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Background: Vitamin B12 deficiency is associated with hematological, neurological, and cardiovascular consequences. Epidemiologic data on these related illnesses indicate gender differences. Methods: A cross-sectional study was designed to examine gender differences in vitamin B12 deficiency among a healthy population. Data from healthy individuals aged 18-65, who were provided with a routine medical evaluation during 2000-2014, were retrieved from the medical charts. Individuals with background illnesses and those who had used medications or nutritional supplements were excluded. Vitamin B12 deficiency was defined by 2 cutoff values (206 and 140 pmol/L). The multivariate analysis was adjusted for age, body mass index, estimated glomerular filtration rate, hyperhomocysteinemia, folate deficiency, albumin, and transferrin saturation. Sensitivity analyses were implemented by excluding individuals with anemia, hyperhomocysteinemia, or folate deficiency and by age stratification. Results: In all, 7,963 individuals met the inclusion criteria. Serum vitamin B12 mean levels were 312.36 and 284.31 pmol/L for women and men respectively (p < 0.001). Deficiency prevalence was greater for men (25.5%) in comparison with women (18.9%; p < 0.001). Men were strongly associated with severe deficiency (adjusted OR 2.26; 95% CI 1.43-3.56). Conclusions: Among the healthy population, men are susceptible to vitamin B12 deficiency. This can be explained by neither diet habits nor estrogen effects. Genetic variations are therefore hypothesized to play a role.
Original Paper
Ann Nutr Metab 2018;72:265–271
Vitamin B12 Deficiency and the Role of
Gender: A Cross-Sectional Study of a
Large Cohort
Ili Margalit
a Eytan Cohen
a, b Elad Goldberg
a, b Ilan Krause
a, b
a Department of Internal Medicine F-Recanati, Rabin Medical Center, Beilinson Hospital, Petah Tikva, Israel;
b Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
Received: December 7, 2017
Accepted after revision: March 12, 2018
Published online: March 29, 2018
Ili Margalit
Department of Internal Medicine F-Recanati
Rabin Medical Center, Beilinson Hospital, 39 Jabotinsky Road
IL–49100 Petah Tikva (Israel)
E-Mail ili.margalit @
© 2018 S. Karger AG, Basel
DOI: 10.1159/000488326
Albumin · Cobalamin · Gender · Sex · Vitamin B12
Background: Vitamin B12 deficiency is associated with he-
matological, neurological, and cardiovascular consequenc-
es. Epidemiologic data on these related illnesses indicate
gender differences. Methods: A cross-sectional study was
designed to examine gender differences in vitamin B12 de-
ficiency among a healthy population. Data from healthy in-
dividuals aged 18–65, who were provided with a routine
medical evaluation during 2000–2014, were retrieved from
the medical charts. Individuals with background illnesses
and those who had used medications or nutritional supple-
ments were excluded. Vitamin B12 deficiency was defined
by 2 cutoff values (206 and 140 pmol/L). The multivariate
analysis was adjusted for age, body mass index, estimated
glomerular filtration rate, hyperhomocysteinemia, folate
deficiency, albumin, and transferrin saturation. Sensitivity
analyses were implemented by excluding individuals with
anemia, hyperhomocysteinemia, or folate deficiency and by
age stratification. Results: In all, 7,963 individuals met the
inclusion criteria. Serum vitamin B12 mean levels were
312.36 and 284.31 pmol/L for women and men respectively
(p < 0.001). Deficiency prevalence was greater for men
(25.5%) in comparison with women (18.9%; p < 0.001). Men
were strongly associated with severe deficiency (adjusted
OR 2.26; 95% CI 1.43–3.56). Conclusions: Among the healthy
population, men are susceptible to vitamin B12 deficiency.
This can be explained by neither diet habits nor estrogen
effects. Genetic variations are therefore hypothesized to
play a role. © 2018 S. Karger AG, Basel
The prevalence of vitamin B12 (cobalamin) deficiency
in the total population is estimated to be 2.9–25.7%, de-
pending on the cutoff value [1]. Elderly people, individu-
als with gastrointestinal disorders, and those following a
vegetarian or vegan diet have been identified as suscep-
tible populations [2].
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DOI: 10.1159/000488326
In addition to megaloblastic anemia, vitamin B12 de-
ficiency can lead to neurocognitive abnormalities, im-
mune dysfunction, and osteoporosis [3]. Furthermore,
vitamin B12 plays an important role in the one carbon
metabolism and its deficiency may lead to hyperhomo-
cysteinemia [4]. Vitamin B12 deficiency has been accord-
ingly associated with increased risk for cardiovascular
diseases, including coronary disease and stroke [5].
The role of gender in morbidity has been broadly dis-
cussed and is assumed to derive from both biological al-
terations and sociocultural aspects [6]. Men have been
shown to have an increased risk for cardiovascular events,
especially for acute coronary syndrome [7]. Women, on
the other hand, have been shown to be at a slightly higher
risk for various forms of cognitive impairments and de-
mentia [8–10]. These may be at least partially related to
vitamin B12 deficiency and raise the question regarding
the role of gender in vitamin B12 metabolism.
In the current study, we aimed to examine whether
gender has a role in vitamin B12 deficiency among non-
elderly adults, and to assess its possible contributors.
The study was designed as a cross-sectional, single-center
study, conducted in the Rabin Medical Center (RMC), a large pri-
mary-and-tertiary care, university-affiliated hospital, in Petah-
Tikva, Israel. RMC provides a comprehensive medical annual or
biannual medical evaluation for males and non-pregnant females.
During each visit, the patients undergo a thorough medical his-
tory intake, a physical examination, a broad range of blood and
urine tests, an ergometric stress testing, a chest radiogram, and a
lung functions test.
For the purpose of this study, the medical charts of individuals
with a documented serum vitamin B12 level were retrieved. In cas-
es of repeated visits, only the last one was extracted.
Healthy individuals aged 18–65 were included. Individuals with
any background illness were excluded. After a primary filtration
done on the basis of medical diagnoses, data were refined by imple-
menting a careful review. Individuals prescribed with medications
indicating the presence of a chronic illness and those taking vita-
mins or nutritional supplements of any sort were further omitted.
The extracted variables of interest included demographic de-
tails: age, sex, and body mass index; as well as laboratory parame-
ters: serum vitamin B12, homocysteine, and folic acid (FA) levels,
complete blood count including leucocyte differential count, cre-
atinine, fasting blood glucose, albumin, liver function tests, thy-
roid stimulating hormone and lipids profile.
Between May 2000 and May 2011, serum vitamin B12 and FA
levels were measured using Immulite® assay (Siemens). Between
May 2011 and by the end of the study, these were measured using
Architect® assay (Abbott). For both machines, measuring methods
were similar and reference levels were 138–781 pmol/L for serum
vitamin B12 and 7.0–46.4 nmol/L for serum FA. Serum homocys-
teine levels were measured using TDx® assay (Abbott) between
May 2000 and January 2005 and using AxSYM® assay (Abbott)
since then. For both machines, measuring methods of serum ho-
mocysteine were similar and reference levels were 5.0–20.0 μmol/L.
Different authors use slightly different cutoff values for the defi-
nition of vitamin B12 deficiency [1, 11]. However, it seems that a
cutoff value around 200 pmol/L has a relatively fair sensitivity and
specificity [12]. Two cutoff values were used to define vitamin B12
deficiency: a liberal cutoff with serum concentrations lower than 206
pmol/L [13] and a restrictive cutoff value with serum concentrations
lower than 140 pmol/L [14, 15], reflecting a deeper deficiency and a
greater specificity. In addition to its acceptance as a cutoff for defi-
nite deficiency, the 140 pmol/L cutoff is similar to our institutional
laboratory lower limit of reference range. Anemia was defined as
hemoglobin level ≤14.0 and ≤ 12.0 g/dL for men and women respec-
tively [13]. Hyperhomocysteinemia was defined as serum homocys-
teine levels of 15.0 μmol/L or higher [16]. Folate deficiency was de-
fined based on serum folate levels using a cutoff value of 12.2 nmol/L
or lower [13]. The renal function was evaluated using the Chronic
Kidney Disease Epidemiology Collaboration equation, treated as a
dichotomous variable with normal estimated glomerular filtration
rate (eGFR) defined as equal to 90 mL/min/1.73 m2 or higher [17].
Transferrin saturation was calculated as iron divided by iron-bind-
ing capacity (i.e., transferrin multiplied by 1.25) [18].
Statistical analyses included a univariate analysis implement-
ing Student’s t test and chi-square test for continuous and cate-
gorical variables respectively. A multivariate analysis conducted
implementing logistic regression models adjusted for universal
confounders and possible interfering factors. Sensitivity analyses
were thereafter carried out. As anemia may interfere with serum
components related to the consequences of vitamin B12 deficien-
cy, data were reanalyzed after an exclusion of individuals with
anemia. As homocysteine and folate share the biochemical path-
ways with vitamin B12, an additional analysis was implemented
after the exclusion of individuals with hyperhomocysteinemia or
follate deficiency. As gender differences are at least partially re-
lated to hormonal alterations, all analyses were repeated with
stratification to 2 age groups: before and after the age of 55 (by
which time menopause is certainly assumed for the entire female
For all analyses, a p value of <0.05 was considered significant.
Statistical analysis was carried out using IBM SPSS version 23.
The study was approved by the Institutional Review Board.
Between May 2000 and October 2014, 25,511 individ-
uals aged 18–65 underwent a routine evaluation in the
RMC. Of these, 14,440 had a documented serum vitamin
B12 level during their last visit. After excluding individu-
als with background illnesses, regular medications and
consumption of vitamins or other nutritional supple-
ments, 7,963 allegedly healthy individuals were included
for analysis.
Women’s mean vitamin B12 level was significantly
higher, measured 312.36 (SD 134.10) pmol/L for wom-
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Vitamin B12 Deficiency and Gender
Ann Nutr Metab 2018;72:265–271
DOI: 10.1159/000488326
en and 284.31 (SD 116.88) pmol/L for men (p< 0.001).
Of the total study population, 1,865 (23.4%) were iden-
tified with vitamin B12 deficiency using the 206 pmol/L
cutoff value, and 286 individuals (3.6%) were identified
with severe deficiency using the 140 pmol/L cutoff val-
ue. Patients’ characteristics and laboratory parameters
of interest are shown in Table 1. Men had a significant-
ly higher prevalence of vitamin B12 deficiency. Of the
men, 25.5 and 4.2% had serum vitamin B12 levels <206
and <140 pmol/L respectively; Of the women, 18.9 and
2.3% had serum vitamin B12 levels <206 and <140
pmol/L respectively (p< 0.001 for both comparisons).
Individuals with vitamin B12 deficiency had higher se-
rum homocysteine levels and lower folate levels. Their
albumin, eGFR, and transferrin saturation levels were
significantly lower, while their uric acid and hemoglo-
bin values were slightly higher. Individuals with vitamin
B12 deficiency also had lower high density lipoprotein
and higher triglyceride levels. Among the total study
population, albumin ranged 3.3–6.0 g/dL with a mean
level of 4.51 (SD 0.27) g/dL and mean levels of 4.56 and
4.40 g/dL for men and women respectively (p< 0.001).
These levels remained unchanged when analysis was re-
stricted to non-anemic individuals with normal homo-
cysteine and FA levels.
The results of the multivariate analysis are shown in
Table 2. Men were more likely than women to be diag-
nosed with vitamin B12 deficiency (OR 1.46, 95% CI
1.30–1.65 for all cases of deficiency; 1.82, 95% CI 1.36–
2.43 for severe deficiency). When adjusted for age, body
mass index, eGFR status, hyperhomocysteinemia, and fo-
late deficiency, the OR declined. However, the greater risk
for men remained significant. When further adjustments
additionally included both albumin and transferrin, OR
remained high, and the risk for severe vitamin B12 defi-
ciency was nearly twofold greater for men in comparison
to women.
When analysis was restricted to non-anemic individ-
uals with normal homocysteine and FA levels, the ad-
justed odds ratio for men raised to 1.60 (95% CI 1.35–
1.90) for all deficiency cases and to 2.26 (95% CI 1.43–
3.56) for severe deficiency cases. Data stratification
Table 1. Patients’ characteristics according to their serum vitamin B12 status. A cross-sectional study of 7,963 healthy adults who
underwent screening at Rabin Medical Center, 2000–2014
Serum vitamin B12 level Total
(n= 7,963)
(≥206 pmol/L; n= 6,098)
(<206 pmol/L; n= 1,865)
p value
Gender, n (%) <0.001
Male 5,478 (100) 4,083 (74.5) 1,395 (25.5)
Female 2,485 (100) 2,015 (81.1) 470 (18.9)
Age, years 45.13±7.96 45.08±7.96 45.30±7.93 0.285
BMI, kg/m226.36±4.18 26.31±4.19 26.55±4.12 0.025
eGFR*, mL/min/1.73 m297.35±13.65 97.87±13.51 95.63±13.98 <0.001
Hemoglobin, g/dL 14.35±1.34 14.32±1.29 14.46±1.48 <0.001
MCV, fL 85.84±7.00 85.96±6.98 85.47±7.00 0.009
Transferrin saturation** 31.37±12.06 31.56±12.08 30.78±11.96 0.015
Glucose, mg/dL 95.74±14.59 95.79±15.07 95.55±12.88 0.521
Albumin, g/dL 4.51±0.27 4.52±0.26 4.48±0.28 <0.001
Uric acid, mg/dL 5.50±1.39 5.46±1.39 5.64±1.40 <0.001
Homocysteine, μmol/L 11.69±5.64 10.92±4.11 14.23±8.50 <0.001
Folate, nmol/L 19.37±8.26 20.06±8.47 17.10±7.07 <0.001
TSH, μIU/L 1.90±1.64 1.90±1.44 1.92±2.18 0.708
Total cholesterol, mg/dL 199.29±36.79 199.47±36.70 198.72±37.06 0.443
HDL, mg/dL 51.55±12.57 52.26±12.77 49.22±11.60 <0.001
Triglycerides, mg/dL 123.17±80.65 120.01±76.60 133.48±91.99 <0.001
p value for differences between groups, calculated using Student t test for continuous variables and chi-square test for categorical
data. Unless stated otherwise, figures represent mean (SD).
Statistically significant difference.
*Calculated according to the Chronic Kidney Disease Epidemiology Collaboration equation.
**Transferrin saturation= (serum iron/[serum transferrin * 1.25]) * 100.
BMI, body mass index; eGFR, estimated glomerular filtration rate; MCV, mean corpuscular volume; TSH, thyroid stimulating hor-
mone; HDL, high density lipoprotein.
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according to age groups suggested that the excessive
risk for men to be diagnosed with vitamin B12 defi-
ciency was slightly greater before the age of 55 (OR
1.66, 95% CI 1.38–2.00). Among the older age group,
the results were not significant, but the point estimate
suggested a lesser risk for men (OR 1.35, 95% CI 0.87–
Multivariable logistic regression analysis was estab-
lished with adjustments for possible confounders (Ta-
ble 3). As expected, hyperhomocysteinemia and folate
deficiency were significantly associated with vitamin
B12 deficiency. In addition, albumin was found as a de-
termining factor for vitamin B12 deficiency among
healthy individuals. With each rise of 1 gram of albu-
min, the risk for vitamin B12 deficiency declined by
58% (95% CI 48–67). Both transferrin saturation and
albumin level were negatively associated with vitamin
B12 deficiency. Normal renal function was also nega-
tively associated, although it had a lesser protective
In the current study, we found that vitamin B12 defi-
ciency is relatively common among the Middle Eastern
healthy population with a prevalence of 23%. The study
revealed that gender plays a role in vitamin B12 metabo-
lism, with a twofold greater risk for deficiency among
men, independent of anemia, folate, and homocysteine
status. Although the prevalence is similar to the level re-
ported in a neighboring Middle Eastern country, the gen-
der differences are surprising [19].
Diseases along the gastrointestinal tract may cause vi-
tamin B12 deficiency, by hampering normal food-cobal-
amin absorption. These include predominantly gastric
diseases such as Helicobacter pylori infection, atrophic
gastritis, gastric surgery [20], or cancer [21] but also in-
clude inflammatory bowel disease [22], diabetes mellitus,
Table 3. Determining factors for vitamin B12 deficiency (serum
level lower than 206 pmol/L). A cross-sectional study of 7,963
healthy adults who underwent screening at Rabin Medical Center,
2000–2014. OR adjusted using logistic regression
OR 95% CI
Gender, male 1.47 1.28–1.68
Age, years 0.99 0.99–1.00
BMI, kg/m21.00 0.98–1.01
Normal eGFR (≥90 mL/min/1.73 m2) 0.82 0.72–0.93
Hyperhomocysteinemia (>15.0 μmol/L) 3.26 2.79–3.81
Folate deficiency (<12.2 nmol/L) 1.20 1.05–1.39
Albumin, g/dL 0.42 0.33–0.52
Transferrin saturation*0.47 0.30–0.76
ᵠStatistically significant determinant.
* Transferrin saturation = (serum iron/[serum transferrin *
1.25]) * 100.
BMI, body mass index; eGFR, estimated glomerular filtration
Table 2. Male gender as a determining factor for vitamin B12 deficiency. A cross-sectional study of 7,963 healthy adults who underwent
screening at Rabin Medical Center, 2000–2014. OR with adjustments and sensitivity analyses using logistic regression models (95% CI)
Vitamin B12 deficiency <140 pmol/L <206 pmol/L
all participants all participants age <55 years age ≥55 years
Unadjusted 1.82 (1.36–2.43) 1.46 (1.30–1.65) 1.47 (1.30–1.67) 1.41 (1.00–1.98)
Model 1a1.33 (0.96–1.83) 1.18 (1.04–1.34) 1.18 (1.03–1.35) 1.20 (0.84–1.71)
Model 2b1.85 (1.32–2.60) 1.40 (1.23–1.60) 1.40 (1.21–1.61) 1.31 (0.91–1.88)
Model 3c2.02 (1.43–2.86) 1.47 (1.28–1.68) 1.44 (1.24–1.67) 1.48 (1.02–2.15)
Sensitivity analysis 1d2.05 (1.33–3.14) 1.56 (1.33–1.83) 1.61 (1.35–1.91) 1.32 (0.88–2.00)
Sensitivity analysis 2e2.26 (1.43–3.56) 1.60 (1.35–1.90) 1.66 (1.38–2.00) 1.35 (0.87–2.09)
aAdjusted for age, BMI, eGFR status, hyperhomocysteinemia, and folate deficiency.
bAdjusted for age, BMI, eGFR status, hyperhomocysteinemia, folate deficiency, and albumin.
cAdjusted for age, BMI, eGFR status, hyperhomocysteinemia, folate deficiency, albumin, and transferrin saturation.
dIndividuals with normal homocysteine and folate levels (n= 5,926), adjusted for age, BMI, eGFR status, albumin, and transferrin
eNon-anemic individuals who have normal homocysteine and folate levels (n= 5,151), adjusted for age, BMI, eGFR status, albumin,
and transferrin saturation.
BMI, body mass index; eGFR, estimated glomerular filtration rate.
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DOI: 10.1159/000488326
or thyroid diseases [20]. As the current study encom-
passed a healthy population, it is unlikely that an underly-
ing significant disease could mediate the association be-
tween men and vitamin B12 deficiency. Celiac disease
may have a more concealing nature; however, it predom-
inantly affects women [23] and its local prevalence is low-
er than 1% [24, 25]. Therefore, it cannot explain the ob-
served phenomenon.
In 2014, 4.7% of the local population identified them-
selves as vegetarians (abstaining from consuming meat
and usually also fish) and an additional 1.7% identified
themselves as vegans (abstaining from consumption of
all animal-derived products). These rates reached 9.0%
for both diet styles among individuals with higher edu-
cation [26]. Individuals following either vegetarianism
or veganism are highly susceptible to vitamin B12 defi-
ciency [27]. It has been recently demonstrated that con-
sumption of a well-balanced diet including supple-
ments, as required, can potentially fulfill all nutritional
requirements [28]. Nonetheless, one may hypothesize
that the study included vegetarians or vegans who do
not consume supplements and are potentially at risk for
vitamin B12 deficiency. However, the rate of vegetarian
or vegan women is almost twice as higher than that of
men [26], suggesting that diet alone could not explain
the observed relationship between male gender and vi-
tamin B12 deficiency.
As most included individuals were adults younger
than 50 years, the stratification to age groups reduced the
statistical power in the older age group. Nonetheless, gen-
der differences at the risk for vitamin B12 deficiency,
tended to diminish with age. As menopause is almost cer-
tain at the age of 55, estrogen may play a protective role
against vitamin B12 deficiency. Higher estrogen status
was previously reported to be associated with decreased
serum homocysteine levels [29]. It was postulated that
estrogen decreases methionine levels by stimulating me-
thionine transamination, thus decreasing homocysteine
levels. Nonetheless, hormonal replacement therapy did
not alter serum vitamin B12 levels [30, 31]. Although sev-
eral studies reported that oral contraceptives decreased
serum vitamin B12 levels, there is currently no concrete
evidence for any such influence [32]. Even if endogenous
estrogen somehow plays a protective role, it seems that
the findings of the current study cannot be solely ex-
plained by estrogen. A further research on the role of es-
trogen in the one carbon metabolism is therefore war-
In the current study, albumin was inversely associated
with vitamin B12 deficiency. It is well established that al-
bumin is positively associated with muscle mass [33]. It
was also established that vitamin B12 deficiency may lead
to sarcopenia [34]. This can explain the observed inverse
association between albumin and vitamin B12 deficiency,
although it is somewhat surprising, considering that the
study population was relatively young and healthy. In ad-
dition, albumin was also inversely associated with high
serum vitamin B12 levels (>664 pmol/L) [35]. The rela-
tionship between albumin and vitamin B12 may also be
mediated through Cubilin, an enzyme that facilitates
both the absorption of the B12-Intrinsinc factor complex
in the ileum and the reabsorption of the majority of the
filtered albumin from the urine [36]. The association be-
tween vitamin B12 and albumin awaits further clarifica-
Genetic factors may explain sex differences. Single
nucleotide polymorphism (SNP) in the gene fucosyl-
transferase 2 has been associated with vitamin B12 absorp-
tion and serum concentration [37]. It has been suggested
to interact with diet and to significantly contribute the
high prevalence of vitamin B12 deficiency in India [38].
The fucosyl-transferase 2 gene is located within chromo-
some 19, in which sex-specific probability for recombina-
tion has been shown [39]. Moreover, sex-related associa-
tions with SNPs have been recently demonstrated for cor-
onary artery disease, suggesting that a specific SNP could
influence each sex differently [40]. We therefore hypoth-
esize that genetic polymorphism within the local popula-
tion is likely to explain the observed association between
men and vitamin B12 deficiency. However, this is yet to be
examined in future genetic research.
The current study has several limitations. The cross-
sectional design hinders the ability to infer causality re-
garding the different determinants of vitamin B12 defi-
ciency. However, due to the inherent nature of sex, tem-
porality is not actually absent for the main examined
association. The direction of the association could there-
fore not be mistakenly interpreted. Additionally, repeat-
ed measurements generally have an added value in infer-
ring causation. However, the study focuses on inter-gen-
der relations, and these are not expected to change
significantly over time.
Nutrition is of utmost importance in regard to vitamin
B12 metabolism. Due to the retrospective nature of the
study, data on nutritional habits of the participants were
unavailable. Such data could have cast some light on the
mechanism for the observed gender differences. In addi-
tion, as data on medications and supplements consump-
tion was self-reported, a reporting bias might exist, that
is, individuals could potentially avoid disclosing their real
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Ann Nutr Metab 2018;72:265–271
DOI: 10.1159/000488326
intake. However, such a bias is expected to be insignifi-
cant, as the reporting bias for group B vitamin consump-
tion, was shown to be generally low [41].
Another limitation is related to the fact that the major-
ity of the examined population were white collar workers.
This homogeneity may diminish the study’s external va-
lidity. Yet, as the study demonstrated firm evidence for
gender differences, it is likely that these represent a phe-
nomenon prevailing beyond a specific socioeconomic
To our knowledge, this study is the first to demon-
strate a strong association between gender and vitamin
B12 deficiency among the non-elderly healthy adult
population. Men were found more likely to be diagnosed
with both mild and severe vitamin B12 deficiency. The
causative mechanism for this phenomenon remains to
be determined, although genetic variations including
sex-related genetic expressions are likely to play an im-
portant role. Revealing the relations between gender and
vitamin B12 deficiency may contribute to the develop-
ment of screening guidelines, early identification of in-
dividuals at risk, and potentially to prevent its conse-
Disclosure Statement
The authors have no conflicts of interest to disclose.
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... Deficiency of vitamin B12, an important methyl-cobalamin synthesis enzyme, can lead to impaired Hcy re-methylation and Hcy accumulation 17 . Additionally, vitamin B12 deficiency was found to be significantly associated with gender, and the mean values of serum vitamin B12 concentration for men are lower than those for women 21,22 . The above suggest that vitamin B12 may explain the relationship between gender and Hcy concentration. ...
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The primary goals of this study were to evaluate the gender- and age-related differences in homocysteine concentration in the general population of China and possible influencing factors. A total of 7872 subjects, divided into male and female groups, participated in this retrospective study. The average homocysteine level, prevalence of hyperhomocysteinemia, and independent factors affecting homocysteine concentration were analyzed. The homocysteine level was significantly higher in males than in females in each age range (aged 20–30, aged 30–40, aged 40–50, aged 50–60, aged 60–80, aged over 80) (P < 0.0001), and the trend did not abate with age. The homocysteine concentration first decreased and then increased, being lowest at 30–50 years of age and significantly increased after 50 years of age. Factors associated with homocysteine concentration in males were smoking status (current smokers versus ex-smokers: β: 0.112), estimated glomerular filtration rate (β = − 0.192), blood urea nitrogen (β = − 0.14), diastolic blood pressure (β = − 0.113), free triiodothyronine (β = − 0.091), serum potassium (β = − 0.107) and cystatin C (β = 0.173). In females, independent factors associated with homocysteine concentration were cystatin C (β = 0.319), albumin (β = 0.227), free thyroxine (β = 0.179), age (β = 0.148), free triiodothyronine (β = − 0.217) and serum potassium (β = − 0.153). The homocysteine level was significantly higher in males than in females and increased markedly after 50 years of age in both groups. The independent factors associated with increased homocysteine concentration differed between males and females.
... Green et al. (2017) reviewed many studies and found that 2.5-26% of the general population is affected by sub-clinical deficiency of vitamin B 12 all over the world. Margalit et al. (2018) reported a higher prevalence of vitamin B 12 deficiency in men (25.5 %) than in women (18.9 %). A study conducted in south India revealed 35 % prevalence of vitamin B 12 deficiency with vegetarians (54 %) at a greater risk than population consuming mixed diet (31 %) (Sivaprasad et al., 2016). ...
Fortification of commodity foods has been accepted as a successful strategy to overcome micronutrient deficiencies. This work evaluates the stability of vitamin B12 and vitamin D3 during different processing techniques and/or storage. Kinetic behavior of vitamins B12 and D3 degradation in fortified whole wheat flour (FWWF) during storage at varying temperature and relative humidity (RH) was evaluated. An increase in temperature accelerated the degradation of both vitamins in FWWF during storage. However, RH affected the degradation of vitamin D3 but not that of vitamin B12. Products prepared from FWWF showed highest retention of vitamin B12 in chapatti (91%) and vitamin D3 in cake (84%), respectively. Retention of vitamins B12 and D3 was lowest (14% and 10% respectively) during frying. Further stability of vitamin D3 was evaluated during multiple frying cycles of vitamin D3-fortified rice bran oil (FRBO) in batter based and dough based products. Absorption of vitamin D3 in both the products reduced significantly and progressively after the first frying cycle. Dough based products showed better absorption of vitamin D3 from FRBO during frying. This work will help to establish suitable fortification limits in the wheat flour and edible oil considering processing and storage losses.
... Studies on pre-adolescent children and infants indicate that prevalence of anemia and iron deficiency are significantly higher in males than in females (Marino et al., 2011;Woodhead et al., 1991), possibly corroborating the idea that cribra cranii may occur with higher frequencies in children males. Similarly, previous work suggests that vitamin B 12 deficiency is more common in males than in females, with a higher incidence of severe cases in men (Margalit et al., 2018). Similarly, endocranial lesions are more frequent in males (5/11) than in females (0/13), likely indicating an averagely worst health status for male children. ...
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In this work, osteological and paleopathological analyses are combined with liquid-chromatography mass spectrometry to study life and death of 30 non-adult individuals from an Early Medieval Italian funerary context (Valdaro, 7th-8th cent. AD). We estimated individual sex by exploiting sexual differences in enamel-bounded peptides. Enamel proteins were extracted through an acid etching of the whole tooth crowns for 4 samples and through a partial digestion of small enamel chunks for the remaining 26 samples. Both protocols were informative on the sex of the individuals through the identification of amelogenin isoforms (AMELX and AMELY). In addition, low-mineralized tooth germs were analysed and they provided reliable information on the infants' sex. We observed the presence of 13 males and 17 females among the non-adults of Valdaro, not significantly different from a random sample with an equal frequency of males and females. Cribra cranii and endocranial lesion occurrence showed an association with sex, with higher frequencies in male individuals.
... Gender is another factor that could play a role in vitamin B12 metabolism. Although epidemiological studies evaluating the prevalence of vitamin B12 in vegetarians did not report significant differences between sexes (6) , a recent analysis of a large cohort of healthy adults found that males had a risk of deficiency twice as high as females (24) . The causal mechanism of this phenomenon is yet to be determined, but previous studies have shown that genetic variations related to sex and estrogen status could be involved in the absorption of vitamin B12 and the resulting circulating levels (25) . ...
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Previous studies have suggested that vegetarianism can result in a reduction of vitamin B 12 circulating levels. The aim of the present study was to investigate the effects of a 3-month dietary intervention with a lacto-ovo-vegetarian diet (VD) on the levels of circulating vitamin B 12 in a group of omnivores. We analysed fifty-four omnivorous subjects who followed a VD as a first dietary intervention within the CARDIVEG (Cardiovascular Prevention with Vegetarian Diet) study, a dietary intervention study. VD resulted in a significant reduction ( P <0·001) of 51·2 % of vitamin B 12 intake and in a significant reduction ( P =0·005) of 6·2 % of the circulating levels of vitamin B 12 (–24·5 pg/ml). Changes in vitamin B 12 intake were significantly correlated with changes in circulating levels of vitamin B 12 ( R 0·61, P <0·001). Subgroup analyses showed that reduction in circulating vitamin B 12 levels was more evident in participants who were younger, overweight, non-smokers and had hypercholesterolaemia. A logistic regression analysis showed that a reduction in vitamin B 12 intake greater than the first quartile of the delta changes obtained in the study population (–28·5 %) conferred a significantly higher risk of experiencing a decrease in circulating vitamin B 12 levels (OR 10·1; 95 % CI 1·3, 76·1). In conclusion, a 3-month VD period determined a significant reduction in circulating levels of vitamin B 12 , being significantly correlated with the reduction in vitamin B 12 intake. Although a well-planned VD can provide adequate nutrition across all life stages, special care must be taken to ensure adequate vitamin B 12 intake and to help prevent deficiency.
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Amaç: Bu çalışmada farklı tiplerinde değişen oranlarda multisistemik tutuluma, nörolojik bulguların da eşlik ettiği mukopolisakkaridozlu hastalarda, serum vitamin B12 düzeylerinin de klinik seyir üzerine etkisi araştırılmıştır.Gereç ve Yöntem: Bu çalışmaya enzim düzeyi ve mutasyon analizi ile mukopolisakkaridoz tanısı konulan 114 hasta çalışmaya dahil edildi. Bu hastalardan periyodik takipleri sırasında sistemik ve nörolojik değerlendirmeye ek olarak serum vitamin B12 düzeyleri ölçüldü. Vitamin B12 düzeyi <300 pg/ml eksiklik olarak kabul edildi.Bulgular: Ortalama serum vitaminB12 seviyeleri 399,4 ± 258,5 pg/mL idi. Hastaların 53’ünde (%46,5) serum B12 seviyesi 300 pg/ml'nin altındaydı. Mukopolisakkaridozlu çocuklarda serum B12 vitamini düzeyi, literatürdeki sağlıklı çocuklardan önemli ölçüde düşüktü. Erkeklerde vitamini B12 eksikliği kızlara göre istatistiksel olarak anlamlı derecede fazlaydı. Tipler arası değerlendirmede MPS tip II tanılı hastalarda vitamin B12 düzeyindeki düşüklüğün anlamlı olarak diğer alt gruplardan daha yüksek olduğu görüldü.Sonuç: Mukopolisakkaridozlu hastalarda etiyopatogenezi net olmamakla birlikte, vitamin B12 seviyesi sağlıklı ve kronik hastalığı olan diğer bireylerden daha düşük bulunmuştur. Vitamin B12 eksikliği hastalığın doğal seyrinde ki büyüme geriliği ve nöromotor fonksiyon etkilenmesini daha da arttıracağı için, çalışmamız sonucunda mukopolisakkaridozlu hastalarda vitamin B12 düzeyinin de rutin monitorizasyonunun gerekliliği ortaya konulmuştur.
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Elevated homocysteine in the blood, or hyperhomocysteinemia, is a recognized risk factor for multiple causes of dementia including Alzheimer’s disease. While reduction of homocysteine levels can generally be accomplished in a straightforward manner, the evidence regarding the cognitive benefits of this approach is less clear. To identify adjunct therapeutic targets that might more effectively restore cognition, the present series of experiments characterizes early and later cerebrovascular changes in a model of hyperhomocysteinemia. Sex-balanced groups of adult C57BL/6J mice were administered a diet deficient in vitamins B6, B12, and B9 (folate) and supplemented with excess methionine. They were subsequently assessed for changes in cerebral blood flow, memory, blood–brain barrier permeability, and selected vascular-associated genes. Blood flow deficits and barrier permeability changes occurred alongside changes in memory and in genes associated with metabolism, endothelial nitric oxide signaling, barrier integrity, and extracellular matrix remodeling. Significant sexually dimorphic responses to the diet were also detected. Taken together, these data deepen our understanding of a major contributor to dementia burden.
Background and aims High concentrations of homocysteine are considered a risk factor for atherosclerosis and coronary artery disease. The aim of this study was to assess whether or not there are gender differences in the plasma concentrations of homocysteine. Methods and results Data were collected from medical records of individuals examined at a screening center in Israel between the years 2000–2014. Cross sectional analysis was carried out on 9237 men and 4353 women. Mean (SD) age of the study sample was 48.4 (9.7) and 47.7 (9.7) years for men and women respectively. Average homocysteine concentrations were 12.6 (5.9) and 9.6 (3.2) μmol/L in men and women respectively (p < 0.001). Prevalence of homocysteine concentrations above 15 μmol/L was found to be significantly higher in men than in women; 15.5% vs 3.9% respectively (p < 0.001). Low concentrations of vitamin (B12 < 200 pmol/L) and low concentrations of folate (<12 nmol/L) were found to be significantly higher in men than in women 20.4% vs. 16.0% and 18.5% vs. 10.8% respectively. Compared to women, men had a significantly higher odds ratio (95% CI) of having homocysteine concentrations above 15 μmol/L: non adjusted model, 4.47 (3.80–5.26); adjusted model for age, smoking status, body mass index, diabetes mellitus, kidney function and low serum concentrations of vitamin B12 and folate, 3.44 (2.89–4.09). Conclusion Plasma homocysteine concentrations are higher in men than in women. This may be a contributing factor to gender differences for developing atherosclerosis and coronary artery disease.
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Identification of modifiable risk factors provides a crucial approach to the prevention of dementia. Nutritional or nutrient-dependent risk factors are especially important because dietary modifications or use of dietary supplements may lower the risk factor level. One such risk factor is a raised concentration of the biomarker plasma total homocysteine, which reflects the functional status of three B vitamins (folate, vitamins B12, B6). A group of experts reviewed literature evidence from the last 20 years. We here present a Consensus Statement, based on the Bradford Hill criteria, and conclude that elevated plasma total homocysteine is a modifiable risk factor for development of cognitive decline, dementia, and Alzheimer's disease in older persons. In a variety of clinical studies, the relative risk of dementia in elderly people for moderately raised homocysteine (within the normal range) ranges from 1.15 to 2.5, and the Population Attributable risk ranges from 4.3 to 31%. Intervention trials in elderly with cognitive impairment show that homocysteine-lowering treatment with B vitamins markedly slows the rate of whole and regional brain atrophy and also slows cognitive decline. The findings are consistent with moderately raised plasma total homocysteine (>11 μmol/L), which is common in the elderly, being one of the causes of age-related cognitive decline and dementia. Thus, the public health significance of raised tHcy in the elderly should not be underestimated, since it is easy, inexpensive, and safe to treat with B vitamins. Further trials are needed to see whether B vitamin treatment will slow, or prevent, conversion to dementia in people at risk of cognitive decline or dementia.
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It is well-known that processing speed and executive functions decline with advancing age. However, physical activity (PA) has a positive impact on cognitive performances in aging, specifically for inhibition. Less is known concerning intraindividual variability (iiV) in reaction times. This study aims to investigate the influence of PA and sex differences on iiV in inhibitory performance during aging. Healthy adults were divided into active and sedentary groups according to PA level. To analyse iiV in reaction times, individual mean, standard deviation and the ex-Gaussian parameters were considered. An interaction between activity level and sex was revealed, sedentary females being slower and more variable than sedentary men. No sex differences were found in the active groups. These results indicate that the negative impact of sedentariness on cognitive performance in older age is stronger for females. The present findings underline the need to consider sex differences in active aging approaches.
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Importance: It is unclear whether female carriers of the apolipoprotein E (APOE) ε4 allele are at greater risk of developing Alzheimer disease (AD) than men, and the sex-dependent association of mild cognitive impairment (MCI) and APOE has not been established. Objective: To determine how sex and APOE genotype affect the risks for developing MCI and AD. Data sources: Twenty-seven independent research studies in the Global Alzheimer's Association Interactive Network with data on nearly 58 000 participants. Study selection: Non-Hispanic white individuals with clinical diagnostic and APOE genotype data. Data extraction and synthesis: Homogeneous data sets were pooled in case-control analyses, and logistic regression models were used to compute risks. Main outcomes and measures: Age-adjusted odds ratios (ORs) and 95% confidence intervals for developing MCI and AD were calculated for men and women across APOE genotypes. Results: Participants were men and women between ages 55 and 85 years. Across data sets most participants were white, and for many participants, racial/ethnic information was either not collected or not known. Men (OR, 3.09; 95% CI, 2.79-3.42) and women (OR, 3.31; CI, 3.03-3.61) with the APOE ε3/ε4 genotype from ages 55 to 85 years did not show a difference in AD risk; however, women had an increased risk compared with men between the ages of 65 and 75 years (women, OR, 4.37; 95% CI, 3.82-5.00; men, OR, 3.14; 95% CI, 2.68-3.67; P = .002). Men with APOE ε3/ε4 had an increased risk of AD compared with men with APOE ε3/ε3. The APOE ε2/ε3 genotype conferred a protective effect on women (OR, 0.51; 95% CI, 0.43-0.61) decreasing their risk of AD more (P value = .01) than men (OR, 0.71; 95% CI, 0.60-0.85). There was no difference between men with APOE ε3/ε4 (OR, 1.55; 95% CI, 1.36-1.76) and women (OR, 1.60; 95% CI, 1.43-1.81) in their risk of developing MCI between the ages of 55 and 85 years, but women had an increased risk between 55 and 70 years (women, OR, 1.43; 95% CI, 1.19-1.73; men, OR, 1.07; 95% CI, 0.87-1.30; P = .05). There were no significant differences between men and women in their risks for converting from MCI to AD between the ages of 55 and 85 years. Individuals with APOE ε4/ε4 showed increased risks vs individuals with ε3/ε4, but no significant differences between men and women with ε4/ε4 were seen. Conclusions and relevance: Contrary to long-standing views, men and women with the APOE ε3/ε4 genotype have nearly the same odds of developing AD from age 55 to 85 years, but women have an increased risk at younger ages.
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To determine whether sex differences affect the association between genetic polymorphisms and coronary artery disease (CAD) in the Chinese Han population, we conducted a study comparing the frequency of SH2B3 and SMARCA4 variants in 456 CAD patients (291 men, 165 women) and 685 age-matched controls (385 men, 300 women). Ten single nucleotide polymorphisms (SNPs) in SH2B3 and SMARCA4 were genotyped using MassARRAY technology. Allelic and genotypic models and haplotype frequencies were compared between groups. Logistic regression was used to estimate the CAD risk associated with the genotypes. We found that the “A” alleles in both rs11879293 and rs12232780 of SMARCA4 were associated with CAD risk in men (p = 0.036 and p = 0.001, respectively). The genetic model showed that SH2B3 was associated with CAD susceptibility in both women and men, while SMARCA4 was associated with reduced odds of CAD in men. SH2B3 haplotypes were associated with decreased CAD risk in women (p = 0.007) and increased CAD risk in men (p = 0.047). By providing evidence for the sex-related association between SH2B3 and SMARCA4 gene variants and CAD susceptibility in the Chinese Han population, this study may help define useful diagnostic and preventive markers for these patients.
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Vitamin B12 (B12; also known as cobalamin) is a B vitamin that has an important role in cellular metabolism, especially in DNA synthesis, methylation and mitochondrial metabolism. Clinical B12 deficiency with classic haematological and neurological manifestations is relatively uncommon. However, subclinical deficiency affects between 2.5% and 26% of the general population depending on the definition used, although the clinical relevance is unclear. B12 deficiency can affect individuals at all ages, but most particularly elderly individuals. Infants, children, adolescents and women of reproductive age are also at high risk of deficiency in populations where dietary intake of B12‑containing animal-derived foods is restricted. Deficiency is caused by either inadequate intake, inadequate bioavailability or malabsorption. Disruption of B12 transport in the blood, or impaired cellular uptake or metabolism causes an intracellular deficiency. Diagnostic biomarkers for B12 status include decreased levels of circulating total B12 and transcobalamin-bound B12, and abnormally increased levels of homocysteine and methylmalonic acid. However, the exact cut-offs to classify clinical and subclinical deficiency remain debated. Management depends on B12 supplementation, either via high-dose oral routes or via parenteral administration. This Primer describes the current knowledge surrounding B12 deficiency, and highlights improvements in diagnostic methods as well as shifting concepts about the prevalence, causes and manifestations of B12 deficiency.
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Background: Inflammatory bowel disease (IBD) patients may be at risk of vitamin B12 and folate insufficiencies, as these micronutrients are absorbed in the small intestine, which is affected by IBD. However, a consensus has not been reached on the association between IBD and serum folate and vitamin B12 concentrations. Methods: In this study, a comprehensive search of multiple databases was performed to identify studies focused on the association between IBD and serum folate and vitamin B12 concentrations. Studies that compared serum folate and vitamin B12 concentrations between IBD and control patients were selected for inclusion in the meta-analysis. Results: The main outcome was the mean difference in serum folate and vitamin B12 concentrations between IBD and control patients. Our findings indicated that the average serum folate concentration in IBD patients was significantly lower than that in control patients, whereas the mean serum vitamin B12 concentration did not differ between IBD patients and controls. In addition, the average serum folate concentration in patients with ulcerative colitis (UC) but not Crohn's disease (CD) was significantly lower than that in controls. This meta-analysis identified a significant relationship between low serum folate concentration and IBD. Conclusions: Our findings suggest IBD may be linked with folate deficiency, although the results do not indicate causation. Thus, providing supplements of folate and vitamin B12 to IBD patients may improve their nutritional status and prevent other diseases.
Previous studies have found associations between one-carbon metabolism nutrients and risk of several cancers, but little is known regarding upper gastrointestinal tract (UGI) cancer. We analyzed pre-diagnostic serum concentrations of several one-carbon metabolism nutrients (vitamin B12, folate, vitamin B6, riboflavin, and homocysteine) in a nested case-control study within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study of male smokers, which was undertaken in Finland between 1985 and 1988. We conducted a nested case-control study including 127 non-cardia gastric adenocarcinoma (NCGA), 41 esophago-gastric junctional adenocarcinoma (EGJA), and 60 esophageal squamous cell carcinoma (ESCC) incident cases identified within ATBC. Controls were matched to cases on age, date of serum collection, and follow-up time. One-carbon nutrient concentrations were measured in fasting serum samples collected at baseline (up to 17 years prior to cancer diagnosis). Odds ratios (OR) and 95% confidence intervals (CI) were calculated using conditional logistic regression. Lower pre-diagnostic vitamin B12 concentrations at baseline were associated with a 5.8-fold increased risk of NCGA (95% CI = 2.7 to 12.6 for lowest compared to highest quartile, p-trend < 0.001). This association remained in participants who developed cancer more than 10 years after blood collection, and after restricting the analysis to participants with clinically normal serum vitamin B12 (>300 pmol/L). In contrast, pepsinogen I, a known serologic marker of gastric atrophy, was not associated with NCGA in this population. As vitamin B12 absorption requires intact gastric mucosa to produce acid and intrinsic factor, our findings suggest vitamin B12 as a possible serologic marker for the atrophic gastritis that precedes NCGA, one more strongly associated with subsequent NCGA than pepsinogen. This article is protected by copyright. All rights reserved.
Sarcopenia and dynapenia are related to repeated falls, mobility restriction, depression, frailty, increased mortality and morbidity. The aim of this study is to evaluate the relationship between vitamin B12 deficiency and sarcopenia in older adults. 403 patients, who attended to outpatient clinic and underwent comprehensive geriatric assessment, were included study. All cases' skeletal muscle mass (SMM), walking speed and hand grip strength were recorded by bioimpedance, 4 meter walking test and hand dynamometer respectively. The diagnosis of sarcopenia was defined according to the criteria of the European Working Group on Sarcopenia in Older People. Sarcopenia was accepted low SMM with low handgrip strength or low physical performance. Dynapenia was defined as handgrip strength < 30 kg (men) and < 20 kg (women). The prevalence of sarcopenia and dynapenia was 24.8% and 32.0%, respectively. In the patients with sarcopenia, mean age, osteoporosis and frailty were higher, and MMSE, and instrumental ADL scores were lower than the patients without sarcopenia (p < 0.05). The frequency of sarcopenia and dynapenia were 31.6% and 35.4%, respectively, in patients with vitamin B12 levels < 400 pg/mL. In addition lean body mass, total skeletal mass and skeletal muscle mass index were lower in the patients with vitamin B12 levels < 400 pg/mL compared to higher than 400 pg/mL (p < 0.05). Sarcopenia, which results in lots of negative clinical outcomes in older adults, might be related to vitamin B12 deficiency. Therefore, these patients should be periodically examined for vitamin B12 deficiency due to the potential negative clinical outcomes such as sarcopenia in older adults.
Aim: The aim of the present study was to evaluate the age-specific prevalence of dementia, and develop a metabolic risk indicator for dementia according to sex. Methods: This cross-sectional study was carried out from September 2007 through December 2012 with 19 935 elderly participants in metropolitan Seoul, Korea. Multiphase assessments were used to measure metabolic risk factors and confirm dementia according to sex. Specifically, multivariate logistic regression analyses were used to identify how elderly men and women differed in regard to metabolic risk indicators of dementia. Results: The adjusted prevalence rates of dementia in elderly Seoul residents were estimated at 4.9%, 6.1% and 5.6% in men, women and the overall population, respectively. Stroke conferred an odds ratio of 5.14 (95% CI 3.91-6.77) and 2.55 (95% CI 2.01-3.25) in men and women, respectively. Additionally, within the female population, diabetes mellitus conferred an odds ratio of 1.29 (95% CI 1.09-1.53), whereas alcohol consumption conferred an odds ratio of 0.77 (95% CI 0.61-0.97). Conclusions: Stroke played a primary role as a metabolic risk indicator of dementia in elderly men, while diabetes mellitus and alcohol abstinence were important metabolic risk factors in elderly women. Taken together, the data show that when designing preventative measures against dementia based on metabolic risk, sex needs to be taken into account. Geriatr Gerontol Int 2017; ••: ••-••.