Volume 4 Issue 2
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ISSN: 2767-6560

ES Journal of Case Reports

Relationship between Decline in Cognitive Function and Homocysteine,
Folate, and Vitamin B12

Research Article

DOI: 10.59152/ESJCR/1042

Takuji Shirasawa1,2,*
12Ochanomizu Health and Longevity Clinic, Tokyo, Japan
Shirasawa Anti-Aging Medical Institute, Tokyo, Japan

Received: June 20, 2023; Accepted: July 03, 2023; Published: July 05, 2023

*Corresponding author: Takuji Shirasawa, Shirasawa Anti-Aging Medical Institute, Sagawa BLD 701, Kanda Surugadai
2-8, Chiyoda-Ku, Tokyo 101-0062, Japan.

Copyright: © 2023 Takuji Shirasawa. This is an open-access article distributed under the terms of the Creative Commons Attribution
License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source arecredited.

Summary
Hyperhomocysteinemia (HHcy) causes various diseases, including cardiovascular disease, osteoporotic fracturesand dementia. Although there have been reports that HHcy impairs cognitive function, findings are inconsistent on theassociation of homocysteine (Hcy), folate, and vitamin B12 with cognitive function. Considering that a lower-quality dietincreases the risk of dementia in elderly individuals, the effect of nutritional status must be clarified. In the present
study, a case‒control study and an intervention study were conducted. In Study 1, 85 patients who visited the clinic withcomplaints of memory impairment were evaluated for their plasma Hcy, serum folate, serum vitamin B12 concentrations
and cognitive function. Although not statistically significant, plasma Hcy concentrations in dementia patients (11.00 ±4.90 nmol/mL) as well as MCI patients (10.7 ± 2.49 nmol/mL) were higher than those in the normal cognitive-functiongroup (9.74 ± 3.84 nmol/mL). In Study 2, 42 patients with HHcy at the first visit were administered Memorin®, a dietary
supplement containing vitamin B12, folate, vitamin B6, and other ingredients, for 10 months. HHcy (12.3 ± 4.58 nmol/mL) was significantly improved 4 months (10.0 ± 3.85 nmol/mL) and 10 months (10.16 ± 3.12 nmol/mL) after theadministration of Memorin®. The pharmacological actions of dietary supplements for HHcy were discussed in thisarticle.
Keywords: Folate, Vitamin B12, Homocysteine, Cognitive Function, Dementia, MCI.

Abbreviations

HHcy: Hyperhomocysteinemia; Hcy: Homocysteine; MCI: Mild Cognitive Impairment; AD: Alzheimer’s Disease; VaD:
Vascular Dementia; ANOVA: Analysis of Variance; TG: Triglyceride; CRISIS: Coronary Risk of Insulin Sensitivity in Indian
Subjects study; THF: Tetrahydrofolate; MTHFR: Methylenetetrahydrofolate Reductase.

Introduction
The prevalence and economic costs of Alzheimer’s
disease (AD) and other types of dementia are increasingalong with the increasing elderly population [1]. It istherefore important to identify the modifiable risk factors
for dementia [2]. Mild cognitive impairment (MCI) is anintermediate stage in the neurodegenerative pathology

from normal brain aging to dementia [2]. Elderly individuals
with MCI are at high risk of developing dementia, including
AD and vascular dementia (VaD). Subjects with a diagnosis
of MCI constitute a clinical entity that can be subjected topreventive measures [2]. B vitamins such as folate, vitamin
B2, vitamin B6, and vitamin B12 are involved in one-carbon

Citation: Shirasawa T. Relationship between Decline in Cognitive Function and Homocysteine, Folate, and Vitamin B12.
ES J Case Rep. 2023; 4(2): 1042.

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ES Journal of Case Reports

transfer reactions such as methylation, which is necessary
for the production of monoamine neurotransmitters,
phospholipids, and nucleotides in the brain [3,4]. Low
concentrations of these B vitamins have been associatedwith HHcy [5,6], which is neurotoxic [7]. Moreover, several
cross-sectional and longitudinal studies have indicatedthat HHcy is an independent risk factor for impaired
cognitive function [8-11], although other studies found no
significant association between Hcy and cognitive function[12,13].

For HHcy, various vitamin-B complex supplements
are available to date. However, absorption of vitamin B12
from gastrointestinal mucosa is often impaired in theelderly population [14], and the appropriate duration
and amount of vitamin B supplementation required forthe improvement of HHcy in elderly patients is not welldefined. In the current study, the efficacy of Memorin®, acommercially available vitamin-B complex supplement for
HHcy in elderly individuals, was investigated.

Materials and Methods

Subjects and study design
Study 1 was a case‒control study conducted with 85
patients who visited the Ochanomizu Health & Longevity
Clinic from May 2018 to February 2023. Written consent
to participate in this study was obtained from each subject
after explanation of the objective and protocol of this study.
Subjects were excluded if they were taking vitamin B12,
folate, or vitamin B6 at the time of enrollment.

Study 2 was an intervention study conducted from
June 2020 to February 2023 for 42 patients withhyperhomocysteinemia from Study 1. The dietary
supplement Memorin® was administered orally once a
day for 10 months. Blood chemistry and Mini-Mental State
Examination (MMSE) were done before, 4 months, and 10
months after the administration of Memorin®.
Dietary supplementation

Memorin® (Lequio Pharma Co. Ltd., https://www.
lequio-pha.co.jp/en/index.html) containing 50 mg
curcuminoids, 55 mg DHA, 10 mg squalene, 5 mg turmeric
powder, 2 mg piperine, 10 mg vitamin B2, 12.5 mg vitamin
B6, 250 μg vitamin B12, 400 μg folic acid, 50 mg vitamin C,
25 mg vitamin E, 3.2 mg vitamin B1, and 13 μg huperzine A
in one capsule.
Cognitive evaluations

Cognitive evaluations were performed with the MiniMental State Examination (MMSE). The MMSE is a wellvalidated screening tool for global cognitive impairment
and dementia in clinical settings [15]. It evaluates multiple
cognitive domains, including attention, memory, andexecutive function. Patients with an MMSE score ≥27
points were categorized as having normal cognitive
function, those with a score between 23 and 26 points
were categorized as having mild cognitive impairment(MCI), and those with a score <23 points were categorized
as having dementia.
Statistical analyses

Statistical analyses were performed using JMP version
17.0.0 (SAS Institute Japan, Tokyo). The difference
between men and women was analyzed by Student’s t test.
Comparisons of subjects’ characteristics among normal,
MCI, and dementia were carried out using one-way
ANOVA followed by Tukey‒Kramer multiple comparison
tests. Spearman’s correlation was used to examine therelationship between plasma Hcy and serum folate, vitamin
B12, creatinine concentrations, eGFR, and other biomarkers.
Repeated measures ANOVA was used to analyze the effects
of Memorin® on Hcy, LDL, TG, vitamin B12, serum folate
concentration and MMSE score.
Molecular illustration

The 3D chemical structures of tetrahydrofolate,
5-MTHF, folate, homocysteine, cystathionine, cysteine,and methionine were imported from the PubChem library(https://pubchem.ncbi.nlm.nih.gov/docs/about).
3D
protein structures of methionine synthase, cystathionine
ß-synthase, and MTHFR were retrieved from the RCSB
Protein Data Bank (RCSB PDB, https://www.rcsb.org andthen imported into UCSF Chimera-X (https://www.cgl.
ucsf.edu/chimerax/). The molecules are displayed withmolecular surfaces colored by amino acid hydrophobicity.

Results

In Study 1, 85 patients who visited the clinic withcomplaints of memory impairment from May 2018 to
February 2023 were enrolled. In Study 1, the patients who
had been prescribed any supplement containing vitamin
B12 or folate prior to visiting the clinic were excluded.
Background profiles of the subjects in Study 1 are shown in
Table 1. They were aged 69.4 years on average with no sex
difference. Sex differences were detected in body height,
body weight, BMI, creatinine, plasma Hcy, and MMSE score.
The average plasma Hcy level in men (11.9 ± 5.3 nmol/mL) was significantly higher than that in women (9.2 ± 2.2nmol/mL) (p=0.0019). The average MMSE score in men(25.8 ± 5.2) was significantly higher than that in women(22.3 ± 7.9) (p=0.0284). There was no sex difference inserum albumin, MCV, eGFR, TGs, LDL, serum folate, serum
vitamin B12, or HbA1c. Their serum concentrations ofalbumin, eGFR, triglyceride (TG), LDL, and HbA1c were
within the reference range, suggesting that these subjects
were not generally malnourished.

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Table 1: Background profiles of the subjects (Study 1)
Total(n = 85)AgeMen(n=34)

Women(n =51)

p value

69.4 ± 12.7 68.1 ± 12.4 70.2 ± 12.9 0.4450

Body Hight (cm)Body Weight (Kg)
BMI (Kg/m )2

158.2 ±
10.3

166.7 ± 8.4 151.7 ± 6.3 <0.0001**

53.5 ± 10.8 62.4 ± 8.9

47.6 ± 7.3 <0.0001**

21.4 ± 3.1

20.7 ± 3.0 0.0114* *22.5 ± 3.0

Serum Albumin (g/dL) 4.20 ± 0.29 4.20 ± 0.31 4.20 ± 0.29 0.9881
MCV (fL)

94.6 ± 4.8

94.4 ± 3.8

94.8 ± 5.4

Normal(n = 43)0.72 ± 0.30 0.88 ± 0.43 0.62 ± 0.11 0.0001**

eGFR (mL/min/1.73m2)

73.9 ± 15.3 73.9 ± 17.6 73.8 ± 13.7 0.9714

TG (mg/dL)
LDL (mg/dL)
Plasma Hcy (nmol/mL)

112.4 ±
44.6
125.3 ±
42.3

10.3 ± 3.9

11.9 ± 5.3

HbA1c (%)

Age
Body Hight (cm)97.7 ± 53.8 0.1901

Body Weight (Kg)

123.4 ±
34.5

0.81549.2 ± 2.20.0019**

BMI (Kg/m2)

MCI(n =18)Dementia
p value(n =24)76.1 ±<0.0001**
63.6 ±11.9 74.3 ± 11.2**
10.2**
161.6 ±
155.2 ±
152.7 ±
0.0012**
10.4
10.3**
7.3**
54.7 ± 12.0 54.7 ± 9.2

50.5 ± 9.2

0.2731

20.8 ± 3.1

21.6 ± 3.4

0.102722.6 ± 2.4

Serum Albumin (g/dL) 4.25 ± 0.27 4.13 ± 0.34 4.17 ± 0.29 0.2993
MCV (fL)

94.2 ± 5.0

95.7 ± 4.8

94.8 ± 4.5

0.5313Creatinine (mg/dL)

0.70 ± 0.16 0.71 ± 0.15 0.76 ± 0.53 0.7541

0.2863eGFR (mL/min/1,73m2)

77.1 ± 13.8 70.7 ± 12.7 70.5 ± 18.7 0.1496

5.45 ± 0.31 5.46 ± 0.30 5.44 ± 0.31 0.6899

TG (mg/dL)

98.0 ± 52.3 119.8 ± 60.1

LDL (mg/dL)

122.0 ±34.4 135.8 ± 42.4

Plasma Hcy (nmol/mL)

9.74 ± 3.84 10.79 ± 2.49

Serum Folate (ng/mL) 16.1 ± 14.6 15.1 ± 11.3 16.8 ± 16.5 0.6020
Serum Vitamin B12(pg/mL)

Table 2: Characteristics of the subjects according to MMSE score(Study 1).

0.6538Creatinine (mg/dL)

103.6 ±
50.6
124.2
±37.6

folate was found to be lower in the MCI group (15.1 ± 10.03
ng/mL) and dementia group (14.5 ± 15.7 ng/mL) than thatin the normal cognitive function group (17.5 ± 15.6 ng/mL). There was no difference in BMI, serum albumin, MCV,
creatinine, eGFR, TG, LDL, serum vitamin B12, or CRP among
the normal control, MCI and dementia groups (Table 2).

590.8 ±
451.8

526.4 ±
358.4

633.7 ±
503.4

CRP (mg/dL)

0.078±0.1450.112 ±
0.184

0.056 ±
0.107

0.0826

MMSE

23.7 ± 7.1

25.8 ± 5.2

22.3 ± 7.9

0.0284*

Data are expressed as mean ± SD.
Comparison was made according to gender using Student t test.
*Statistically significant (p<0.05).
**Statistically significant (p<0.01).

101.3 ±
37.5
119.4 ±
39.2
11.00 ±
4.90

0.30330.3294
0.3931

Serum Folate (ng/mL) 17.5 ± 15.6 15.1 ± 10.03 14.5 ± 15.7 0.6827
Serum Vitamin B12(pg/mL)

Plasma Hcy concentrations were higher in the MCI anddementia groups than in the normal cognitive functiongroup.

Then, the subjects in Study 1 were categorized into
normal cognitive function (n = 43), MCI (mild cognitive
impairment) (n = 18), and dementia (n = 24) groups
according to MMSE score, as mentioned in the Methods
section (Table 2). To analyze the association between
cognitive function and biomarkers such as body height,
body weight, BMI, serum albumin, MCV, creatinine, eGFR,
TGs, LDL, plasma Hcy, serum folate, serum vitamin B12,
HbA1c, and CRP, the values of these biomarkers among thenormal control group, MCI group, and dementia group werecompared using ANOVA (Table 2). There were significant
differences in age and body height between the MCI andnormal control groups and between the normal dementia
and control groups. A significant difference was also foundin HbA1c between the MCI and normal control groups(P=0.0377). Although not statistically significant, theplasma Hcy concentration was found to be higher in the MCI
group (10.79 ± 2.49 nmol/mL) and dementia group (11.00± 4.90 nmol/mL) than in the normal cognitive functiongroup (9.74 ± 3.84 nmol/mL). The serum concentration of

652.8 ±
509.6

434.4 ±
253.5

596.9 ±
444.1

HbA1c (%)

5.38 ± 0.25 5.59 ± 0.33* 5.47 ± 0.35 0.0377*

CRP (mg/dL)

0.06 ± 0.11 0.14 ± 0.25 0.07 ± 0.08 0.1658

MMSE

28.9 ± 1.1 24.2 ± 1.4** 14.0 ± 5.6** <0.0001**

Data are expressed as mean ± SD.
Comparison was carried out using ANOVA, followed by Tukey-Kramer
muyltiple comparison test.
*Statistically significant (p<0.05).
**Statistically significant (p<0.01).

Correlation of plasma Hcy, serum folate and vitamin
B12 concentrations
To elucidate the association of the biomarkers listedin Study 1 with plasma Hcy, two-way ANOVA showed thatplasma Hcy was significantly correlated with serum folate,serum vitamin B12, creatinine and eGFR. As shown in Figure
1A, serum folate was negatively correlated with plasma
Hcy (r = -0.297, p=0.0088) with the linear regression
equation “Folate = 29.979058–1.3541775*Hcy”. Serum
vitamin B12 was negatively correlated with plasma Hcy (r= -0.297, p=0.0140) with the linear regression equation“VB12 = 971.27356–37.975914*Hcy” (Figure 1B). Serum
creatinine was positively correlated with plasma Hcy (r =0.498, p<0.001) with the linear regression equation “Cre

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ES Journal of Case Reports= 0.4704215 + 0.0227039*Hcy” (Figure 1C). Finally, eGFR
was negatively correlated with plasma Hcy (r = -0.280,
p=0.0137) with the linear regression equation “eGFR =86.350383-1.2094062*Hcy” (Figure 1D).

or 10 months after administration of Memorin® (Table 3,
Figure 2).
Table 3: Biomarkers before and after the administration of Memorin(Study 2, n = 42)
Biomarkers

Before4 month

10 month

Hcy (nmol/mL)

12.3 ± 4.58

10.0 ± 3.85**

10.16 ± 3.12**

LDL (mg/dL)

122.0 ± 36.3

127.6 ± 32.2

125.2 ± 31.2

103.2 ± 49.0
725.6±
Vitamin B12 (pg/mL)
1717.2
Folate (ng/mL)
19.4 ± 33.7

118.1 ± 85.8
1018.1 ±1829.6**43.0 ± 86.3**

116.3 ± 76.1
1042.9 ±1568.8**32.5 ± 16.9**

22.3 ± 7.9

21.8 ± 8.7

TG (mg/dL)

MMSE score22.8 ± 7.3

Data are expressed as mean ± SD.
Comparison was carried out using repeated measures ANOVA.
**Statistically significant (p<0.001).

Figure 1: Correlation of Hcy with folate, vitamin B12, creatinine, and eGFR.
Correlation between Hcy and serum folate (A), serum vitamin B12 (B), serum
creatinine (C), and eGFR (D). The linear regression line is shown by the redline. The linear regression equation, r value and p value are shown in theupper panel of the graph. The r value represents Spearman’s correlation
coefficient. *Statistically significant (p<0.05). **Statistically significant(p<0.01).

Administration of Memorin® lowered the plasma
Hcy concentration in HHcy patients
In Study 2, Memorin® was prescribed for 10 months
to 42 patients from Study 1 who showed HHcy in thefirst visit. Memorin® is a dietary supplement containing
curcuminoids, DHA, squalene, turmeric powder, piperine,
vitamin B2, vitamin B6, vitamin B12, folic acid, vitamin C,
vitamin E, vitamin B1 and huperzine A. Plasma Hcy, LDL,
TG, vitamin B12, folate, and MMSE were assessed 4 months
and 10 months after Memorin® administration. The initialaverage plasma Hcy concentration in the Study 2 group (12.3± 4.58 nmol/mL) significantly decreased after 4 months(10.0 ± 3.85 nmol/mL) and 10 months (10.16 ± 3.12 nmol/mL) of Memorin® administration (p<0.01) (Table 3, Figure2A). The initial average serum vitamin B12 concentration(726.6 ± 1717.2 pg/mL) significantly increased after 4
months (1018.1 ± 1829.6 pg/mL) and 10 months (1042.9± 1568.8 pg/mL) of Memorin® administration (p< 0.01)(Table 3, Figure 2D). The initial average serum folate
concentration (19.4 ± 33.7 ng/mL) significantly increased
after 4 months (43.0 ± 86.3 ng/mL) and after 10 months(32.5 ± 16.9 ng/mL) of Memorin® administration (p< 0.01)(Table 3, Figure 2E). However, no significant changes were
found in LDL, TG, and MMSE scores before and 4 months

Figure 2: Plasma Hcy, LDL, triglyceride (TG), vitamin B12, serum folate,and MMSE scores of 42 patients before, 4 months, and 10 months after
the administration of Memorin®. Data are expressed as the mean + SD.
Comparisons were carried out using repeated-measures ANOVA. **Statistically significant (p<0.01).

Discussion
In the present study, a case‒control design was applied
to examine the associations of plasma Hcy, serum vitamin
B12, folate and cognitive function in patients with normal
cognitive function, MCI, and dementia. The plasma
Hcy concentration was higher in MCI and dementia
patients than in the normal cognitive function group.
The pharmacological effect of Memorin®, a commerciallyavailable vitamin-B complex dietary supplement, wasevaluated on the lowering effect of plasma Hcy in patientswith HHcy.

There have been reports on the association between
folate, vitamin B12 or Hcy and cognitive function [8,10,16,17].
HHcy has been reported to be an independent risk factor
for cognitive decline in a case‒control study of MCI and AD
in China [8] and an Italian cohort study on dementia andCitation: Shirasawa T. Relationship between Decline in Cognitive Function and Homocysteine, Folate, and Vitamin B12.
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AD [10]. In the current study, the plasma Hcy concentration
was elevated in the MCI and dementia groups comparedwith those in patients with normal cognitive function,
but the differences were not statistically significant. Oneof the factors that limited the statistical significance may
be the smaller number of patients with HHcy enrolled in
the current study compared to the previously publishedreports [8,10]. A larger number of cases and controls would
be needed to achieve statistical significance. In the current
study, a sex difference was found in plasma Hcy, in which
men showed significantly higher Hcy concentrations than
women (Table 1). A previous study, the cross-sectional
Coronary Risk of Insulin Sensitivity in Indian Subjects
study (CRISIS), showed a sex difference in Hcy between
men and women [18]. The authors suggested that sex
differences in plasma Hcy may be related to sex hormone
concentrations, lifestyle factors such as diet and smoking,and sexual dimorphism in gene expression that contributeto differences in body composition [18]. Mudd and Poolealso suggested that the difference in Hcy between men andwomen may be related to creatine or creatinine synthesis
and the higher muscle mass in men [19]. This possibility iscompatible with the positive correlation observed between
plasma Hcy and serum creatinine concentration in Study 1(Figure 1C).

Metabolically, Hcy is either metabolized to methionine
by methionine synthase or to cystathionine by cystathionine
ß-synthase, as shown in Figure 3. Methionine synthase is
one of two enzymes that require cobalamin or vitamin B12
for their enzymatic activity and catalyzes the transfer of amethyl group from N5-methyltetrafolate to homocysteine,
generating tetrahydrofolate (THF) and methionine (Figure3). Vitamin B12 serves as an intermediate methyl groupcarrier and cycles between methylcobalamin and cob(I)alamin [20]. Cystathionine ß-synthase catalyzes the firststep of the transsulfuration pathway from homocysteine tocystathionine, uses pyridoxal-phosphate (vitamin B6) as a
cofactor, and is allosterically regulated by effectors such as
the ubiquitous cofactor S-adenosyl-L-methionine (AdoMet)[21]. Methylenetetrahydrofolate reductase (MTHFR) is therate-limiting enzyme in the methyl cycle and catalyzes
the conversion of 5,10-methylenetetrahydrofolate to
5-methyltetrahydrofolate (5-NTHFR), a cosubstratefor Hcy remethylation to methionine (Figure 3). Somegenetic variations in the MTHFR gene have been reported
to influence susceptibility to occlusive vascular disease,neural tube defects, Alzheimer’s disease and other forms
of dementia, colon cancer, and acute leukemia [22].
As a dietary supplement, Memorin® not only contains
a vitamin-B complex, including vitamin B1, B2, B6, B12,and folate, but also curcuminoid, turmeric powder, andpiperine, which may facilitate the absorption of vitamin
B from the gastrointestinal tract. When HHcy is not
improved after 4 months of administration of Memorin®

for 4 months, an intravenous administration of a vitamin-B
complex was applied for HHcy patients who poorly absorb
B vitamins from the gastrointestinal route.

Figure 3: Homocysteine degradation pathway. Homocysteine is catalyzed
by methionine synthase to methionine in concomitant catalysis of 5-MTF(5-methyltetrahydrofolate) to THF (tetrahydrofolate). Methionine synthase(PDB ID 1K98) requires vitamin B12 as a cofactor. 5-MTHF (serum folate)is catalyzed from folate (dietary origin). Homocysteine is also catalyzed bycystathionine ß-synthase to cystathionine (PDB ID 7XOH) and then further
catalyzed to cysteine. Cystathionine ß-synthase requires vitamin B6 as a
cofactor. MTHFR, 5, 10-methyltetrahydrofolate reductase (PDB ID 6FCX).
*Methyl residue transferred to methionine by methionine synthase.

No significant improvements were found with MMSE
score in Study 2 of the current study, although the majorityof patients were administered cytokines that induce
neurogenesis and angiogenesis as previously described
together with the dietary supplement [23-25]. Various
factors, including nutritional status, physical activity
levels, and other lifestyle factors, influence the cognitive
function of HHcy patients, and further study is needed todefine what combination of treatments is optimal for the
improvement of cognitive function in HHcy patients.

Conclusion

Higher plasma Hcy concentrations as well as lower
serum folate concentrations were associated withcognitive decline in outpatients who visited the clinic.
Administration of Memorin® conferred the maintenance ofappropriate folate and vitamin B12 status and lowered theconcentration of plasma Hcy.

Acknowledgements

The author thanks Ms. Sayuri Sato and Ms. Masami
Fukuda for assistance in the preparation of this manuscript.

Informed Consent

Written informed consent was obtained from thepatients.

Citation: Shirasawa T. Relationship between Decline in Cognitive Function and Homocysteine, Folate, and Vitamin B12.
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Conflict of Interest

13. Ravaglia G, Forti P, Maioli F, Vettori C, Grossi G, Bargossi AM, et al.
Elevated plasma homocysteine levels in centenarians are notassociated with cognitive impairment. Mech Ageing Dev. 2000;
121(1-3): 251-261.

The author declares no conflicts of interest.

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