J Nutr Health Aging

Volume 19, Number 10, 2015

EXAMINING THE ASSOCIATION BETWEEN VITAMIN B12 DEFICIENCY AND

DEMENTIA IN HIGH-RISK HOSPITALIZED PATIENTS
O. SISWANTO1, K. SMEALL1, T. WATSON1, M. DONNELLY-VANDERLOO1,2, C. O’CONNOR1,
N. FOLEY1, J. MADILL1
1. Brescia University College, London, ON, Canada; 2 London Health Sciences Centre, London, ON, Canada. Corresponding author: J Madill, Brescia University College, London ON,
N6G1H2, Canada. jmadill7@uwo.ca

Abstract: Objectives: To explore the association between vitamin B12 deficiency and dementia in patients at
high risk for vitamin B12 deficiency. Design: Chart review. Setting: Emergency, critical care/ trauma, neurology,
medicine, and rehabilitation units of two hospitals in Southwestern Ontario, Canada. Participants: Adult patients
(n = 666) admitted from 2010 to 2012. Data collection included: reason for admission, gender, age, clinical signs
and symptoms of B12 deficiency, serum B12 concentration, and B12 supplementation. Patients with dementia
were identified based on their medication profile and medical history. Vitamin B12 deficiency (pmol/L) was
defined as serum B12 concentration <148; marginal deficiency: ≥148-220 and adequate >220. Comparisons
between B12-deficient patients with and without dementia were examined using parametric and non-parametric
tests. Results: Serum B12 values were available for 60% (399/666) of the patients, of whom 4% (16/399) were
B12-deficient and 14% (57/399) were marginally deficient. Patients with dementia were not more likely to
be B12-deficient or marginally deficient [21% (26/121)] compared to those with no dementia [17% (47/278),
p=0.27)]. Based on documentation, 34% (25/73) of the B12-deficient and marginally-deficient patients did not
receive B12 supplementation, of whom 40% (10/25) had dementia. Conclusion: In this sample of patients, there
was no association between B12 deficiency and dementia. However, appropriate B12 screening protocols are
necessary for high risk patient to identify deficiency and then receive B12 supplementation as needed.

Key words: Vitamin B12 supplementation, vitamin B12 deficiency, vitamin B12 screening, dementia, Canadian
hospital.

Introduction PPI therapy and B12 deficiency (manuscript in preparation).

Vitamin B12 (B12) is essential for normal blood formation
and neurological functions. Although some foods are fortified,
B12 can only be obtained from animal sources such as meat,
poultry, fish, dairy products, and eggs (1). Clinical signs of B12
deficiency are often non-specific and can include paresthesia,
weakness, gait abnormalities, depression, confusion, dementia,
and cognitive or behavioral changes (1). If left untreated, B12
deficiency may lead to serious and irreversible neurological
damage. Furthermore, mandatory folic acid fortification
may contribute to undiagnosed B12 deficiency by correcting
macrocytosis or normalizing mean corpuscular volume (MCV)
values while neurological damage progresses, thus masking
macrocytic anemia that is commonly associated with B12
deficiency (2).
In particular, older adults are especially vulnerable to B12
deficiency. Conditions such as atrophic gastritis are common
and for which proton-pump inhibitors (PPIs) are used for
treatment (3). PPIs reduce the production of stomach acid,
which is needed to release B12 that is bound to protein in food
(3). This separation process by gastric acid is not needed for the
absorption of B12 from oral supplements and fortified foods
because B12 from these sources exists in crystalline form (i.e.,
not bound to protein). While B12 can be administered via
intramuscular injection, high-dose oral B12 supplementation
(1000 to 2000 μg) taken daily is just as effective (4, 5).
Research by the current authors found no association between
Received September 3, 2014
Accepted for publication January 6, 2015
1003
Dementia is an umbrella term, used to encompass a group
of related neurodegenerative disorders including Alzheimer’s
disease, Lewy body dementia, frontotemporal dementia,
vascular dementia, and Parkinson’s disease dementia, and it
is associated with premature disability and death. Dementia is
of increasing concern as its prevalence is expected to increase
with an aging population. According to the World Health
Organization, there are 35.6 million people worldwide currently
living with dementia; this number will double by 2030 and
more than triple by 2050 (6). This increased prevalence of
dementia will burden the economy, by increasing demand for
long-term care (7). While associations between B12 deficiency
and dementia have been demonstrated previously (8–13),
the exact nature of the relationship is not well understood.
Possible mechanisms have been explored (14). For example,
serum vitamin B12 levels <308 pmol/L have been found to
be associated with brain atrophy (15) and greater severity
of white-matter lesions (16). Elevated concentrations of
homocysteine and/or methylmalonic acid (MMA), which are
thought to be neurotoxic in vitro, may also play a role (17, 18).
Because elevated homocysteine and MMA can be lowered with
B12 supplementation, it is considered a potentially modifiable
risk factor for dementia (19). Vitamin B12 supplementation has
been shown to improve cognition in subjects with symptoms
of cognitive impairment for < 12 months (20, 21), suggesting
there may be a time-limited window of opportunity for
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EXAMINING THE ASSOCIATION BETWEEN VITAMIN B12 DEFICIENCY AND DEMENTIA

effective vitamin B12 supplementation. donepezil, galantamine, rivastigmine, or memantine) and

We conducted this study to estimate the prevalence of B12 medical history.
deficiency in a high-risk sample of hospitalized patients and
to investigate the association between B12 deficiency and Definition of B12 Deficiency
dementia. Based on the literature B12 deficiency was defined as
(pmol/L): 1. Deficiency < 148; 2. marginal deficiency ≥148 to
Methods 220 and 3. adequate > 220 (22).

Subjects, Setting, and Study Design Statistical Analysis

The study was conducted at two university-affiliated
hospitals in Southwestern Ontario. The medical charts of
patients ≥18 years of age, admitted to the emergency, critical
care/ trauma, neurology, general medicine, and spinal cord &
stroke rehabilitation units between January 2010 and December
2012, were randomly selected. These groups of patients were
selected as there was increased likelihood that they would
be deficient in B12. Charts of patients < 50 years of age who
were admitted to the spinal cord and stroke rehabilitation unit
(n = 44) were excluded as these patients were likely to be
admitted to the hospital due to accident-related injuries instead
of neurological problems. As this is an exploratory study, a
sample size calculation was not performed.
Data were collected using an Excel spreadsheet which was
pilot tested by three of the authors (OS, KS, and TW) and was
revised prior to study use. Variables of interest, which were
collected based on the literature and clinical expertise of the
research team, included: gender, age, serum B12 concentrations
at admission, clinical signs and symptoms of B12 deficiency
(e.g. confusion, dementia, paresthesia, bizarre behavior, falls,
ataxia, hallucinations), and B12 supplementation. History of
gastrointestinal disease or surgery was also recorded including
gastrectomy, ileal resection, irritable bowel syndrome, and
celiac disease. Patients with dementia were identified based
on medication profile (whether the patient was prescribed
Table 1
Characteristics of all patients in the study
Descriptive statistics were used to present patients’
demographic data. Mann-Whitney U test, Fisher’s Exact test
and Pearson’s Chi-Square test were used, as appropriate, to
explore differences in demographic characteristics and
hematological profiles i) between all patients with and without
dementia, and by ii) Vitamin B12 status and dementia. A
p value of <0.05 was considered statistically significant.
Data analyses were conducted using Statistical Package for
Social Science (SPSS) (IBM Corp. Released 2012, Version
21.0 Armonk NY). Additional analyses examining possible
interactions between dementia, B12 and folate status were
performed using SAS 9.4 (SAS Institute Inc Cary NC).
Ethical Approval
This study received ethics approval from Western’s
Research Ethics Board and the ethics boards of the participating
hospitals.
Results
A total of 666 charts were included in this study. When
classified using the World Health Organization’s International
Statistical Classification of Diseases and Related Health
Problems 10th revision (ICD-10) criteria, the top three primary
reason for admission to hospital were: I64 - stroke, not

Dementia No dementia P-value

Total number of patients 262 404
Demographics
Age, mean ± SD 81.98 ± 9.48 67.35 ± 6.70 <0.001
Male, n (%) 118 (45%) 222 (55%) 0.012

Hematological, median (IQR)

Serum B12 (pmol/L) 322 (234 – 488.5) n = 121 335.5 (239.8 – 501) n = 278 0.95
RBC folate (nmol/L) 1278.5 (1087.8 – 1601.3) n = 88 1492.5 (1101.3 – 2002.8) n = 24 0.41
MCV (femtolitre or fL) 92.3 (88.8 – 95.4) n = 251 91.5 (88.1 – 94.7) n = 388 0.07
Hemoglobin (g/L) 125 (112 – 137) n = 251 126 (113 – 140) n= 388 0.23
Previous medical history (n, %)
Had gastrointestinal disease or surgery 59 (22.5%) 79 (19.6%) 0.36

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specified as hemorrhage or infarction (n=106,15.9%); R41.0 -
disorientation (n=49, 7.4%); and S06.9 -unspecified intracranial
injury (n=44, 6.6%). The characteristics of all patients are
summarized in Table 1. Dementia of some form was reported
in 39% (n=262) of patients. Patients with dementia were
older compared to patients without dementia (82 ± 9.5 vs. 67
± 6.7 years, p=0.001). There were no differences in gender
distribution between groups (55% vs. 45% female, p=0.51).
Serum B12 values were available for 60% (399/666) of
the patients, of whom 4% (16/399) were B12-deficient and
14% (57/399) were marginally deficient. Taken together
the prevalence of B12 deficiency (including marginal
deficiency) was 18%. Of those with dementia (n=262), only
46% (121/262) were screened for B12 deficiency. Patients
with dementia were not more likely to be B12-deficient or
marginally deficient [21% (26/121)] compared to those with no
dementia [17% (47/278), p=0.27)]. Based on documentation,
34% (25/73) of the B12-deficient or marginally-deficient
patients did not receive B12 supplementation, of whom 40%
(10/25) had dementia. The characteristics of patients with and
without dementia are summarized in Table 2.
Figure 1
Proportion of patients a) screened for B12 deficiency; b) not
B12-deficient (serum B12 >220 pmol/L) and B12-deficient
(serum B12 < 148 pmol/L) or marginally-deficient (serum
B12 ≥148 – 220 pmol/L); and c) those with B12 deficiency
(deficient and marginally-deficient) and dementia vs. no
dementia
There was no difference in incidence of dementia between
those who were B12 deficient (7(44%) vs 9 (56%), p=.2701)
and those with marginal B12 status (19 (34%) vs 38(67%) p=
0.2701). When examining adequate B12 status >220 pmol/L,
there were no significant differences in mean serum B12
values in those with dementia (504 ± 328) compared to those
without dementia (448 ± 233). Data were tested with outliers
for high B12 concentrations removed (±2SD) with no change
to significance (p=.5356). After controlling for the effect of
folate status [adequate levels defined as ≤ 1360 nmol/L and
high levels as >1360 nmol/L (23)] the association between B12
status (classification <148; ≥148-220 and > 220 pmol/L) and
1005
dementia remained non-significant (p=.1434). Additionally,
testing for the interaction between B12 and folate in relation
to dementia did not yield significant interactions in the model
(p=.1181).
Discussion
The purpose of this study was to estimate the prevalence of
B12 deficiency in a high-risk sample of hospitalized patients
and to investigate the association between B12 deficiency and
dementia. To our knowledge, this is the first study examining
the prevalence of B12 deficiency in a Canadian hospital setting.
The prevalence of B12 deficiency in this sample of hospitalized
patients was 18% which is comparable to the prevalence of
B12 deficiency among older adults reported in other studies
ranging from 5-46% (2). In a Canadian retrospective cross
sectional study of 6000 elderly patients reported that 10% of
elderly woman were found to be vitamin B12 deficient (B12
deficiency defined as ≤ 150 pmol/L) (24), whereas in a cross
sectional chart review of 988 patients Gupta (25) reported that
46% of South Asian patients in family practice in Toronto were
vitamin B12 deficient (defined as <132 pmol/L). In contrast, a
Canadian population-based survey (22) found no association
between advancing age and B12 deficiency which the authors
postulated was likely due to increased supplement use by older
Canadians. The vast ranges in prevalence of B12 deficiency
among studies is likely dependent on the setting of the study,
as well as the cut-off values and the methods used to define
deficiency (e.g. serum B12 only, or a combination of serum
B12 and MMA) (2, 3).
While we selected patients who were considered to be
at increased risk for B12 deficiency, including those with a
history of dementia, 54% of these patients were not screened.
This is very concerning as B12 deficiency can lead to
irreversible neurological damage. The American Psychiatric
Association Practice Guidelines for Alzheimer’s Disease and
Other Dementias recommends that patients with dementia
be screened for B12 deficiency (26). The Guidelines on the
Diagnosis of Cognitive Impairment in the Elderly, released by
the Guidelines and Protocols Advisory Committee of British
Columbia, also recommends B12 screening to be included in
the initial assessment of those with suspected mild cognitive
impairment or dementia (27). The results from this study
support that B12 screening protocols and supplementation
guidelines be developed and implemented.
In this study, most B12-deficient patients with and without
dementia had normal MCV (table 2) and normal hemoglobin
level (data not shown). Thus, megaloblastic macrocytic
anemia was not evident in our study sample which could
be attributed to normal or high RBC folate concentrations
among most patients in this study. Megaloblastic macrocytic
anemia, characterized by elevated MCV and mean corpuscular
hemoglobin, is one of the manifestations of B12 deficiency.
However, studies have indicated that up to 28% of affected
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Table 2
Characteristics of patients based on 3 levels of Vitamin B12 (22)

Dementia No dementia P-value

Total number of patients 121 278
MCV (Mean± SD) 94.7±6.41 (n=7) 91.1±4.9 (n=5) .6431
92.3±4.81 (n=19) 91.4±4.6 (n=38)
92.2±5.9 (n=88) 91.0±5.4 (n=228)
Hematological
Serum B12 (pmol/L), mean ± SD 0.270
<148 130 ± 12 (n = 7) 118 ± 20 (n = 9)
≥148 – 220 192 ± 20 (n = 19) 186 ± 20 (n = 38)
>220 504 ± 328 (n = 95) 448 ± 233 (n = 231)
Serum B12 (pmol/L), mean ± SD of patients with RBC folate <1360 nmol/L
< 148 129 ± 14 (n = 5) n=0
≥148 – 220 195 ± 20 (n = 11) 166 ± 18 (n = 3)
>220 397 ± 169 (n = 36) 387 ± 201 (n = 6)
Serum B12 (pmol/L), mean ± SD of patients with RBC folate >1360 nmol/L
< 148 141 (n = 1) n=0
≥148 – 220 n=0 177 (n = 1)
>220 482 ± 228 (n = 29) 569 ± 358 (n = 12)
Use of supplements, n (%)
Cyanocobalamin
Serum B12 < 148 pmol/L 6 (85.7%) 7 (77.8%)
Serum B12 ≥148 – 220 pmol/L 10 (52.6%) 25 (65.8%)
Serum B12 >220 pmol/L 34 (35.8%) 77 (33.3%)

patients may have normal hemoglobin level and up to 17%
may have normal MCV (1). While folate deficiency may
cause megaloblastic anemia, it is not typically of concern in
North America since fortification of grain and cereal products
ensures most people consume adequate folic acid (2, 22). High
concentrations of folic acid in the blood can treat anemia by
allowing normal pyrimidine synthesis to continue, thereby
masking the anemia that is normally associated with B12
deficiency (2). High folic acid concentrations can potentially
mask B12-associated anemia by normalizing MCV values.
Colapinto reported that <1% of Canadians had low RBC folate
levels whereas 40% had high levels >1360 nmol/L (28). It is
important that B12 screening is conducted using serum B12
concentrations as a marker of deficiency since relying on
abnormal hemoglobin and MCV values may result in poor
detection of deficiency in the presence of adequate folate status.
Despite the well-documented irreversible consequences of
B12 deficiency, it was surprising to find that approximately
1/3 of the B12-deficient patients did not receive B12
supplementation. One explanation for this finding could be the
use of a lower cut–off value for B12 deficiency (<156 pmol/L)
in the hospitals where this study was conducted. This could
result in no supplementation being given to patients with serum
B12 concentrations in the “indeterminate range” (156 - 200
pmol/L).
Currently, there is insufficient evidence to recommend
B12 supplementation as a treatment for dementia or cognitive
impairment (14, 29). However, the studies assessing the
effectiveness of B12 supplementation in improving cognitive
function included both subjects without B12 deficiency or
without dementia and the supplementation period was short in
duration (less than 6 months) (14, 29). Larger randomized trials
are needed to better assess the impact of B12 supplementation
on cognitive function in those with cognitive impairments or
dementia. Regardless, many patients may still benefit from
B12 supplementation to help prevent other manifestations of
B12 deficiency. The results of a randomized, controlled trial of
homocysteine-lowering B vitamins (folic acid, B6, and B12)
in subjects with mild cognitive impairment suggested that
treatment with B vitamins may help reduce the rate of brain
atrophy (30).
Although there is research suggesting a positive association
between serum homocysteine (hcy) concentrations and
Alzheimer’s disease and/or other cognitive impairments (31,

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32) this could not be evaluated in our study as hcy values were
not measured.
One of the key issues is that many B12-deficient patients
may still benefit from supplementation, and thus all clinicians
need to ensure that high-risk patients are screened and
supplementation initiated promptly.
Study limitations
As this study relied on patient charts, not all data that was
required for the present study was collected and recorded as
part of routine practice. For example, the diagnosis of dementia
could not be verified and the prevalence of B12 deficiency
can only be reported in patients whose B12 lab values were
available. Therefore the true number of patients with dementia
and/or B12 deficiency may have been underestimated.
Additionally the small sample size limited the power of our
analyses. Future studies should consider including MMA
values whenever feasible as MMA is considered the best
predictor of B12 deficiency (33).
Relevance to practice
This study did not find any association between B12
deficiency and dementia, likely due to a low sample size.
Overall the prevalence of B12 deficiency (including marginal
deficiency) was 18%; however, only 46% of patients with
dementia were screened for B12 deficiency. The findings of
this study support one of the recommendations of the ASC to
continue investing in research on key aspects of dementia such
as prevention and treatment options.
Future research should include designing, implementing
and evaluating a screening and supplementation protocol
for B12 deficiency and dementia. Currently, there is no
established marker that can be used to selectively identify
patients who need to be supplemented. Thus, clinicians should
consider screening all patients at high risk for B12 deficiency,
particularly those with dementia. In addition, the Institute of
Medicine and Health Canada recommends that all individuals
over 50 years of age consume a B12 supplement or B12-
fortified foods to meet their Recommended Dietary Allowance
(2.4 µg) for B12 (34, 35). This strengthens the argument to
improve B12 screening in all individuals at risk for deficiency.
Although serum B12 is the most common method used
to assess B12 deficiency, its sensitivity and specificity are
not reliable (5). This could be due to the lack of a consistent
reference standard to assess serum B12 levels; cut-off values
used to define deficiency in published studies range from
148 to 350 pmol/L (5, 22, 29). A more specific indicator of
B12 deficiency is serum MMA because elevated MMA is a
direct metabolic consequence of B12 deficiency (36). MMA
can be used as a confirmatory test to verify B12 deficiency.
Unfortunately, the high cost of MMA testing is a limiting
factor in its use (29). Nevertheless, round table discussions
suggest that future NHANES data include both serum B12
and MMA values (37). This may help shed some light on the
1007
usefulness of MMA as a biomarker of B12 status. It is also
extremely important that MMA be measured particularly when
clinicians relying on serum B12 values to define deficiency not
rule out deficiency in patients with serum B12 values within the
“normal range”, especially if patients present with clinical signs
and symptoms of B12 deficiency (5).
This study provides convincing evidence that vitamin B12
supplementation should be given to elderly patients with
dementia and vitamin B12 deficiency or marginal deficiency.
Acknowledgments: We would like to thank the Dietitians of Canada Gerontology
Network as well as Egg Farmers Canada for funding this study. Also a special thank you
to Egg Farmers for providing financial support for this publication. Both organizations had
no influence on any stage of the study process or on the writing of the manuscript.
Disclosure: The authors report no conflicts of interest in this work.
Ethical Standards: This study was conducted in compliance with the current laws in
Canada.
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