ArticlePDF AvailableLiterature Review

Alzheimer’s Disease and Type 2 Diabetes Mellitus: The Use of MCT Oil and a Ketogenic Diet

Authors:
  • Tohoku University, Institute of Department, Aging and Cancer

Abstract

Recently, type 2 diabetes mellitus (T2DM) has been reported to be strongly associated with Alzheimer’s disease (AD). This is partly due to insulin resistance in the brain. Insulin signaling and the number of insulin receptors may decline in the brain of T2DM patients, resulting in impaired synaptic formation, neuronal plasticity, and mitochondrial metabolism. In AD patients, hypometabolism of glucose in the brain is observed before the onset of symptoms. Amyloid-β accumulation, a main pathology of AD, also relates to impaired insulin action and glucose metabolism, although ketone metabolism is not affected. Therefore, the shift from glucose metabolism to ketone metabolism may be a reasonable pathway for neuronal protection. To promote ketone metabolism, medium-chain triglyceride (MCT) oil and a ketogenic diet could be introduced as an alternative source of energy in the brain of AD patients.
International Journal of
Molecular Sciences
Review
Alzheimers Disease and Type 2 Diabetes Mellitus: The Use of
MCT Oil and a Ketogenic Diet
Junpei Takeishi 1, Yasuko Tatewaki 1, 2, *, Taizen Nakase 1,2,3,*, Yumi Takano 1,2, Naoki Tomita 1,2,
Shuzo Yamamoto 1,2, Tatsushi Mutoh 1,2 and Yasuyuki Taki 1,3


Citation: Takeishi, J.; Tatewaki, Y.;
Nakase, T.; Takano, Y.; Tomita, N.;
Yamamoto, S.; Mutoh, T.; Taki, Y.
Alzheimer’s Disease and Type 2
Diabetes Mellitus: The Use of MCT
Oil and a Ketogenic Diet. Int. J. Mol.
Sci. 2021,22, 12310. https://doi.org/
10.3390/ijms222212310
Academic Editor: Masashi Tanaka
Received: 24 September 2021
Accepted: 11 November 2021
Published: 15 November 2021
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Copyright: © 2021 by the authors.
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4.0/).
1Department of Aging Research and Geriatric Medicine, Institute of Development, Aging and Cancer,
Tohoku University, Sendai 980-8575, Japan; junpei.takeishi.s5@dc.tohoku.ac.jp (J.T.);
yumi.takano.b7@tohoku.ac.jp (Y.T.); naoki.tomita.b1@tohoku.ac.jp (N.T.);
shuzo.yamamoto.c7@tohoku.ac.jp (S.Y.); tmutoh@tohoku.ac.jp (T.M.); yasuyuki.taki.c7@tohoku.ac.jp (Y.T.)
2Department of Geriatric Medicine and Neuroimaging, Tohoku University Hospital, Sendai 980-8575, Japan
3Smart Aging Research Center, Tohoku University, Sendai 980-8575, Japan
*Correspondence: yasuko.tatewaki.a7@tohoku.ac.jp (Y.T.); taizen.nakase.a4@tohoku.ac.jp (T.N.)
Abstract:
Recently, type 2 diabetes mellitus (T2DM) has been reported to be strongly associated
with Alzheimer’s disease (AD). This is partly due to insulin resistance in the brain. Insulin signal-
ing and the number of insulin receptors may decline in the brain of T2DM patients, resulting in
impaired synaptic formation, neuronal plasticity, and mitochondrial metabolism. In AD patients,
hypometabolism of glucose in the brain is observed before the onset of symptoms. Amyloid-
β
accu-
mulation, a main pathology of AD, also relates to impaired insulin action and glucose metabolism,
although ketone metabolism is not affected. Therefore, the shift from glucose metabolism to ketone
metabolism may be a reasonable pathway for neuronal protection. To promote ketone metabolism,
medium-chain triglyceride (MCT) oil and a ketogenic diet could be introduced as an alternative
source of energy in the brain of AD patients.
Keywords:
Alzheimer’s disease; amyloid-beta; type 2 diabetes mellitus; insulin resistance; glucose
metabolism; ketone metabolism; ketogenic diet; coconut oil; MCT oil
1. Introduction
Today, as many as 50 million people worldwide have dementia, the most common
form of which is Alzheimer’s disease (AD). AD typically manifests as a progressive loss
of memory and cognitive function. Cerebral plaques laden with amyloid-
β
(A
β
) and
intracellular neurofibrillary tangles composed of tau are important hallmarks of AD [
1
].
Aβaccumulation is associated with functional and structural brain alterations, consistent
with the patterns of abnormalities seen in patients with mild cognitive impairment (MCI) as
well as AD [
2
]. The amyloid cascade hypothesis suggests that the deposition of A
β
triggers
neuronal dysfunction, vascular damage, and cell death in the brain [
3
]. Moreover, A
β
has
been reported to directly impair the glycolytic and tricarboxylic acid (TCA) pathway [
1
]. In
fact, patients with AD show insulin resistance in the brain [4].
Regarding glucose metabolism disorders, diabetes mellitus (DM) is one of the most
common public health problems worldwide. The global prevalence of DM in 2019 was
estimated to be 9.3% (463 million people), rising to 10.2% (578 million) by 2030 and 10.9%
(700 million) by 2045 [5]. The pathogenesis of type 2 DM (T2DM) is primarily initiated by
the inadequate function of pancreatic
β
-cells in response to glycemic overload, which then
causes insulin resistance. Thus, patients with T2DM are relatively insulin deficient.
Herein, it can be said that insulin plays an important role in the mechanisms involved
in the pathophysiological hypometabolism of glucose in both AD and T2DM. In fact, T2DM
was reported to predispose patients to neurodegenerative disorders, including AD [
6
]. A
meta-analysis reported that the odds ratio for conversion from MCI into AD in patients
Int. J. Mol. Sci. 2021,22, 12310. https://doi.org/10.3390/ijms222212310 https://www.mdpi.com/journal/ijms
Int. J. Mol. Sci. 2021,22, 12310 2 of 10
with and without diabetes was 1.65 (95% CI 1.12 to 2.43) [
7
]. Therefore, in this review,
we will focus on the shared pathogeneses in AD and T2DM and the decreased use of
glucose in the brain. To this end, for a potential of nonpharmacological molecular biology
treatment, we will discuss the ketogenic diet (KD), a high-fat and low-carbohydrate diet in
which coconut oil and medium-chain triglyceride (MCT) oil are often used as an alternative
source of energy against glucose.
2. Risk of AD
The risk of developing AD is divided into two categories: inherited and modifiable.
Genetic involvement is an inherited risk factor for AD. Mutations in the genes of
amyloid precursor protein (APP), presenilin 1 (PSEN1), and PSEN2 are associated with the
early onset of familial AD [
8
]. APP is normally cleaved by
α
-secretase, but its mutation
affects
α
-cleavage and increases
β
- and
γ
-cleavage, resulting in the accumulation of A
β
.
PSEN1 and PSEN2 are components of
γ
-secretase, and their mutation influences the
increased activity of
γ
-secretase, resulting in the accumulation of A
β
. Additionally, a
polymorphism in the apolipoprotein E (APOE) gene can be a major risk factor for sporadic
AD. APOE has three isoforms: E2, E3, and E4. Thus, APOE4 is thought to increase the A
β
burden by interfering with Aβclearance [9].
Numerous modifiable factors have been investigated as risk factors for AD [
10
].
Among them, lifestyle habits, such as decreased physical activity, midlife obesity, alcohol
intake, and smoking, are important since they can be controlled in our daily life [
11
]. More-
over, such lifestyle habits are also risks of cerebrovascular disease [
12
], hypertension [
13
],
dyslipidemia, and DM [
14
]. In fact, these diseases are involved in AD pathogenesis. There-
fore, it can be said that we can partly control the onset of AD by changing such modifiable
risk factors.
3. AD and DM: Mechanisms of Cognitive Decline Associated with Insulin Resistance
Insulin is secreted from the pancreas, and regulates glucose metabolism by means of
activation of the insulin receptor (IR). In patients with T2DM, because of the inappropriate
secretion of insulin triggered by an abnormal glucose overload, insulin resistance will
primarily be observed. Then, the persistent stress of insulin secretion may result in the
dysfunction of pancreatic
β
-cells. Meanwhile, insulin has long been implicated in cognitive
performance [
15
,
16
]. First, IRs are located in the central nervous system synapses [
17
,
18
],
and insulin, which comes from the general circulation, can cross the blood–brain barrier
(BBB) [
19
] via a saturable transporter [
20
]. Then, as shown in Figure 1, insulin binds to the
IR at the synapse, and autophosphorylation of the IR occurs. An activated IR phosphory-
lates the insulin receptor substrate (IRS). This results in the cascade of phosphoinositide
3-kinase (PI3K) activation, phosphoinositide-dependent protein kinase-1 (PDK-1) activa-
tion, and protein kinase B (Akt) activation. Activated Akt can activate glycogen synthase
kinase 3β(GSK3β), mammalian target of rapamycin complex 1 (mTORC1), and forkhead
box O (FOXO1). Then, these downstream cascades influence the activity of AMPA-type
glutamate receptor subunit-1 (GluA1) and NMDA-type glutamate receptor subunit 2 B
(GluN2B)
[2123]
. Since both GluA1 and GluN2B play a critical role in synaptic plasticity,
insulin can be associated with memory and learning in the hippocampus [
24
]. Moreover,
activated Akt promotes the phosphorylation of AMP-activated protein kinase (AMPK),
leading to the activation of Sirtuin 1 (SIRT1) and peroxisome-proliferator-activated recep-
tor
γ
co-activator 1
α
(PGC1
α
). This pathway plays an important role in mitochondrial
metabolism, a major source of ATP [2527].
Similar to the insulin pathology in T2DM patients, it has been reported that impaired
insulin action is observed in the brain of AD patients [
4
]. Three pathologies have been
suspected: reduced transport of insulin into the brain [
28
,
29
], reduced insulin levels in
the brain [
30
], and poorly functioning IRs in the brain [
31
,
32
]. It was reported that, in the
brains of aged mice, Akt was optimally phosphorylated by the infusion of insulin, not into
peripheral blood, but into the cerebral ventricle. A reduced cerebrospinal fluid/serum
Int. J. Mol. Sci. 2021,22, 12310 3 of 10
insulin ratio was observed in an elderly human brain. This study concluded that insulin
uptake at the BBB may be affected in the aged brain [
28
]. Another study reported that both
brain insulin and c-peptide levels decreased alongside aging, and were lower in an AD
brain than in an age-matched control. Moreover, decreased IR density was milder in an
AD brain than in an age-matched control, suggesting that IR activity may be decreased in
AD pathology [
33
]. In the hippocampal formation of an AD brain, the increased phospho-
rylation of the IRS was reported to be related to the deactivation of the IR-IRS-PI3K-Akt
pathway. This observation was independent from the DM and APOE phenotype, and
presented a negative correlation with A
β
accumulation, concluding that impaired function
of IRs may be caused by Aβ-related IRS phosphorylation [31].
Int. J. Mol. Sci. 2021, 22, x FOR PEER REVIEW 3 of 10
brains of aged mice, Akt was optimally phosphorylated by the infusion of insulin, not into
peripheral blood, but into the cerebral ventricle. A reduced cerebrospinal fluid/serum in-
sulin ratio was observed in an elderly human brain. This study concluded that insulin
uptake at the BBB may be affected in the aged brain [28]. Another study reported that both
brain insulin and c-peptide levels decreased alongside aging, and were lower in an AD
brain than in an age-matched control. Moreover, decreased IR density was milder in an
AD brain than in an age-matched control, suggesting that IR activity may be decreased in
AD pathology [33]. In the hippocampal formation of an AD brain, the increased phos-
phorylation of the IRS was reported to be related to the deactivation of the IR-IRS-PI3K-
Akt pathway. This observation was independent from the DM and APOE phenotype, and
presented a negative correlation with Aβ accumulation, concluding that impaired func-
tion of IRs may be caused by Aβ-related IRS phosphorylation [31].
Figure 1. Implications of insulin in cognitive performance. Once an insulin receptor is activated,
phosphorylation of the insulin receptor substrate (IRS) is triggered. Then, phosphoinositide 3-kinase
(PI3K) and phosphoinositide-dependent protein kinase-1 (PDK-1) are activated, resulting in the ac-
tivation of protein kinase B (Akt). Activated Akt promotes several downstream cascades and influ-
ences synaptic plasticity as well as mitochondrial dysfunction.
4. Declining Glucose Utilization and Preserving Ketone Metabolism in the Brain of
AD
The decline in glucose metabolism is accompanied by the accumulation of Aβ. Aβ in
cells directly damage mitochondria by attacking not only electron transport complex III
[34], but also cytochrome c and many enzymes in the TCA cycle [1]. Moreover, Aβ pro-
duces reactive oxygen species (ROS) and reactive nitrogen species (RNS), which will dam-
age the cell membrane, including glucose transporters and N-methyl-D-aspartate recep-
tors [1]. These molecular reactions, induced by Aβ, may cause declining glucose utiliza-
tion. In reality, Aβ deposition has been detected 15 years before the onset of AD symp-
toms, and cerebral hypometabolism has also been observed 10 years before the onset of
AD [35,36].
A dual-tracer positron emission tomography (PET) study reported that the cerebral
metabolic rate of glucose (CMRGlu) in AD patients was ~11% lower in the frontal, parietal,
and temporal lobes in addition to the cingulate gyrus (p < 0.05), compared to healthy older
Figure 1.
Implications of insulin in cognitive performance. Once an insulin receptor is activated,
phosphorylation of the insulin receptor substrate (IRS) is triggered. Then, phosphoinositide 3-kinase
(PI3K) and phosphoinositide-dependent protein kinase-1 (PDK-1) are activated, resulting in the
activation of protein kinase B (Akt). Activated Akt promotes several downstream cascades and
influences synaptic plasticity as well as mitochondrial dysfunction.
4. Declining Glucose Utilization and Preserving Ketone Metabolism in the Brain
of AD
The decline in glucose metabolism is accompanied by the accumulation of A
β
. A
β
in cells directly damage mitochondria by attacking not only electron transport complex
III [
34
], but also cytochrome c and many enzymes in the TCA cycle [
1
]. Moreover, A
β
produces reactive oxygen species (ROS) and reactive nitrogen species (RNS), which will
damage the cell membrane, including glucose transporters and N-methyl-D-aspartate
receptors [
1
]. These molecular reactions, induced by A
β
, may cause declining glucose
utilization. In reality, A
β
deposition has been detected 15 years before the onset of AD
symptoms, and cerebral hypometabolism has also been observed 10 years before the onset
of AD [35,36].
A dual-tracer positron emission tomography (PET) study reported that the cerebral
metabolic rate of glucose (CMRGlu) in AD patients was ~11% lower in the frontal, parietal,
and temporal lobes in addition to the cingulate gyrus (p< 0.05), compared to healthy older
adults. Moreover, the uptake rate constants of glucose (KGlu) in AD were ~15% lower in the
same regions and subcortical regions than in healthy older adults [
37
]. Meanwhile, neither
the regional nor whole-brain CMR of acetoacetate (CMRAcAc) and uptake rate constants
Int. J. Mol. Sci. 2021,22, 12310 4 of 10
of AcAc were significantly different between the healthy older adult controls and MCI or
AD groups [
37
,
38
]. Additionally, it has been reported that CMRAcAc did not significantly
differ between healthy young adults and healthy older adults [
39
]. These reports suggest
that glucose metabolism easily declines when people get older or experience cognitive
decline, while ketone metabolism is almost unchanged.
Interventional studies focusing on a KD have reported that a 14-day high-fat KD
using older rats showed a 28% and 44% increase in whole-brain CMRAcAc and CMRGlc,
respectively [
40
,
41
]. On the other hand, a trial on human adults with a KD showed that the
CMRAcAc was significantly increased (p= 0.005) but that the CMRGlu was significantly
decreased by 20% (p= 0.014) [
42
]. Whether a KD increases or decreases glucose uptake in
the brain after intervention remains an issue to be decided.
5. KD, CO, and MCT Oil
As mentioned above, in contrast to the decline in cerebral glucose metabolism, since
cerebral ketone metabolism is well preserved, a KD could be a potential intervention
against decreased brain activity.
Ordinary Americans consume 50–65% of their energy from carbohydrates, whereas a
KD is a very high-fat, low-carbohydrate diet that restricts carbohydrates to
10% of the
energy consumed. It is considered to be a difficult diet to maintain. This macronutrient
profile promotes a systemic shift from glucose metabolism toward the conversion of fatty
acids into ketone bodies as a substrate for energy. Some food products that are known
to contain rich ketone body precursors are coconut oil and MCT oil. The coconut tree
bears a large number of fruits in regions of India, Sri Lanka, Malaysia, and the Philippines.
Coconut oil is derived from the pulp of coconut fruit and is used for cooking oil. Coconut
oil is a source of polyphenols and is rich in dietary fiber, vitamins, and minerals [
43
].
Coconut oil is comprised of saturated fatty acids (SFAs) (>90%) and small amounts of
mono- and poly-unsaturated fatty acids. In a randomized trial, coconut oil was shown
to significantly increase high-density lipoprotein (HDL) levels compared to butter and
olive oil [
44
,
45
]. The lipid profile of coconut oil was demonstrated to be better than that of
animal oils and other plant oils [
46
,
47
]. Additionally, coconut oil has been reported to have
numerous medicinal benefits, including antibacterial, antifungal, antiviral, antiparasitic,
antidermatophytic, antioxidant, hypoglycemic, hepatoprotective, and immunostimulant
effects [
48
]. Nonetheless, regular coconut oil intake should be cautiously considered
because of its high levels of SFAs. Diets rich in SFAs are associated with coronary heart
disease [
49
,
50
]. More research is needed to balance the risk of coconut oil in cardiovascular
diseases against its other benefits.
On the other hand, MCT oil consists only of MCTs, which are lipid molecules that are
more readily absorbed and oxidized than most lipids. Medium-chain fatty acids (MCFAs)
are saturated fatty acids with carbon chain lengths of C6, C8, C10, or C12. MCTs are com-
prised primarily of octanoic acid (C8), decanoic acid (C10), and small proportions of caprice
acid (C6) and lauric acid (C12). In reality, 62–70% of SFAs become MCTs [
51
]. Therefore,
it can be said that MCT oil is more effective than coconut oil, since coconut oil contains
various kinds of SFAs. Dietary MCTs are partially hydrolyzed by lingual lipase in the stom-
ach and then hydrolyzed rapidly and efficiently by pancreatic lipase within the intestinal
lumen. A minor proportion of MCFAs bypass the liver and are distributed to peripheral
tissues via general circulation [
52
54
]. Subsequently, MCFAs are directly absorbed through
the gut via the portal vein to the liver, rather than through the thoracic duct lymph system,
which is the conventional route for the absorption of triglycerides containing light-chain
fatty acids [
52
]. Within the liver mitochondria, MCFAs are rapidly metabolized through
β
-oxidation and finally become ketone bodies, such as
β
-hydroxybutyrate (
β
HB), AcAc,
and acetone. Thus, the unique characteristics of MCFAs, which are easily absorbed and
metabolized, have led to interest in their use in the management of several gastrointestinal
disorders, where MCTs have been primarily used to reduce fat malabsorption and serve as
a source of calories to optimize their nutritional status.
Int. J. Mol. Sci. 2021,22, 12310 5 of 10
6. Influence of a KD and MCT Oil on AD
The KD was originally developed as a treatment for epilepsy in the 1920s, as fasting
was known to reduce the frequency of seizures [55]. Numerous studies have revealed the
efficacy of a KD for epilepsy treatment [5658].
On the other hand, a KD has been attractive as non-pharmacological treatment for
T2DM. It was reported that, after 56 weeks of a KD, body weight, BMI, blood glucose
level, total cholesterol, low-density lipoprotein cholesterol (LDL), triglycerides, and urea
levels significantly decreased, whereas the level of HDL cholesterol significantly increased.
Interestingly, these changes were more significant in subjects who had a high blood glucose
level than in those with a normal blood glucose level [
59
]. Moreover, a KD was reported to
show beneficial effects on weight loss in overweight and obese participants when compared
to a conventional low-calorie diet [60].
By extension, the shift from glucose metabolism to ketone metabolism in patients with
AD may be reasonable for neuronal protection. Patients with mild-to-moderate AD were
assessed by neurocognitive tests after taking 50 g of a ketogenic formula containing 20 g
of MCTs or an isocaloric placebo formula without MCTs [
61
]. The patients then took the
ketogenic formula daily for up to 12 weeks and underwent neurocognitive tests monthly.
At 8 weeks after the start of the trial, the patients showed a significant improvement in
their immediate and delayed logical memory tests compared to their baseline scores; at
12 weeks, they showed significant improvements in the digit–symbol coding test and
immediate logical memory test compared to the baseline. Hence, chronic consumption of
the ketogenic formula has been suggested to have positive effects on verbal memory and
processing speed in patients with AD. It was reported that AD patients with a KD who
achieved sustained physiological ketosis showed an increase in mean within-individual AD
cooperative study–activities of daily living (ADCS-ADL) (+3.13
±
5.01 points, p= 0.0067)
and quality of life in AD (+3.37
±
6.86 points, p= 0.023) scores compared to those with
a usual diet [
62
]. A meta-analysis of randomized controlled trials with 422 participants
showed, compared with a placebo, a trend toward cognitive improvement on the AD
assessment scale–cognitive subscale (ADAS-Cog) (MD =
0.539; 95% CI,
1.239–0.161,
I2 = 0%
), and significantly improved cognition when combining ADAS-Cog with the Mini-
Mental State Examination (MMSE) (SMD =
0.289; 95% CI,
0.551–
0.027,
I2 = 0%
) [
63
].
Moreover, in frail elderly patients, MCT supplementation increased the MMSE score
by 3.5 points at the 3-month intervention from baseline (p< 0.001), whereas long-chain
triglyceride supplementation decreased the MMSE score by 0.7 points [64].
7. The Collateral Effects of MCT Oil for Cerebral Glucose Hypometabolism
Studies involving treating epilepsy patients with a KD have suggested that a KD
introduces ketone bodies which influence the TCA cycle, membrane potential hyperpo-
larization,
γ
-aminobutyric acid synthesis, and decreasing glutamate release [
65
]. A KD
may have many different effects as an anti-epileptic treatment. The possible benefit of a
KD on T2DM patients is mainly because of the reduction in blood glucose level as well as
improving the homeostasis model assessment of insulin resistance (HOMA-IR) [
66
]. In
patients with AD, several mechanisms can be expected for the improvement of cognitive
function regarding the introduction of a KD.
In brief, within the liver mitochondria, MCFAs are rapidly metabolized to ketone
bodies, whereas the liver does not have enzymes that produce Ac-CoA from ketones [
67
,
68
],
which means that the liver cannot produce energy from ketones via the TCA cycle. Ketones
and minor MCFAs escape from liver metabolism and are transported to the whole body,
especially the brain, where the enzymes produce Ac-CoA. Arriving at the brain, ketones and
MCFAs can cross the BBB [
69
,
70
]; therefore, they enter the TCA cycle and generate energy.
Ac-CoA is also generated from pyruvate, a glycolytic product, by pyruvate dehydrogenase.
This can then enter the TCA cycle to generate more energy [
71
]. However, in AD patients,
they cannot utilize sufficient glucose; thus, Ac-CoA, which comes through the glycolytic
pathway, will lower its concentration in the mitochondria, resulting in a decrease in energy
Int. J. Mol. Sci. 2021,22, 12310 6 of 10
production. This mechanism may also be applied to patients with DM who cannot take
glucose from the bloodstream. Ketone can bypass the blockade of glycolysis induced by
insulin deficiency, thereby providing an alternative source of mitochondrial Ac-CoA [
72
].
AcAc and
β
HB, which are produced in the liver and supplied to the brain, may serve
as alternative sources of energy in neurons. Through this pathway, a KD contributes to
maintaining neuronal activity, leading to the improvement of cognitive performance.
8. The Hypothesis of Direct Effects of MCT Oil (MCFAs) on Cognitive Performance
In addition to the role of ketones as energy sources for decreased glucose utilization
in patients with AD, MCFAs may have other effects. Although there is insufficient firm
evidence to support the hypothesis presented below, it is important to explore the possibility
of other effects of MCT oil.
8.1. Ligand for Peroxisome-Proliferator-Activated Receptor γ(PPARγ)
As mentioned above, A
β
attacks the mitochondria, whereas a KD may be involved in
the maintenance of mitochondrial biogenesis (MB) and the mitochondrial respiratory chain
(MRC). MB is controlled by nuclear sirtuins (SIRT1) [
25
,
73
], and a KD has been reported to
improve energy metabolism and MB in the hippocampus of rats [
74
]. A KD may improve
MB in neuronal cells, probably via PGC1-
α
and/or sirtuins [
75
]. It has been reported that
when an HT22 mouse hippocampal neuronal cell line was incubated with decanoic acid,
a main component of MCT oil, or
β
HB, a metabolite of MCFAs, a significant elevation of
SIRT1 enzyme activity and an overall upregulation of MRC were observed [
76
]. In addition,
decanoic acid was reported to function as a direct PPAR
γ
ligand [
77
]. PPAR
γ
is a subfamily
of nuclear receptors that plays a significant role in glucose and lipid metabolism. In fact, it
is a therapeutic target of the DM drug, thiazolidinedione [
78
]. Furthermore, PPAR
γ
ago-
nists were reported to promote the biogenesis of functional mitochondria [79]. One study
attempted treatment with decanoic acid in individuals diagnosed with mitochondrial dis-
ease. This treatment increased citrate synthase activity, a marker of cellular mitochondrial
content, in 50% of fibroblasts obtained from patients with Leigh syndrome [
80
]. Another
study also showed that decanoic acid, but not octanoic acid, caused a marked increase
in citrate synthase, along with complex I activity and catalase activity, in neuronal cell
lines. They also observed an increase in mitochondrial number, as indicated by electron
microscopy [
81
]. The other study reported that the HT22 mouse hippocampal neuronal
cell line, incubated with decanoic acid, showed prominent increases in maximal activities
of complexes I + III and complex IV of the MCR as well as ratios of their activities to that of
citrate synthase [76].
8.2. Lactate Shuttle
As the lactate/pyruvate concentration ratio is significantly increased under hy-
poxia
[82,83]
, lactate has long been considered a metabolic byproduct under hypoxic
conditions. However, many recent studies have changed this view of lactate, shifting
from a glycolytic waste product to an important energy fuel with an interesting molecular
pathway [
84
,
85
]. It can be said that lactate produced by astrocytic glycolysis could
be a supplementary fuel for neighboring neurons [
86
88
]. This is referred to as the
astrocyte–neuron lactate shuttle (ANLS) hypothesis. As a consequence of high glycolytic
activity, astrocytes release lactate into the extracellular space, which can then be taken up
by neighboring neurons and serve as an oxidative fuel for their mitochondria [
89
,
90
]. One
study showed that, using single-cell imaging, decanoic acid produced lactate by inducing
glycolysis [
89
]. The researchers implied that decanoic acid works for astrocyte metabolism
and supplies lactate to neighboring neurons by the ANLS. In the brain of patients with AD,
this hypothesis remains controversial [
84
,
91
,
92
]. Since MCT oil contains decanoic acid, the
effect of MCT oil through the ANLS may be an interesting target for the future.
Int. J. Mol. Sci. 2021,22, 12310 7 of 10
9. Conclusions
In the brain of patients with AD, deficiencies of insulin utility and glucose metabolism
are observed, similar to the pathophysiological connection to T2DM. In this pathological
condition, not glucose but a ketone metabolism cascade could be an alternative pathway
for protecting neurons. MCT oil, a critical component of a KD, is an interesting material
for competing AD pathology, because it can be an effective source of ketone as well as
maintaining mitochondrial function. Exploring the metabolic impairment in the brain of
patients with AD will currently be important from the viewpoint of non-pharmaceutical
therapy of AD.
Author Contributions:
Conceptualization, J.T. and Y.T. (Yasuko Tatewaki), T.N.; Methodology, Y.T.
(Yasuko Tatewaki) and T.N.; Investigation, J.T.; Resources, Y.T. (Yasuko Tatewaki) and T.N.; Writing—
Original Draft Preparation, J.T., Y.T. (Yasuko Tatewaki), T.N., Y.T. (Yumi Takano), N.T., S.Y., T.M.,
and Y.T. (Yasuyuki Taki); Writing—Review and Editing, Y.T. (Yasuko Tatewaki), T.N. and T.M.;
Supervision, T.M. and Y.T. (Yasuyuki Taki); Project Administration, Y.T. (Yasuyuki Taki) and T.N. All
authors have read and agreed to the published version of the manuscript.
Funding: This research received no external funding.
Acknowledgments:
The authors would like to thank Shinji Watanabe, Chika Sakurai, Chie Arai,
and Noriyuki Yamamoto (Central Research Center, The Nisshin OilliO Group Ltd.) for continuous
encouragement of this manuscript.
Conflicts of Interest: The authors declare no conflict of interest.
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Alzheimer's disease (AD) has emerged as the most prevalent and complex neurodegenerative disorder among the elderly population. However, the genetic comorbidity etiology for AD remains poorly understood. In this study, we conducted pleiotropic analysis for 41 AD phenotypic comorbidities, identifying ten genetic comorbidities with 16 pleiotropy genes associated with AD. Through biological functional and network analysis, we elucidated the molecular and functional landscape of AD genetic comorbidities. Furthermore, leveraging the pleiotropic genes and reported biomarkers for AD genetic comorbidities, we identified 50 potential biomarkers for AD diagnosis. Our findings deepen the understanding of the occurrence of AD genetic comorbidities and provide new insights for the search for AD diagnostic markers. Graphical Abstract Study pipeline.
... Likewise, type 2 diabetes mellitus is tightly correlated with the pathobiology of AD. Some basic science research and clinical trials have elucidated that certain antidiabetic drugs, such as insulin, metformin, and glucagon-like peptide-1 agonists, may reduce the risk of developing AD (Diniz Pereira et al., 2021;Li et al., 2021;Takeishi et al., 2021;Zheng et al., 2021;Du et al., 2022;Kopp et al., 2022). Nonetheless, current evidence is derived largely from hypothetical papers or studies in mouse and cell models. ...
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Alzheimer’s disease (AD) is a neurodegenerative disorder caused by a variety of factors, including age, genetic susceptibility, cardiovascular disease, traumatic brain injury, and environmental factors. The pathogenesis of AD is largely associated with the overproduction and accumulation of amyloid-β peptides and the hyperphosphorylation of tau protein in the brain. Recent studies have identified the presence of diverse pathogens, including viruses, bacteria, and parasites, in the tissues of AD patients, underscoring the critical role of central nervous system infections in inducing pathological changes associated with AD. Nevertheless, it remains unestablished about the specific mechanism by which infections lead to the occurrence of AD. As an important post-transcriptional RNA modification, RNA 5-methylcytosine (m⁵C) methylation regulates a wide range of biological processes, including RNA splicing, nuclear export, stability, and translation, therefore affecting cellular function. Moreover, it has been recently demonstrated that multiple pathogenic microbial infections are associated with the m⁵C methylation of the host. However, the role of m⁵C methylation in infectious AD is still uncertain. Therefore, this review discusses the mechanisms of pathogen-induced AD and summarizes research on the molecular mechanisms of m⁵C methylation in infectious AD, thereby providing new insight into exploring the mechanism underlying infectious AD.
... T2DM is a metabolic disease that may lead to a variety of complications, such as cardiovascular disease and neurodegenerative disease [28]. AD is a neurodegenerative disease characterized by progressive loss of memory and cognitive abilities, eventually leading to severe cognitive impairment [29]. Several studies have suggested [30] that T2DM may increase the risk of developing AD. ...
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Chapter
The primary cause of dementia in older people is Alzheimer’s disease (AD), which is typified by specific clinical and biochemical symptoms such as worsening memory loss and cognitive impairment. Furthermore, people with AD experience behavioural and psychological symptoms such as depression, apathy, aggression, and others, which will be explored in this chapter of the book. We will also discuss the clinical correlation between psychosis and AD. Recent research indicates a connection between sleep disturbances and AD. They are regarded as predictors of neurodegenerative disease. Long-term memory consolidation depends on sleep, and disturbances such as excessive daytime drowsiness and frequent awakenings may be early signs of AD. There are clinical links between AD and metabolic disorders. This chapter analyses the signs of osteoporosis and diabetes mellitus in an AD patient. Equally important is the link between AD and cardiovascular diseases such as atrial fibrillation and coronary heart disease, which can result in premature mortality. The association between older people’s gut microbiota and cognitive impairment will be discussed in this chapter. Older people’s microbiome structure maybe involved in controlling neuroinflammation, which is connected to various ageing-related neurological disorders, including AD.
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Alzheimer's disease (AD) is the most common type of dementia and typically manifests through a progressive loss of episodic memory and cognitive function, subsequently causing language and visuospatial skills deficiencies, which are often accompanied by behavioral disorders such as apathy, aggressiveness and depression. The presence of extracellular plaques of insoluble β-amyloid peptide (Aβ) and neurofibrillary tangles (NFT) containing hyperphosphorylated tau protein (P-tau) in the neuronal cytoplasm is a remarkable pathophysiological cause in patients' brains. Approximately 70% of the risk of developing AD can be attributed to genetics. However, acquired factors such as cerebrovascular diseases, diabetes, hypertension, obesity and dyslipidemia increase the risk of AD development. The aim of the present minireview was to summarize the pathophysiological mechanism and the main risk factors for AD. As a complement, some protective factors associated with a lower risk of disease incidence, such as cognitive reserve, physical activity and diet will also be addressed.
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Coconut oil is being heavily promoted as a healthy oil, with benefits that include support of heart health. To assess the merits of this claim, the literature on the effect of coconut consumption on cardiovascular risk factors and outcomes in humans was reviewed. Twenty-one research papers were identified for inclusion in the review: 8 clinical trials and 13 observational studies. The majority examined the effect of coconut oil or coconut products on serum lipid profiles. Coconut oil generally raised total and low-density lipoprotein cholesterol to a greater extent than cis unsaturated plant oils, but to a lesser extent than butter. The effect of coconut consumption on the ratio of total cholesterol to high-density lipoprotein cholesterol was often not examined. Observational evidence suggests that consumption of coconut flesh or squeezed coconut in the context of traditional dietary patterns does not lead to adverse cardiovascular outcomes. However, due to large differences in dietary and lifestyle patterns, these findings cannot be applied to a typical Western diet. Overall, the weight of the evidence from intervention studies to date suggests that replacing coconut oil with cis unsaturated fats would alter blood lipid profiles in a manner consistent with a reduction in risk factors for cardiovascular disease.
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Background: Supplementation with medium-chain triglycerides (MCTs) was previously shown to increase muscle function in frail elderly individuals. Objective: We aimed to assess effects of MCTs on cognition in such individuals. Methods: We enrolled 64 elderly nursing home residents (85.5 ± 6.8 y; 13 men, 51 women; BMI 18.6 ± 2.5 kg/m2) in a 3-mo randomized, controlled, single-blinded, intervention trial. Participants were randomly allocated to 3 groups: the first group received supplemental L-leucine (1.2 g) and cholecalciferol (20 μg) enriched with 6 g/d of MCTs (LD + MCT group) as a positive control, the second group received 6 g/d of MCTs (MCT group) as the test nutrient, and the third group received 6 g/d of long-chain triglycerides (LCT group) as a negative control. Cognition (secondary outcome) was monitored 4 times: baseline, 1.5 and 3 mo after initiation of the intervention (intervention), and 1.5 mo after termination of the intervention (postintervention follow-up). Cognition scores were assessed by a linear mixed model (intention-to-treat analysis). Results: MCT supplementation increased the Mini-Mental State Examination (MMSE) score by 3.5 points at the 3-mo intervention from baseline (P < 0.001) [intention-to-treat adjusted means: baseline 17.5 points (95% CI: 14.9, 20.2), 3-mo intervention 21.0 points (18.3, 23.7)], whereas LCT supplementation decreased the MMSE score by -0.7 points [baseline 17.0 points (95% CI: 14.4, 19.6), 3-mo intervention 16.3 points (13.6, 18.9)]. At the 3-mo intervention, the difference in MMSE score between the MCT (21.0 points) and LCT (16.3 points) groups became significant (P < 0.05). The increase in MMSE score in response to MCTs was 2.1-fold greater at 3 mo than at 1.5 mo and had returned to baseline value at the 4.5-mo postintervention follow-up visit. Conclusion: Supplementation with 6 g MCTs/d may improve the cognition of frail elderly individuals. This trial was registered at umin.ac.jp as UMIN000023302.
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Alzheimer's disease (AD) is the most common form of dementia. Currently, there is no effective medication for the prevention or treatment of AD. This has led to the search for alternative therapeutic strategies. Coconut oil(CO) has a unique fatty acid composition that is rich in medium chain fatty acids(MCFA), a major portion of which directly reaches the liver via the portal vein, thereby bypassing the lymphatic system. Given that brain glucose hypometabolism is a major early hallmark of AD, detectable well before the onset of symptoms, ketone bodies from MCFA metabolism can potentially serve as an alternative energy source to compensate for lack of glucose utilisation in the brain. Additionally, neuroprotective antioxidant properties of CO have been attributed to its polyphenolic content. This review discusses how the metabolism of CO and MCFA may aid in compensating the glucose hypometabolism observed in the AD brain. Furthermore, we present the current evidence of the neuroprotective properties of CO on cognition, amyloid-β pathogenicity, inflammation and oxidative stress. The current review addresses the influence of CO/MCFA on other chronic disorders that are risk factors for AD, and addresses existing gaps in the literature regarding the use of CO/MCFA as a potential treatment for AD.
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Introduction/aim: The brain in Alzheimer’s disease shows glucose hypometabolism but may utilize ketones for energy production. Ketone levels can potentially be boosted through oral intake of Medium Chain Triglycerides (MCTs). The aim of this meta-analysis is to investigate the effect of MCTs on peripheral ketone levels and cognitive performance in patients with mild cognitive impairment and Alzheimer’s disease. Methods: Medline, Scopus and Web of Science were searched for literature up to March 1, 2019. Meta-analyses were performed by implementing continuous random-effects models and outcomes were reported as weighted Mean Differences (MDs) or Standardized Mean Differences (SMDs). Results: Twelve records (422 participants) were included. Meta-analysis of RCTs showed that, compared with placebo, MCTs elevated beta-hydroxybutyrate [MD = 0.355; 95 % CI (0.286, 0.424), I2 = 0 %], showed a trend towards cognitive improvement on ADAS-Cog [MD = −0.539; 95% CI (−1.239, 0.161), I2 = 0 %], and significantly improved cognition on a combined measure (ADAS-Cog with MMSE) [SMD = −0.289; 95 % CI (−0.551, −0.027), I2 = 0 %]. Conclusions: In this meta-analysis, we demonstrated that MCTs can induce mild ketosis and may improve cognition in patients with mild cognitive impairment and Alzheimer’s disease. However, risk of bias of existing studies necessitates future trials.
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Aims: To provide global estimates of diabetes prevalence for 2019 and projections for 2030 and 2045. Methods: A total of 255 high-quality data sources, published between 1990 and 2018 and representing 138 countries were identified. For countries without high quality in-country data, estimates were extrapolated from similar countries matched by economy, ethnicity, geography and language. Logistic regression was used to generate smoothed age-specific diabetes prevalence estimates (including previously undiagnosed diabetes) in adults aged 20-79 years. Results: The global diabetes prevalence in 2019 is estimated to be 9.3% (463 million people), rising to 10.2% (578 million) by 2030 and 10.9% (700 million) by 2045. The prevalence is higher in urban (10.8%) than rural (7.2%) areas, and in high-income (10.4%) than low-income countries (4.0%). One in two (50.1%) people living with diabetes do not know that they have diabetes. The global prevalence of impaired glucose tolerance is estimated to be 7.5% (374 million) in 2019 and projected to reach 8.0% (454 million) by 2030 and 8.6% (548 million) by 2045. Conclusions: Just under half a billion people are living with diabetes worldwide and the number is projected to increase by 25% in 2030 and 51% in 2045.