another study in young, healthy mice shows that KD
may influence the brain vascular function, improve metabolic profile (decreased blood glucose and
increased KBs levels), and alter the gut microbiome [118].
Various mouse models of AD (APP/PS1, mouse models of Aβ deposition, carrying mutations
in APP and/or presenilin 1, and Tg4510, mouse model as a model of tau deposition) under KD
(low carbohydrate, MCT-rich diet) had elevated KBs level and reduced glucose levels in the
bloodstream [11,12]. In this study, any reduction in Aβ or tau protein accumulation was not
observed; however, an improved motor performance on the Rotarod apparatus was present [11,12].
Kashiwaya et al. [30] demonstrated that long-term (8 months) feeding of a ketone ester in middle-aged
mice (8.5 months old) improved their cognition and ameliorated Aβ and tau protein pathology [30].
KD may mitigate apoptosis by inhibition of kainic acid-induced accumulation of the protein clusterin,
thought to influence apoptotic signaling [59]. Moreover, KD and β-OHB administration may protect
dopaminergic neurons from degeneration [59].
In aged rats, the administration of KD for over three weeks improved learning skills and memory.
It was associated with increased angiogenesis and capillary density suggesting that KD may support
cognition through improved vascular function [119]. Moreover, pretreatment with MCT showed
reduced Aβ deposition in rat cortical neurons affecting glucose metabolism via activation of signaling
pathways [120]. Study on senile dogs also indicates that the MCT diet may improve mitochondrial
function by control of the oxidation process, and decrease Aβ concentration in the brain [121].
5.2. Clinical Studies
In the first randomized controlled trial, 20 patients with MCI or AD received a single oral dose
of MCT [23]. Reger et al. [23] found that the acute administration of MCT improves memory in AD
patients [23]. Further, the degree of memory performance was positively correlated with a β-OHB
concentration in plasma, produced by oxidation of the MCT. AD patients have been demonstrated to
possess defects in brain glucose metabolism, which may be caused by neurotoxic Aβs or disturbed lipid
homeostasis [9]. Moreover, the apolipoprotein E4 (ApoE4) genotype has an impact on the outcome of the
KD treatment. Patients without ApoE4(−) allele exhibited improved short-term cognitive performance
on a screening tool of memory, language, attention, and praxis [23]. Moreover, the cognitive effects
of long-term elevation of β-OHB concentrations may speak for the feasibility and efficacy of MCT as
a novel treatment strategy [23].
Reger et al. [23] and Henderson et al. [47] compared the influence of an MCT on memory and
cognition in double-blind trials controlled with placebo. Both trials clearly indicated that elevated
serum β-OHB levels caused improvements in cognitive function and memory. Further sub-analysis in
the evaluated cohorts was carried out to assess for the ApoE4 status of the patients. ApoE4(+) patients
have a mutation associated with an increased risk of AD development. In both studies, ApoE4(+) was
associated with a reduced response to KD.
Besides, Krikorian et al. [77] compared a low carbohydrate diet with a high carbohydrate diet
in 23 adult patients with MCI treated for over six weeks. The low carbohydrate diet showed better
verbal memory performance, positively correlated with KBs levels in the carbohydrate-restricted group.
Nevertheless, no significant difference in cognitive function between the groups was evident [77].
Int. J. Mol. Sci. 2019, 20, 3892
12 of 19
The authors conclude that even short-term use of a low-carbohydrate diet could have a beneficial
impact on memory function in older adults with an increased risk for AD. However, the mechanism
could be associated with reduced inflammation and enhanced energy metabolism.
In the case study by Newport et al. [78], effects on cognitive functions were evaluated in an adult
AD patient using ketone monoester (R)-3-hydroxybutyl-(R)-3-hydroxybutyrate supplementation for
20 months to stimulate ketosis [78]. Actually, the patient was improved in terms of mood, affect, self-care,
cognitive, and daily activity performance [78]. Another three studies were performed in patients with
MCI or mild to moderate AD. Using at least three-month treatment protocols (two randomized studies
of MCT or a ketogenic product compared to placebo for three to six months and one observational
study administering KD over three months), it was reported that the cognitive benefit of KD treatment
was highest in ApoE4(−) patients [79]. In the observational study, it was limited to ApoE4(−) patients
with mild AD [80]. These clinical studies propose that KD may improve cognitive function in patients
with AD by inducing metabolic ketosis. However, the ApoE4(+) genotype and the degree of disease
progression have an impact on body response to metabolic ketosis.
In addition, increased ketone intake, as shown by imaging of PET 11C acetoacetate in the
brain before and after treatment, was evident in patients with mild to moderate AD after MCT
supplementation within one month. It can be suggested that ketones from MCT can compensate
for brain tissue glucose deficit in patients with AD [84]. The clinical evidence seems to support the
hypothesis that KDs may improve cognition in AD patients. However, data may be strictly associated
with the stage of AD, its progression, and the ApoE4 genotype, which may determine response to
dietary administration [84].
The additional study was a single-arm pilot trial in 15 patients with mild-moderate AD,
where MCT-supplemented ≥1:1 ratio KD was administered for three months. It showed cognitive
function improvement in 9 out of 10 patients who completed the study and achieved ketosis [81].
Moreover, in another study called the Ketogenic Diet Retention and Feasibility Trial, MCT-supplemented
KD was provided to 15 AD patients (~70% of energy as fat). When ketosis was achieved, the ADAS-cog
test was significantly improved during the KD [81].
In a recent study, MCT were administered to 20 Japanese patients with mild to moderate AD over
12 weeks [82]. After 120 min of intake, KBs level was increased, then after eight weeks, the patients
demonstrated significant improvement in their immediate and delayed memory tests compared to
their baseline score [82].
6. Conclusions
The perspective of the use of KD in various diseases has been growing recently. Abnormal glucose
metabolism uptake, diminished mitochondrial-associated brain energy metabolism, changes in
neurotransmitter release, and increased inflammatory response are the key pathophysiological
metabolic alterations observed in AD. Furthermore, KD may modulate a broad array of metabolic and
signaling changes underlying the pathophysiology of neurodegenerative disorders.
Based on the limited animal studies and clinical trials, KD has beneficial effects for enhancing
mitochondrial function and cellular metabolism. It is associated with improved cognitive performance
in elderly adults with AD. The improvement of the cognitive outcomes depends on the level and
duration of ketosis. The best results of KD treatment are expected in early presymptomatic stages of
AD. However, it requires a practical diagnostic approach.
The future research should explore the exact mechanism (s) of action of KD that underlie the
neurodegenerative disorders to restore abnormal glucose and energy metabolism in animal models,
as well as in patients with different diseases. Also, further studies are necessary for the long-term effects
of KD for nutritional status, general well-being, and the progress of AD in patients. However, this novel
metabolic treatment seems to be intriguing and deserves further clinical investigations in the progress
of AD.
Int. J. Mol. Sci. 2019, 20, 3892
13 of 19
Author Contributions: Conceptualization, R.P. and M.U.-K.; Methodology, M.R.; Validation, R.P. and S.J.C.;
Formal analysis, R.P., S.J.C and M.U.-K., Investigation, M.R.; Resources, M.R.; Data curation, M.R.; Writing-Original
Draft Preparation, M.R.; Review Editing, R.P., S.J.C. and M.U.-K.; Visualization, M.R. and R.P.; Supervision, R.P.;
Project Administration, R.P. and S.J.C.
Funding: This research was funded by Mossakowski Medical Research Centre –T-3 (R.P.) and Medical University
of Lublin-DS 475/19 (S.J.C.).
Conflicts of Interest: The authors declare no conflict of interest.
Abbreviations
4-HNE
AcAc
AD
LD
ADAS-cog
AGEs
AICD
ApoE4
APP
Aβ
BBB
BDH
CNS
CR
DASH
FAs
FIS1
FOXO
GABA
GSH-Px
GWAS
HDACs
HO-1
KBs
KD
LDL
MCI
MCT
MedDi
MIND
mPT
mTOR
NF-kB
NFTs
NLRP3
NMDA
Nrf2
PCr:Cr
PGC-1α
PHFs
PPARα
PPARγ
PUFAs
ROS
SIRT1
SOD2
UCP
β-OHB
4-hydroxy-2-nonenal
acetoacetate
Alzheimer’s disease
linear dichroism
Alzheimer’s Disease Assessment Scale-Cognitive Subscale
advanced glycation end products
APP intracellular domain
apolipoprotein E4
amyloid precursor protein
amyloid β-peptide
blood-brain barrier
β-OHB dehydrogenase
central nervous system
caloric restriction
Dietary Approaches to Stop Hypertension
fatty acids
fission 1 protein (FIS1)
forkhead transcription factor
γ-aminobutyric acid
glutathione peroxidase
genome-wide association studies
histone deacetylases
heme oxygenase-1 (HO-1)
ketone bodies
ketogenic diet
low-density lipoprotein cholesterol
mild cognitive impairment
medium-chain triglycerides
Mediterranean diet
Mediterranean-DASH diet Intervention for Neurological Delay
membrane permeability transition
mammalian target of rapamycin
nuclear factor kappa-light-chain-enhancer of activated B cells
neurofibrillary tangles
NOD-like receptor 3 inflammasome
N-methyl-D-aspartate
nuclear factor erythroid 2-related factor 2
phosphocreatine: Creatine ratio
peroxisome proliferator-activated receptor γ coactivator-1
paired helical filaments
peroxisome proliferator-activated receptor α
peroxisome proliferator-activated receptor γ
polyunsaturated fatty acids
reactive oxygen species
sirtuin 1
superoxide dismutase 2
uncoupling proteins
β-hydroxybutyrate
Int. J. Mol. Sci. 2019, 20, 3892
14 of 19
References
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
Patterson, C. The World Alzheimer Report 2018: The State of the Art of Dementia Research: New Frontiers;
Alzheimer’s Disease International (ADI): London, UK, September 2018; Available online: https://www.alz.co.
uk/research/world-report-2018 (accessed on 5 August 2019).
Kelley, B.J.; Petersen, R.C. Alzheimer’s disease and mild cognitive impairment. Neurol. Clin. 2007, 25, 577–609.
[CrossRef]
Lange, K.W.; Lange, K.M.; Makulska-Gertruda, E.; Nakamura, Y.; Reissmann, A.; Kanaya, S.; Hauser, J.
Ketogenic diets and Alzheimer’s disease. Food Sci. Hum. Wellness 2017, 6, 1–9. [CrossRef]
Serrano-Pozo, A.; Frosch, M.P.; Masliah, E.; Hyman, B.T. Neuropathological alterations in Alzheimer disease.
Cold Spring Harb. Perspect. Med. 2011, 1, a006189. [CrossRef] [PubMed]
Swerdlow, R.H. Brain aging, Alzheimer’s disease, and mitochondria. Biochim. Biophys. Acta 2011, 1812, 1630–1639.
[CrossRef] [PubMed]
Wilkins, H.M.; Swerdlow, R.H. Amyloid precursor protein processing and bioenergetics. Brain Res. Bull.
2017, 133, 71–79. [CrossRef] [PubMed]
McDonald, T.J.W.; Cervenka, M.C. The expanding role of ketogenic diets in adult neurological disorders.
Brain Sci. 2018, 8, 148. [CrossRef] [PubMed]
Castellano, C.A.; Nugent, S.; Paquet, N.; Tremblay, S.; Bocti, C.; Lacombe, G.; Imbeault, H.; Turcotte, E.;
Fulop, T.; Cunnane, S.C. Lower brain 18F-fluorodeoxyglucose uptake but normal 11C-acetoacetate metabolism
in mild Alzheimer’s disease dementia. J. Alzheimer’s Dis. 2015, 43, 1343–1353. [CrossRef] [PubMed]
Koppel, S.J.; Swerdlow, R.H. Neuroketotherapeutics: A modern review of a century-old therapy.
Neurochem. Int. 2018, 117, 114–125. [CrossRef]
Van der Auwera, I.; Wera, S.; Van Leuven, F.; Henderson, S.T. A ketogenic diet reduces amyloid beta 40 and
42 in a mouse model of Alzheimer’s disease. Nutr. Metab. (Lond). 2005, 2, 28. [CrossRef]
Beckett, T.L.; Studzinski, C.M.; Keller, J.N.; Paul Murphy, M.; Niedowicz, D.M. A ketogenic diet improves
motor performance but does not affect beta-amyloid levels in a mouse model of Alzheimer’s disease.
Brain Res. 2013, 1505, 61–67.
Brownlow, M.L.; Benner, L.; D’Agostino, D.; Gordon, M.N.; Morgan, D. Ketogenic diet improves motor
performance but not cognition in two mouse models of Alzheimer’s pathology. Plos ONE 2013, 8, e75713.
[CrossRef] [PubMed]
Zhang, J.; Cao, Q.; Li, S.; Lu, X.; Zhao, Y.; Guan, J.S.; Chen, J.C.; Wu, Q.; Chen, G.Q. 3-Hydroxybutyrate methyl
ester as a potential drug against Alzheimer’s disease via mitochondria protection mechanism. Biomaterials
2013, 34, 7552–7562. [CrossRef] [PubMed]
Pawlosky, R.J.; Kemper, M.F.; Kashiwaya, Y.; King, M.T.; Mattson, M.P.; Veech, R.L. Effects of a dietary ketone
ester on hippocampal glycolytic and tricarboxylic acid cycle intermediates and amino acids in a 3xTgAD
mouse model of Alzheimer’s disease. J. Neurochem. 2017, 141, 195–207. [CrossRef] [PubMed]
Taylor, M.K.; Sullivan, D.K.; Swerdlow, R.H.; Vidoni, E.D.; Morris, J.K.; Mahnken, J.D.; Burns, J.M. A
high-glycemic diet is associated with cerebral amyloid burden in cognitively normal older adults. Am. J.
Clin. Nutr. 2017, 106, 1463–1470. [CrossRef] [PubMed]
de la Monte, S.M. Insulin resistance and neurodegeneration: Progress towards the development of new
therapeutics for Alzheimer’s disease. Drugs 2017, 77, 47–65. [CrossRef] [PubMed]
Raina, P.; Santaguida, P.; Ismaila, A.; Patterson, C.; Cowan, D.; Levine, M.; Booker, L.; Oremus, M.
Effectiveness of cholinesterase inhibitors and memantine for treating dementia: Evidence review for a clinical
practice guideline. Ann. Intern. Med. 2008, 148, 379–397. [CrossRef] [PubMed]
Scheltens, P.; Blennow, K.; Breteler, M.M.B.; de Strooper, B.; Frisoni, G.B.; Salloway, S.; van der Flier, W.M.
Alzheimer’s disease. Lancet 2016, 388, 505–517. [CrossRef]
Barnard, N.D.; Bush, A.I.; Ceccarelli, A.; Cooper, J.; de Jager, C.A.; Erickson, K.I.; Fraser, G.; Kesler, S.;
Levin, S.M.; Lucey, B.; et al. Dietary and lifestyle guidelines for the prevention of Alzheimer’s disease.
Neurobiol. Aging 2014, 35, S74–S78. [CrossRef]
Omar, S.H. Mediterranean and MIND diets containing olive biophenols reduces the prevalence of Alzheimer’s
disease. Int. J. Mol. Sci. 2019, 20, 2797. [CrossRef]
Pinto, A.; Bonucci, A.; Maggi, E.; Corsi, M.; Businaro, R. Anti-oxidant and anti-inflammatory activity of ketogenic
diet: New perspectives for neuroprotection in Alzheimer’s disease. Antioxid. (BaselSwitz. ) 2018, 7, 63. [CrossRef]
Int. J. Mol. Sci. 2019, 20, 3892
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
41.
42.
43.
15 of 19
Huttenlocher, P.R. Ketonemia and seizures: Metabolic and anticonvulsant effects of two ketogenic diets in
childhood epilepsy. Pediatr. Res. 1976, 10, 536–540. [CrossRef] [PubMed]
Reger, M.A.; Henderson, S.T.; Hale, C.; Cholerton, B.; Baker, L.D.; Watson, G.S.; Hyde, K.; Chapman, D.; Craft, S.
Effects of beta-hydroxybutyrate on cognition in memory-impaired adults. Neurobiol. Aging 2004, 25, 311–314.
[CrossRef]
VanItallie, T.B.; Nonas, C.; Di Rocco, A.; Boyar, K.; Hyams, K.; Heymsfield, S.B. Treatment of Parkinson
disease with diet-induced hyperketonemia: A feasibility study. Neurology 2005, 64, 728–730. [CrossRef]
[PubMed]
Zhao, Z.; Lange, D.J.; Voustianiouk, A.; MacGrogan, D.; Ho, L.; Suh, J.; Humala, N.; Thiyagarajan, M.;
Wang, J.; Pasinetti, G.M. A ketogenic diet as a potential novel therapeutic intervention in amyotrophic lateral
sclerosis. BMC Neurosci. 2006, 7, 29.
Augustin, K.; Khabbush, A.; Williams, S.; Eaton, S.; Orford, M.; Cross, J.H.; Heales, S.J.R.; Walker, M.C.;
Williams, R.S.B. Mechanisms of action for the medium-chain triglyceride ketogenic diet in neurological and
metabolic disorders. Lancet Neurol. 2018, 17, 84–93. [CrossRef]
Zarnowski, T.; Tulidowicz-Bielak, M.; Kosior-Jarecka, E.; Zarnowska, I.A.; Turski, W.; Gasior, M. A ketogenic
diet may offer neuroprotection in glaucoma and mitochondrial diseases of the optic nerve. Med. Hypothesis
Discov. Innov. Ophthalmol. J. 2012, 1, 45–49.
Otto, C.; Kaemmerer, U.; Illert, B.; Muehling, B.; Pfetzer, N.; Wittig, R.; Voelker, H.U.; Thiede, A.; Coy, J.F.
Growth of human gastric cancer cells in nude mice is delayed by a ketogenic diet supplemented with
omega-3 fatty acids and medium-chain triglycerides. Bmc Cancer 2008, 8, 122. [CrossRef] [PubMed]
Costantini, L.C.; Barr, L.J.; Vogel, J.L.; Henderson, S.T. Hypometabolism as a therapeutic target in Alzheimer’s
disease. BMC Neurosci. 2008, 9 (Suppl. 2), S16. [CrossRef]
Kashiwaya, Y.; Bergman, C.; Lee, J.H.; Wan, R.; King, M.T.; Mughal, M.R.; Okun, E.; Clarke, K.; Mattson, M.P.;
Veech, R.L. A ketone ester diet exhibits anxiolytic and cognition-sparing properties, and lessens amyloid and
tau pathologies in a mouse model of Alzheimer’s disease. Neurobiol. Aging 2013, 34, 1530–1539. [CrossRef]
Johri, A.; Beal, M.F. Mitochondrial dysfunction in neurodegenerative diseases. J. Pharm. Exp. 2012, 342, 619–630.
[CrossRef]
Takahashi, R.H.; Nagao, T.; Gouras, G.K. Plaque formation and the intraneuronal accumulation of
beta-amyloid in Alzheimer’s disease. Pathol. Int. 2017, 67, 185–193. [CrossRef] [PubMed]
Akiyama, H.; Barger, S.; Barnum, S.; Bradt, B.; Bauer, J.; Cole, G.M.; Cooper, N.R.; Eikelenboom, P.;
Emmerling, M.; Fiebich, B.L.; et al. Inflammation and Alzheimer’s disease. Neurobiol. Aging 2000, 21, 383–421.
[CrossRef]
Guerreiro, R.; Hardy, J. Genetics of Alzheimer’s disease. Neurotherapeutics 2014, 11, 732–737. [CrossRef]
[PubMed]
Chow, V.W.; Mattson, M.P.; Wong, P.C.; Gleichmann, M. An overview of APP processing enzymes and
products. Neuromolecular Med. 2010, 12, 1–12. [CrossRef] [PubMed]
De-Paula, V.J.; Radanovic, M.; Diniz, B.S.; Forlenza, O.V. Alzheimer’s disease. Subcell. Biochem. 2012, 65, 329–352.
Mondragon-Rodriguez, S.; Perry, G.; Zhu, X.; Moreira, P.I.; Acevedo-Aquino, M.C.; Williams, S. Phosphorylation of
tau protein as the link between oxidative stress, mitochondrial dysfunction, and connectivity failure: Implications for
Alzheimer’s disease. Oxid. Med. Cell Longev. 2013, 2013, 940603. [CrossRef] [PubMed]
Taylor, M.K.; Swerdlow, R.H.; Burns, J.M.; Sullivan, D.K. An experimental ketogenic diet for Alzheimer
disease was nutritionally dense and rich in vegetables and avocado. Curr. Dev. Nutr. 2019, 3, nzz003.
[CrossRef]
Cahill, G.F.J.; Herrera, M.G.; Morgan, A.P.; Soeldner, J.S.; Steinke, J.; Levy, P.L.; Reichard, G.A.J.; Kipnis, D.M.
Hormone-fuel interrelationships during fasting. J. Clin. Invest. 1966, 45, 1751–1769. [CrossRef]
Gasior, M.; Rogawski, M.A.; Hartman, A.L. Neuroprotective and disease-modifying effects of the ketogenic
diet. Behav. Pharm.. 2006, 17, 431–439. [CrossRef]
McNally, M.A.; Hartman, A.L. Ketone bodies in epilepsy. J. Neurochem. 2012, 121, 28–35. [CrossRef]
McDonald, T.J.W.; Cervenka, M.C. Ketogenic diets for adult neurological disorders. Neurotherapeutics 2018, 15, 1018–1031.
[CrossRef] [PubMed]
Bough, K.J.; Rho, J.M. Anticonvulsant mechanisms of the ketogenic diet. Epilepsia 2007, 48, 43–58. [CrossRef]
[PubMed]
Int. J. Mol. Sci. 2019, 20, 3892
44.
45.
46.
47.
48.
49.
50.
51.
52.
53.
54.
55.
56.
57.
58.
59.
60.
61.
62.
63.
64.
65.
66.
16 of 19
Włodarek, D. Role of ketogenic diets in neurodegenerative diseases (Alzheimer’s disease and Parkinson’s
disease). Nutrients 2019, 11, 169. [CrossRef] [PubMed]
Paoli, A.; Bianco, A.; Damiani, E.; Bosco, G. Ketogenic diet in neuromuscular and neurodegenerative diseases.
Biomed. Res. Int. 2014, 2014, 474296. [CrossRef] [PubMed]
Veech, R.L.; Chance, B.; Kashiwaya, Y.; Lardy, H.A.; Cahill, G.F.J. Ketone bodies, potential therapeutic uses.
Iubmb Life 2001, 51, 241–247. [PubMed]
Henderson, S.T.; Vogel, J.L.; Barr, L.J.; Garvin, F.; Jones, J.J.; Costantini, L.C. Study of the ketogenic agent
AC-1202 in mild to moderate Alzheimer’s disease: A randomized, double-blind, placebo-controlled,
multicenter trial. Nutr. Metab. (Lond) 2009, 6, 31. [CrossRef]
Cahill, G.F.J. Fuel metabolism in starvation. Annu. Rev. Nutr. 2006, 26, 1–22. [CrossRef]
Newman, J.C.; Verdin, E. Ketone bodies as signaling metabolites. Trends Endocrinol. Metab. 2014, 25, 42–52.
[CrossRef]
Veyrat-Durebex, C.; Reynier, P.; Procaccio, V.; Hergesheimer, R.; Corcia, P.; Andres, C.R.; Blasco, H. How can
a ketogenic diet improve motor function? Front. Mol. Neurosci. 2018, 11, 15. [CrossRef]
Achanta, L.B.; Rae, C.D. Beta-hydroxybutyrate in the brain: One molecule, multiple mechanisms.
Neurochem. Res. 2017, 42, 35–49. [CrossRef]
Pierre, K.;
Pellerin, L. Monocarboxylate transporters in the central nervous system:
Distribution, regulation and function. J. Neurochem. 2005, 94, 1–14. [CrossRef] [PubMed]
Chowdhury, G.M.I.; Jiang, L.; Rothman, D.L.; Behar, K.L. The contribution of ketone bodies to basal and
activity-dependent deuronal oxidation in vivo. J. Cereb. Blood Flow Metab. 2014, 34, 1233–1242. [CrossRef]
[PubMed]
Elamin, M.; Ruskin, D.N.; Masino, S.A.; Sacchetti, P. Ketone-based metabolic therapy: Is increased NAD+
a primary mechanism? Front. Mol. Neurosci. 2017, 10, 377. [CrossRef] [PubMed]
Cullingford, T.E. The ketogenic diet; fatty acids, fatty acid-activated receptors and neurological disorders.
Prostaglandins. Leukot. Essent. Fat. Acids 2004, 70, 253–264. [CrossRef] [PubMed]
Bough, K.J.; Wetherington, J.; Hassel, B.; Pare, J.F.; Gawryluk, J.W.; Greene, J.G.; Shaw, R.; Smith, Y.;
Geiger, J.D.; Dingledine, R.J. Mitochondrial biogenesis in the anticonvulsant mechanism of the ketogenic
diet. Ann. Neurol. 2006, 60, 223–235. [CrossRef] [PubMed]
Zhang, Y.; Thompson, R.; Zhang, H.; Xu, H. APP processing in Alzheimer’s disease. Mol. Brain 2011, 4, 3.
[CrossRef] [PubMed]
Broom, G.M.; Shaw, I.C.; Rucklidge, J.J. The ketogenic diet as a potential treatment and prevention strategy
for Alzheimer’s disease. Nutrition 2019, 60, 118–121. [CrossRef]
Kashiwaya, Y.; Takeshima, T.; Mori, N.; Nakashima, K.; Clarke, K.; Veech, R.L. D-beta-hydroxybutyrate protects
neurons in models of Alzheimer’s and Parkinson’s disease. Proc. Natl. Acad. Sci. U.S.A. 2000, 97, 5440–5444.
[CrossRef]
Yudkoff, M.; Daikhin, Y.; Nissim, I.; Horyn, O.; Lazarow, A.; Luhovyy, B.; Wehrli, S.; Nissim, I. Response of
brain amino acid metabolism to ketosis. Neurochem. Int. 2005, 47, 119–128. [CrossRef]
Yao, J.; Brinton, R.D. Targeting mitochondrial bioenergetics for Alzheimer’s prevention and treatment.
Curr. Pharm. Des. 2011, 17, 3474–3479. [CrossRef]
Verdile, G.; Keane, K.N.; Cruzat, V.F.; Medic, S.; Sabale, M.; Rowles, J.; Wijesekara, N.; Martins, R.N.;
Fraser, P.E.; Newsholme, P. Inflammation and oxidative stress: The molecular connectivity between insulin
resistance, obesity, and Alzheimer’s disease. Mediat. Inflamm. 2015, 2015, 105828. [CrossRef] [PubMed]
Yang, H.; Shan, W.; Zhu, F.; Wu, J.; Wang, Q. Ketone bodies in neurological diseases: Focus on neuroprotection
and underlying mechanisms. Front. Neurol. 2019, 10, 585. [CrossRef] [PubMed]
Taggart, A.K.P.; Kero, J.; Gan, X.; Cai, T.Q.; Cheng, K.; Ippolito, M.; Ren, N.; Kaplan, R.; Wu, K.; Wu, T.J.; et al.
(D)-beta-hydroxybutyrate inhibits adipocyte lipolysis via the nicotinic acid receptor PUMA-G. J. Biol. Chem.
2005, 280, 26649–26652. [CrossRef] [PubMed]
Rahman, M.; Muhammad, S.; Khan, M.A.; Chen, H.; Ridder, D.A.; Muller-Fielitz, H.; Pokorna, B.;
Vollbrandt, T.; Stolting, I.; Nadrowitz, R.; et al. The beta-hydroxybutyrate receptor HCA2 activates
a neuroprotective subset of macrophages. Nat. Commun. 2014, 5, 3944. [CrossRef] [PubMed]
Dupuis, N.; Curatolo, N.; Benoist, J.F.; Auvin, S. Ketogenic diet exhibits anti-inflammatory properties.
Epilepsia 2015, 56, e95–e98. [CrossRef] [PubMed]
Int. J. Mol. Sci. 2019, 20, 3892
67.
68.
69.
70.
71.
72.
73.
74.
75.
76.
77.
78.
79.
80.
81.
82.
83.
84.
85.
86.
17 of 19
Liu, B.; Hong, J.S. Role of microglia in inflammation-mediated neurodegenerative diseases: Mechanisms and
strategies for therapeutic intervention. J. Pharm. Exp. 2003, 304, 1–7. [CrossRef] [PubMed]
Picard, F.; Kurtev, M.; Chung, N.; Topark-Ngarm, A.; Senawong, T.; Machado de Oliveira, R.; Leid, M.;
McBurney, M.W.; Guarente, L. Sirt1 promotes fat mobilization in white adipocytes by repressing PPAR-γ.
Nature 2004, 429, 771–776. [CrossRef]
Yang, X.; Cheng, B. Neuroprotective and anti-inflammatory activities of ketogenic diet on MPTP-induced
neurotoxicity. J. Mol. Neurosci. 2010, 42, 145–153. [CrossRef]
Maalouf, M.; Rho, J.M.; Mattson, M.P. The neuroprotective properties of calorie restriction, the ketogenic
diet, and ketone bodies. Brain Res. Rev. 2009, 59, 293–315. [CrossRef]
Peixoto, L.; Abel, T. The role of histone acetylation in memory formation and cognitive impairments.
Neuropsychopharmacology 2013, 38, 62–76. [CrossRef]
Youm, Y.H.; Nguyen, K.Y.; Grant, R.W.; Goldberg, E.L.; Bodogai, M.; Kim, D.; D’Agostino, D.;
Planavsky, N.; Lupfer, C.; Kanneganti, T.D.; et al. The ketone metabolite beta-hydroxybutyrate blocks NLRP3
inflammasome-mediated inflammatory disease. Nat. Med. 2015, 21, 263–269. [CrossRef] [PubMed]
Kim, D.Y.; Hao, J.; Liu, R.; Turner, G.; Shi, F.D.; Rho, J.M. Inflammation-mediated memory dysfunction and
effects of a ketogenic diet in a murine model of multiple sclerosis. Plos ONE 2012, 7, e35476. [CrossRef]
[PubMed]
Lee, J.; Kim, S.J.; Son, T.G.; Chan, S.L.; Mattson, M.P. Interferon-gamma is up-regulated in the hippocampus
in response to intermittent fasting and protects hippocampal neurons against excitotoxicity. J. Neurosci. Res.
2006, 83, 1552–1557. [CrossRef] [PubMed]
Vanitallie, T.B. Preclinical sporadic Alzheimer’s disease: Target for personalized diagnosis and preventive
intervention. Metab. Clin. Exp. 2013, 62, S30–S33. [CrossRef] [PubMed]
Winkler, E.A.; Nishida, Y.; Sagare, A.P.; Rege, S.V.; Bell, R.D.; Perlmutter, D.; Sengillo, J.D.; Hillman, S.;
Kong, P.; Nelson, A.R.; et al. GLUT1 reductions exacerbate Alzheimer’s disease vasculo-neuronal dysfunction
and degeneration. Nat. Neurosci. 2015, 18, 521–530. [CrossRef]
Krikorian, R.; Shidler, M.D.; Dangelo, K.; Couch, S.C.; Benoit, S.C.; Clegg, D.J. Dietary ketosis enhances
memory in mild cognitive impairment. Neurobiol. Aging 2012, 33, 425.e19–425.e27. [CrossRef] [PubMed]
Newport, M.T.; VanItallie, T.B.; Kashiwaya, Y.; King, M.T.; Veech, R.L. A new way to produce hyperketonemia:
Use of ketone ester in a case of Alzheimer’s disease. Alzheimer’s Dement. 2015, 11, 99–103. [CrossRef]
Rebello, C.J.; Keller, J.N.; Liu, A.G.; Johnson, W.D.; Greenway, F.L. Pilot feasibility and safety study examining
the effect of medium chain triglyceride supplementation in subjects with mild cognitive impairment:
A randomized controlled trial. Bba Clin. 2015, 3, 123–125. [CrossRef]
Ohnuma, T.; Toda, A.; Kimoto, A.; Takebayashi, Y.; Higashiyama, R.; Tagata, Y.; Ito, M.; Ota, T.; Shibata, N.;
Arai, H. Benefits of use, and tolerance of, medium-chain triglyceride medical food in the management of
Japanese patients with Alzheimer’s disease: A prospective, open-label pilot study. Clin. Interv. Aging
2016, 11, 29–36. [CrossRef]
Taylor, M.K.; Sullivan, D.K.; Mahnken, J.D.; Burns, J.M.; Swerdlow, R.H. Feasibility and efficacy data from
a ketogenic diet intervention in Alzheimer’s disease. Alzheimer’s Dement. (N.Y.) 2018, 4, 28–36. [CrossRef]
Ota, M.; Matsuo, J.; Ishida, I.; Takano, H.; Yokoi, Y.; Hori, H.; Yoshida, S.; Ashida, K.; Nakamura, K.;
Takahashi, T.; et al. Effects of a medium-chain triglyceride-based ketogenic formula on cognitive function in
patients with mild-to-moderate Alzheimer’s disease. Neurosci. Lett. 2019, 690, 232–236. [CrossRef] [PubMed]
Dukart, J.; Mueller, K.; Villringer, A.; Kherif, F.; Draganski, B.; Frackowiak, R.; Schroeter, M.L. Relationship
between imaging biomarkers, age, progression and symptom severity in Alzheimer’s disease. Neuroimage Clin.
2013, 3, 84–94. [CrossRef] [PubMed]
Cunnane, S.C.; Courchesne-Loyer, A.; St-Pierre, V.; Vandenberghe, C.; Pierotti, T.; Fortier, M.; Croteau, E.;
Castellano, C.A. Can ketones compensate for deteriorating brain glucose uptake during aging? Implications
for the risk and treatment of Alzheimer’s disease. Ann. N. Y. Acad. Sci. 2016, 1367, 12–20. [CrossRef]
Srikanth, V.; Maczurek, A.; Phan, T.; Steele, M.; Westcott, B.; Juskiw, D.; Munch, G. Advanced glycation
endproducts and their receptor RAGE in Alzheimer’s disease. Neurobiol. Aging 2011, 32, 763–777. [CrossRef]
[PubMed]
Yao, J.; Rettberg, J.R.; Klosinski, L.P.; Cadenas, E.; Brinton, R.D. Shift in brain metabolism in late onset Alzheimer’s
disease: Implications for biomarkers and therapeutic interventions. Mol. Asp. Med. 2011, 32, 247–257. [CrossRef]
[PubMed]
Int. J. Mol. Sci. 2019, 20, 3892
87.
88.
89.
90.
91.
92.
93.
94.
95.
96.
97.
98.
99.
100.
101.
102.
103.
104.
105.
106.
107.
108.
18 of 19
Lauritzen, K.H.; Hasan-Olive, M.M.; Regnell, C.E.; Kleppa, L.; Scheibye-Knudsen, M.; Gjedde, A.;
Klungland, A.; Bohr, V.A.; Storm-Mathisen, J.; Bergersen, L.H. A ketogenic diet accelerates neurodegeneration
in mice with induced mitochondrial DNA toxicity in the forebrain. Neurobiol. Aging 2016, 48, 34–47. [CrossRef]
Yang, Y.; Sauve, A.A. NAD(+) metabolism: Bioenergetics, signaling and manipulation for therapy.
Biochim. Biophys. Acta 2016, 1864, 1787–1800. [CrossRef]
Chen, D.; Bruno, J.; Easlon, E.; Lin, S.J.; Cheng, H.L.; Alt, F.W.; Guarente, L. Tissue-specific regulation of
SIRT1 by calorie restriction. Genes Dev. 2008, 22, 1753–1757. [CrossRef]
North, B.J.; Marshall, B.L.; Borra, M.T.; Denu, J.M.; Verdin, E. The human Sir2 ortholog, SIRT2, is an
NAD+-dependent tubulin deacetylase. Mol. Cell 2003, 11, 437–444. [CrossRef]
Zelin, E.; Freeman, B.C. Lysine deacetylases regulate the heat shock response including the age-associated
impairment of HSF1. J. Mol. Biol. 2015, 427, 1644–1654. [CrossRef]
Hori, Y.S.; Kuno, A.; Hosoda, R.; Horio, Y. Regulation of FOXOs and p53 by SIRT1 modulators under
oxidative stress. Plos ONE 2013, 8, e73875. [CrossRef] [PubMed]
Kawai, Y.; Garduno, L.; Theodore, M.; Yang, J.; Arinze, I.J. Acetylation-deacetylation of the transcription factor
Nrf2 (nuclear factor erythroid 2-related factor 2) regulates its transcriptional activity and nucleocytoplasmic
localization. J. Biol. Chem. 2011, 286, 7629–7640. [CrossRef] [PubMed]
Gano, L.B.; Patel, M.; Rho, J.M. Ketogenic diets, mitochondria, and neurological diseases. J. Lipid Res. 2014, 55, 2211–2228.
[CrossRef] [PubMed]
Chorley, B.N.; Campbell, M.R.; Wang, X.; Karaca, M.; Sambandan, D.; Bangura, F.; Xue, P.; Pi, J.;
Kleeberger, S.R.; Bell, D.A. Identification of novel NRF2-regulated genes by ChIP-Seq: Influence on
retinoid X receptor alpha. Nucleic Acids Res. 2012, 40, 7416–7429. [CrossRef] [PubMed]
Sullivan, P.G.; Rippy, N.A.; Dorenbos, K.; Concepcion, R.C.; Agarwal, A.K.; Rho, J.M. The ketogenic diet
increases mitochondrial uncoupling protein levels and activity. Ann. Neurol. 2004, 55, 576–580. [CrossRef]
[PubMed]
Milder, J.; Patel, M. Modulation of oxidative stress and mitochondrial function by the ketogenic diet.
Epilepsy Res. 2012, 100, 295–303. [CrossRef] [PubMed]
Harper, M.E.; Bevilacqua, L.; Hagopian, K.; Weindruch, R.; Ramsey, J.J. Ageing, oxidative stress,
and mitochondrial uncoupling. Acta Physiol. Scand. 2004, 182, 321–331. [CrossRef] [PubMed]
Kim, D.Y.; Simeone, K.A.; Simeone, T.A.; Pandya, J.D.; Wilke, J.C.; Ahn, Y.; Geddes, J.W.; Sullivan, P.G.;
Rho, J.M. Ketone bodies mediate antiseizure effects through mitochondrial permeability transition.
Ann. Neurol. 2015, 78, 77–87. [CrossRef]
Stafstrom, C.E.; Rho, J.M. The ketogenic diet as a treatment paradigm for diverse neurological disorders.
Front. Pharm.. 2012, 3, 59. [CrossRef]
Jarrett, S.G.; Milder, J.B.; Liang, L.P.; Patel, M. The ketogenic diet increases mitochondrial glutathione levels.
J. Neurochem. 2008, 106, 1044–1051. [CrossRef]
McDaniel, S.S.; Rensing, N.R.; Thio, L.L.; Yamada, K.A.; Wong, M. The ketogenic diet inhibits the mammalian
target of rapamycin (mTOR) pathway. Epilepsia 2011, 52, e7–e11. [CrossRef]
Hashim, S.A.; VanItallie, T.B. Ketone body therapy: From the ketogenic diet to the oral administration of
ketone ester. J. Lipid Res. 2014, 55, 1818–1826. [CrossRef] [PubMed]
Pluta, R.; Jablonski, M. The ketogenic diet for epilepsy therapy in children: Quo vadis? Nutrition 2011, 27, 615–616.
[CrossRef] [PubMed]
Ulamek-Koziol, M.; Pluta, R.; Bogucka-Kocka, A.; Czuczwar, S.J. To treat or not to treat drug-refractory
epilepsy by the ketogenic diet? That is the question. Ann. Agric. Env. Med. 2016, 23, 533–536. [CrossRef]
[PubMed]
Klein, P.; Janousek, J.; Barber, A.; Weissberger, R. Ketogenic diet treatment in adults with refractory epilepsy.
Epilepsy Behav. 2010, 19, 575–579. [CrossRef]
Dashti, H.M.; Mathew, T.C.; Hussein, T.; Asfar, S.K.; Behbahani, A.; Khoursheed, M.A.; Al-Sayer, H.M.;
Bo-Abbas, Y.Y.; Al-Zaid, N.S. Long-term effects of a ketogenic diet in obese patients. Exp. Clin. Cardiol.
2004, 9, 200–205. [PubMed]
Masino, S.A.; Rho, J.M. Mechanisms of Ketogenic Diet. In Jasper’s Basic Mechanisms of the Epilepsies;
Noebels, J.L., Avoli, M., Rogawski, M.A., Olsen, R.W., Delgado-Escueta, A.V., Eds.; National Center for
Biotechnology Information (US): Bethesda, WA, USA, 2012; pp. 1–28.
Int. J. Mol. Sci. 2019, 20, 3892
19 of 19
109. Olson, C.A.; Vuong, H.E.; Yano, J.M.; Liang, Q.Y.; Nusbaum, D.J.; Hsiao, E.Y. The gut microbiota mediates
the anti-seizure effects of the ketogenic diet. Cell 2018, 173, 1728–1741.e13. [CrossRef] [PubMed]
110. Theriault, P.; ElAli, A.; Rivest, S. High fat diet exacerbates Alzheimer’s disease-related pathology in
APPswe/PS1 mice. Oncotarget 2016, 7, 67808–67827. [CrossRef] [PubMed]
111. Sah, S.K.; Lee, C.; Jang, J.H.; Park, G.H. Effect of high-fat diet on cognitive impairment in triple-transgenic
mice model of Alzheimer’s disease. Biochem. Biophys. Res. Commun. 2017, 493, 731–736. [CrossRef]
[PubMed]
112. Moechars, D.; Dewachter, I.; Lorent, K.; Reverse, D.; Baekelandt, V.; Naidu, A.; Tesseur, I.; Spittaels, K.;
Haute, C.V.; Checler, F.; et al. Early phenotypic changes in transgenic mice that overexpress different mutants
of amyloid precursor protein in brain. J. Biol. Chem. 1999, 274, 6483–6492. [CrossRef] [PubMed]
113. Shie, F.S.; Jin, L.W.; Cook, D.G.; Leverenz, J.B.; LeBoeuf, R.C. Diet-induced hypercholesterolemia enhances
brain A beta accumulation in transgenic mice. Neuroreport 2002, 13, 455–459. [CrossRef] [PubMed]
114. George, A.J.; Holsinger, R.M.D.; McLean, C.A.; Laughton, K.M.; Beyreuther, K.; Evin, G.; Masters, C.L.; Li, Q.X.
APP intracellular domain is increased and soluble Abeta is reduced with diet-induced hypercholesterolemia
in a transgenic mouse model of Alzheimer disease. Neurobiol. Dis. 2004, 16, 124–132. [CrossRef] [PubMed]
115. Ma, D.; Wang, A.C.; Parikh, I.; Green, S.J.; Hoffman, J.D.; Chlipala, G.; Murphy, M.P.; Sokola, B.S.; Bauer, B.;
Hartz, A.M.S.; et al. Ketogenic diet enhances neurovascular function with altered gut microbiome in young
healthy mice. Sci. Rep. 2018, 8, 6670. [CrossRef] [PubMed]
116. Xu, K.; Sun, X.; Eroku, B.O.; Tsipis, C.P.; Puchowicz, M.A.; LaManna, J.C. Diet-induced ketosis improves
cognitive performance in aged rats. Adv. Exp. Med. Biol. 2010, 662, 71–75. [PubMed]
117. Nafar, F.; Clarke, J.P.; Mearow, K.M. Coconut oil protects cortical neurons from amyloid beta toxicity by
enhancing signaling of cell survival pathways. Neurochem. Int. 2017, 105, 64–79. [CrossRef]
118. Studzinski, C.M.; MacKay, W.A.; Beckett, T.L.; Henderson, S.T.; Murphy, M.P.; Sullivan, P.G.; Burnham, W.M.
Induction of ketosis may improve mitochondrial function and decrease steady-state amyloid-beta precursor
protein (APP) levels in the aged dog. Brain Res. 2008, 1226, 209–217. [CrossRef]
119. Milder, J.B.; Liang, L.P.; Patel, M. Acute oxidative stress and systemic Nrf2 activation by the ketogenic diet.
Neurobiol. Dis. 2010, 40, 238–244. [CrossRef]
120. Shimazu, T.; Hirschey, M.D.; Newman, J.; He, W.; Shirakawa, K.; Le Moan, N.; Grueter, C.A.; Lim, H.;
Saunders, L.R.; Stevens, R.D.; et al. Suppression of oxidative stress by beta-hydroxybutyrate, an endogenous
histone deacetylase inhibitor. Science 2013, 339, 211–214. [CrossRef]
121. Torosyan, N.; Sethanandha, C.; Grill, J.D.; Dilley, M.L.; Lee, J.; Cummings, J.L.; Ossinalde, C.; Silverman, D.H.
Changes in regional cerebral blood flow associated with a 45 day course of the ketogenic agent, caprylidene,
in patients with mild to moderate Alzheimer’s disease: Results of a randomized, double-blinded, pilot study.
Exp. Gerontol. 2018, 111, 118–121. [CrossRef]
© 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access
article distributed under the terms and conditions of the Creative Commons Attribution
(CC BY) license (http://creativecommons.org/licenses/by/4.0/).