Diabetes & Metabolic Syndrome: Clinical Research & Reviews 12 (2018) 823–827

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Diabetes & Metabolic Syndrome: Clinical Research &

Reviews
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Case Report

Metabolic syndrome marks early risk for cognitive decline with APOE4
gene variation: A case study
Dawson Browna , Kelly J. Gibasb,*
a
Human Bioenergetics & Applied Health Science, Bethel University, MN, USA
b
Doctorate of Behavioral Health Sciences, Human Bioenergetics & Applied Health Science, Bethel University, MN, USA

A R T I C L E I N F O A B S T R A C T

Keywords: A vast amount of research has been done on the APOE4 genetic marker for Alzheimer's disease (AD), but its
APOE4 connection to metabolic processes associated with peripheral insulin resistance and cerebral glucose
Alzheimer’s disease metabolism is still relatively unknown. The APOE4 allele is the strongest genetic risk factor for developing
Metabolic syndrome
late-onset Alzheimer’s disease, particularly in individuals who have inherited two copies of the gene (Zhao
Ketogenic diet
et al., 2017). In this case study, a 38 year old male with metabolic syndrome (MetS), the APOE4 gene, early
HIIT
stage memory problems and a family history of Alzheimer’s Disease (AD) was placed on a ketogenic diet
combined with high intensity interval training (HIIT) for 10 weeks. The primary intervention goal was
reduce insulin defect, impaired cerebral and peripheral insulin signaling, associated with metabolic
syndrome. Recent research demonstrates that insulin defect competes for space with APOE4 in brain cells,
thus exacerbating amyloid pathology (Zhao et al., 2017). Primary biomarkers for metabolic syndrome were
measured at baseline and after 10 weeks. The MoCA (Montreal Cognitive Assessment) was administered at
baseline and after 10 weeks. The results were statistically significant. The HOMA-IR (homeostatic measure
of insulin resistance) decreased by 59% from 4.3 to 1.8. The triglyceride/HDL ratio decreased by 77% from
14.7 to 3.4. Fasting triglycerides were reduced from 573 mg/dL to 167 mg/dL (71% reduction); VLDL
decreased from 114.6 mg/dL to 33.4 mg/dL (71% decrease); and fasting insulin was reduced by 55% from
15.6 mU/L to 7.1 mU/L. The baseline MoCA score was 22/30; post treatment score was 30/30. If APOEE4 is the
strongest genetic risk factor for developing late-onset Alzheimer's Disease, then implementing a ketogenic
diet and high intensity exercise could essentially turn “off” the effects of this APOE4 gene earlier in life for
prevention of future neurodegeneration.
© 2018 Diabetes India. Published by Elsevier Ltd. All rights reserved.

1. Introduction come with different amounts of amino-acids at residue 112 and

APOE4 has been of great interest in the field of Alzheimer's for
many years, but recent research correlating APOE4 with
metabolic syndrome offers the exciting possibility of inactivating
the gene’s potential for neural decline by reversing peripheral
and cerebral insulin resistance [1–3]. Alzheimer's disease has
long been the most common form of dementia for the elderly. It is
usually accompanied by memory loss, language troubles, and
cognitive depletion [4]. Alzheimer's is difficult to predict and can
be troublesome to treat once it has progressed, however the
discovery of the APOE genetic marker has contributed to the
ability to discern risk before onset occurs. The APOE4 gene has
many single-nucleotide polymorphisms. Each of these (SNPS)
* Corresponding author.
E-mail addresses: Dab93939@bethel.edu (D. Brown), Kelly-gibas@bethel.edu
(K.J. Gibas).
118. These slight variations can cause contrast in function of the
APOE4 gene. These slight variations allow for medical profes-
sionals to accurately assess risk of developing early onset
dementia [5]. `Scientists at the Mayo clinic in Jacksonville,
Florida discovered that APOE4 seems to be in conflict with insulin
for space on the GLUT4 insulin-dependent glucose transporter.
This leads to insulin resistance which is primary to metabolic
syndrome. Not only does APOE4 compete for space on the GLUT4
transporter, but it also encapsulates endosomes. The encapsu-
lating of these endosomes decreases proper insulin signaling in
the brain [3]. Sustained peripheral insulin resistance creates a
flux of insulin across the blood brain barrier (BBB), leading to
gradual impairment in hypothalamic glucose/insulin sensing
with reduced expression of GLUT4 transport. This loss of cerebral
cellular sensitivity is known to be an early biomarker for
dysregulation of glucose homeostasis and defects in neuro-
cognition [2]. Restoring peripheral and hypothalamic insulin
signaling pathways through a ketogenic diet and high intensity

https://doi.org/10.1016/j.dsx.2018.04.030
1871-4021/© 2018 Diabetes India. Published by Elsevier Ltd. All rights reserved.
824 D. Brown, K.J. Gibas / Diabetes & Metabolic Syndrome: Clinical Research & Reviews 12 (2018) 823–827

Table 1
Biomarkers for MetS pre/mid/post intervention.

RESULTS Pre-Intervention Mid-Intervention Post Intervention Percent Change

HOMA-IR (<1.0) 4.3 1.8 1.63 58% reduction
Tri/HDL ratio (<2.0) 14.7 5.5 3.4 77% reduction
WHtR (<.5) 0.58 0.53 0.53 8% reduction
Fasting Insulin mU/L (3–5) 15.6 7.1 7.1 55% reduction
Triglycerides mg/dL (<150) 573 216 167 71% reduction
VLDL mg/dL (9–13) 114.6 43.2 33.4 71% reduction
Weight 221 197.5 190.1 14% reduction
BMI (<25) 31.2 27.7 26.5 15% reduction

Table 2
MoCA scores pre/mid/post intervention.
Memory Assessment Pre- Mid- Post Intervention
Intervention Intervention
MoCA (>26) 22 25 30
exercise may play a key role in negating the effects of the APOE4
gene polymorphism later in life.
2. Methods
Fifteen physiological biomarker tests for metabolic syndrome
(MetS) were administered by healthcare professionals on a 38 year
old male patient. The patient was overweight with a BMI of 31.2,
waist/hip ratio (WHR) of 0.97, and waist/height (WHtR) of 0.58. The
family medical history included Alzheimer’s disease, type 2
diabetes (T2D) and stroke. The MetS biomarker measures were
taken in three different stages: baseline, mid-intervention and post
intervention. Three serum blood tests were administered during
the 10 week intervention which measured the patient’s HOMA-IR,
Tri/HDL ratio, fasting insulin, fasting glucose, LDL, VLDL, HDL and
fasting triglycerides. The final seven tests performed were WHtR,
WHR, body fat mass (BFM), body fat %, lean body mass (LBM), BMI
(body mass index) and weight. The 10 week intervention
incorporated a ketogenic diet with three days per week of high
intensity interval training (HIIT). The HIIT was paired with 2 days of
heavy lifting per week for a total of 5 days of exercise per week.
Under the supervision of healthcare professionals, the ketogenic
diet was prescribed and monitored. The patient’s blood glucose
and ketones were monitored daily using the Abbott Precision Xtra
blood glucose/ketone meter to ensure sustained fasting glucose
below 100 mg/dL and blood ketones in the physiological range of
0.5–2.0 mg/dL. The MoCA cognitive assessment was administered
by a licensed professional clinical counselor (LPCC) pre/mid/post
intervention. The ApoE4 genetic test was administered via buccal
swab prior to the intervention by a healthcare professional. The
patient met with health care professionals once per week to
monitor blood glucose/ketone levels and the student researcher a
total of five times throughout the program in order to guide
workouts and adjust the nutrition intervention as needed.
3. Case report
The patient, a 38-year-old male presenting with signs of mild
cognitive impairment (MCI) and metabolic syndrome, is employed
as a children's pastor and manager of ACR Homes for people with
disabilities. The patient also stays active at home with a wife and
four daughters. Regarding exercise, he consistently finds time to
run 2–3 days per week but is unhappy with the results in terms of
physical and mental health. Prior to the intervention, the patient
had not previously sought treatment for the memory problems but
had been diagnosed with MetS by his primary care physician. The
patient has been concerned about the early subjective memory
complaints due to his familial history of cognitive impairment
including AD and dementia.

Fig. 1. The patient’s HOMA-IR was positively correlated with reduced insulin levels with an adjusted R2 of 0.994 reflecting statistical significance.
 D. Brown, K.J. Gibas / Diabetes & Metabolic Syndrome: Clinical Research & Reviews 12 (2018) 823–827 825

Fig. 2. The patient’s Tri/HDL ratio was positively correlated with reduced insulin levels with an adjusted R2 of 0.939 reflecting statistical significance.

Fig. 3. The patient’s triglycerides were positively correlated with reduced insulin levels with an adjusted R2 of 0.976 reflecting statistical significance.

4. Results
One adult male was enrolled in the 10 week intervention. A
ketogenic diet was combined with HIIT for the duration of the
program. Weekly monitoring of blood ketones and body composi-
tion analysis were implemented. The patient’s primary biomarkers
for MetS and memory scores improved significantly demonstrating
a robust correlation with a ketogenic diet combined with HIIT.
More specifically, the results reveal a strong association between
lowered fasting insulin levels and improved memory function and
MetS biomarkers. The results are consistent with the research
conducted by Zhao et al., which demonstrates the correlations
between APOE4, insulin resistance and poor memory features [3].
The patient’s primary biomarkers for MetS decreased significantly.
The results reflected a 71% reduction in triglycerides from 573 mg/
dL to 167 mg/dL: 77% decrease in Tri/HDL ratio from 14.7 to 3.4;
58% reduction in the HOMA-IR from 4.3 to 1.8; 71% decrease in
VLDL from 114.6 mg/dL to 33.4 mg/dL; and a fasting insulin
reduction of 55% from 15.6 mU/L to 7.1 mU/L. The patient decreased
his body weight by 14%, as he lost 30.9 pounds, and reduced his
BMI by 15%. See Table 1 for MetS biomarker results.
The patient’s memory scores improved significantly during the
10 week intervention. The normal range for MoCA scoring is >26.
The patient scored 22/30 at baseline and 30/30 at the conclusion of
the intervention. See Table 2 for MoCA scores pre/mid/post
intervention.
5. Data
The correlations between lowered insulin and increased ketone
levels with MetS biomarkers and memory scores were statistically
significant. See Figs. 1–5 below.
826 D. Brown, K.J. Gibas / Diabetes & Metabolic Syndrome: Clinical Research & Reviews 12 (2018) 823–827

Fig. 4. The patient’s VLDL was positively correlated with reduced insulin levels with an adjusted R2 of 0.976 reflecting statistical significance.

Fig. 5. The patient’s MoCA score was positively associated with increased ketone levels with an adjusted R2 of 0.945 reflecting statistical significance.

The data from this case study is consistent with previous
research demonstrating correlative properties between insulin
signaling defects on memory [1,6], on neurodegeneration [7–10].
6. Discussion
The statistically significant results suggest that implementing a
ketogenic diet allows for proper GLUT4 translocase on the cell
despite APOE4 competition for space on the insulin-dependent
receptor. In essence, the APOE4 gene is essentially turned off.
Research has shown that the APOE4 gene mutation is the strongest
risk factor for late-onset AD [3]. Early onset AD and dementia are
highly correlated with metabolic syndrome [11]. One of the signs of
early onset dementia is memory impairment. The 38 year old
patient’s baseline MoCA score of 22, fasting triglycerides of
573 mg/dL, and family history of AD suggest a rapid trajectory
toward neurodegeneration. However, the significant improvement
in post intervention MetS biomarkers and memory seems to
demonstrate that a ketogenic diet and HIIT turns off the APOE4
gene, thus eliminating competition for space on the GLUT4 insulin-
dependent transporter. The resulting increase in insulin sensitivity
promotes decreased MetS biomarkers and increased memory
function [1,12].
The primary limitation to this case study is the small sample
size. Future studies should attempt to increase sample size and
equalize the number of men and women involved in research.
 D. Brown, K.J. Gibas / Diabetes & Metabolic Syndrome: Clinical Research & Reviews 12 (2018) 823–827
7. Conclusion
Increased ketone production and high intensity exercise not
only improve MetS biomarkers [13] and memory function [1], but
also seem to turn off the effects of the APOE4 gene mutation as
evidenced by normal insulin signaling [3]. Early testing for APOE4
with patients with MetS may serve to pioneer robust intervention
strategies designed to increase peripheral and cerebral GLUT4
translocase in order to prevent future neurodegeneration.
Statement of ethics
The study was approved by an ethics committee. All the
participants gave their written informed consent before taking
part in the study.
Conflict ofinterest
The authors declare that there is no conflict of interest
associated with this manuscript.
Disclosure statement
Sources of support (funding): No funding was required.
Author contributions
All persons who meet authorship criteria are listed as authors,
and all authors certify that they have participated sufficiently in
the work to take public responsibility for the content, including
participation in the concept.
Research in context
1 Systematic Review: The authors reviewed the literature using
traditional (e.g., google scholar) sources. While the role of the
APOE4 gene and metabolic syndrome is not yet as widely
studied as other aspects of AD physiology, there have been
several recent publications describing the clinical aspects of a
ketogenic diet combined with high intensity interval training
(HIIT). These relevant citations are appropriately cited.
2 Interpretation: Our findings led to an integrated hypothesis
describing the role of a ketogenic diet and HIIT on MetS
biomarkers and memory function. This hypothesis is consistent
with nonclinical and clinical findings currently in the public
domain.
827
3 Future Directions: The manuscript proposes a framework for the
generation of new hypotheses and the conduct of additional
studies regarding this area of study. Examples include further
understanding: (a) the role of sustained normalized MetS
biomarkers on the genesis of AD for patients with APOE4; (b) the
potential of APOE4 testing for all adults over the age of 21 in
order to prevent future neurodegeneration.
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