www.elsevier.com/locate/ypmed

Preventive Medicine 39 (2004) 1256–1266

Review

Cobalamin: a critical vitamin in the elderly

Maike Wolters, Ph.D.,* Alexander Strohle, Ph.D-student, and Andreas Hahn, Prof.

Nutrition Physiology and Human Nutrition Unit, Department of Food Science, Centre of Applied Chemistry, University of Hanover,

D-30453 Hannover, Germany

Available online 11 June 2004

Abstract

Vitamin B12 deficiency is a common problem in elderly subjects. If a serum cobalamin level of about 150 pmol/L (200 pg/mL) is

considered normal, 10–15% of the elderly are deficient. Today, however, a threshold of 220–258 pmol/L (300–350 pg/mL) is

recognized as desirable in the elderly, or else sensitive markers like the blood concentration of homocysteine or methylmalonic acid

(MMA) are used. Then the prevalence of cobalamin deficiency rises to up to 43%. In the elderly, this high prevalence of poor

cobalamin status is predominantly caused by atrophic gastritis type B. Atrophic gastritis results in declining gastric acid and

pepsinogen secretion, and hence decreasing intestinal absorption of the cobalamin protein complexes from food. About 20–50% of the

elderly are affected. Furthermore, the reduced acid secretion leads to an alkalinization of the small intestine, which may result in

bacterial overgrowth and thus to a further decrease of the bioavailability of the vitamin. In addition, some drugs such as proton pump

inhibitors or H2 receptor antagonists inhibit the intestinal absorption of vitamin B12. An already moderately reduced vitamin B12 level

is associated with vascular disease and neurocognitive disorders such as depression and impaired cognitive performance. Furthermore,

a poor vitamin B12 status is assumed to be involved in the development and progression of dementia (e.g., Alzheimer’s dementia).

This is especially observable if the folic acid status is reduced as well. Due to the insecure supply, the cobalamin status of elderly

persons (z60 years) should be regularly controlled and a general supplementation with vitamin B12 (>50 Ag/day) should be

considered.

D 2004 The Institute For Cancer Prevention and Elsevier Inc. All rights reserved.

Keywords: Vitamin B12; Cobalamin; Homocysteine; Methylmalonic acid; Elderly; Atrophic gastritis; Vitamin–drug interactions; Atherosclerosis;

Neurocognitive function

Introduction

There is a variety of reasons why elderly, especially

geriatric subjects, are at high risk for nutrient deficiencies

including age-associated physiological changes, chronic

diseases, and a high prevalence of drug intake. Vitamin

B12 deficiency is one of the most important problems in the

nutrition of the elderly [1,2] since the absorption of cobal-

amin is often reduced in this group [3,4]. Current inves-

tigations indicate that insufficient vitamin B12 status may

increase the risk for atherosclerotic [5–7] and neurodegen-

erative diseases [2,8]. In the meanwhile, several nutrition

boards recommend monitoring the vitamin B12 status of

elderly people and identifying risk persons at an early stage.

0091-7435/$ - see front matter D 2004 The Institute For Cancer Prevention and

doi:10.1016/j.ypmed.2004.04.047

* Corresponding author. Institute of Food Science, Department of

Applied Chemistry, University of Hannover, Wunstorfer Str. 14, D-30453

Hannover, Germany. Fax: +49-511-762-5729.

E-mail address: maike.wolters@lw.uni-hannover.de (M. Wolters).

The aim of this review is to describe the age-associated

changes in cobalamin metabolism and to show pathophys-

iological and therapeutic consequences.

Metabolic function and sources of vitamin B12

Vitamin B12 contains a cobalt-centered corrin nucleus

and shows a complex structure. The term vitamin B12

includes all corrinoids qualitatively exhibiting the biolog-

ical activity of cyanocobalamin. The coenzymatically ac-

tive forms of vitamin B12 are adenosylcobalamin and

methylcobalamin, which are involved in two enzymatic

reactions in human metabolism. One reaction requiring

methylcobalamin is the remethylation of homocysteine to

methionine catalyzed by the methionine synthetase [9]. In

this reaction, 5-methyl tetrahydrofolic acid (5-methyl-FH4)

is involved as a methyl group donor (Fig. 1), whereas

cobalamin is just intermediate acceptor of the methyl

Elsevier Inc. All rights reserved.

Fig. 1. Role of cobalamin in homocysteine metabolism (Ref. [30], modified). Abbreviations: SAH: S-adenosylhomocysteine; SAM: S-adenosylmethionine;

THF: tetrahydrofolate; 5-CH3-THF: 5-methyl tetrahydrofolic acid; TCC: tricarboxylic acid cycle.

M. Wolters et al. / Preventive Medicine 39 (2004) 1256–1266 1257

group. In cobalamin deficiency, methionine synthesis is

impaired and homocysteine can accumulate. Furthermore,

the methionine synthetase reaction provides tetrahydrofolic

acid (THF), which is the essential form for other folate-

dependent reactions [10]. Vitamin B12-deficient subjects

exhibit losses of this functional form of folate since 5-

methyl-FH4 is accumulated via the methyl-folate trap. This

explains why many symptoms of cobalamin deficiency are

similar to folate deficiency. Adenosylcobalamin, which is

located in the mitochondrion, is required as a coenzyme

for methylmalonyl-CoA mutase. Methylmalonyl-CoA mu-

tase catalyzes the conversion of methylmalonyl-CoA to

succinyl-CoA, a metabolite of the citric acid cycle. This is

an important biochemical reaction in the degradation of

odd-chain length fatty acids and requires first the carbox-

ylation of propionyl-CoA (supplied by the h-oxidation) tomethylmalonyl-CoA. Owing to loss of methylmalonyl-

CoA mutase activity, vitamin B12-deficient subjects show

accumulation of methylmalonic acid. Furthermore, the

degradation of the branched-chain amino acids valine

and isoleucine leads to methylmalonyl-CoA, which is then

rearranged to succinyl-CoA [11].

Cobalamins are exclusively synthesized by bacteria [12].

Rich sources of cobalamin are animal organ meats (espe-

cially liver and kidney), fish, mushrooms, eggs, and milk

products [13]. Food from plant sources does normally not

contain cobalamin, but very small amounts can be found in

fermented products or due to bacterial contamination. These

traces are not adequate to meet the vitamin B12 requirement.

Algae are often advertised as vitamin B12 sources. However,

algae contain only ineffective analogs of the vitamin, which

in addition are able to inhibit the metabolic functions of the

biologically active vitamin. Nor does yeast supply available

vitamin B12. Intestinal synthesis of the bacterial flora in

M. Wolters et al. / Preventive Medicine 39 (2004) 1256–12661258

humans is not sufficient; thus, dietary cobalamins are

required [14].

Diagnosis of vitamin B12 deficiency and status indicators

There are various methods for determining inadequate

vitamin B12 status. Deficiency of vitamin B12 leads to

impaired DNA synthesis and thus to delay or failure of

normal cell division, particularly in the erythropoiesis. A

reduction in mitotic rate results in macrocytosis (megalo-

blastic transformation) with an increased mean cellular

volume (MCV) of >100 fl. This MCV elevation with or

without anemia represents a relatively late sign of a pro-

gressed deficiency. It has to be considered that elevated

MCV is not a specific marker of vitamin B12 deficiency but

is also observed in folic acid deficiency. Vitamin B12 and

folate deficiencies are frequently found in hepatic diseases,

hemodialysis patients, and alcoholism; hence, elevated

MCV in those patients can also be a result of folic acid

or vitamin B12 deficiency [15,16]. The determination of the

cobalamin concentration in serum or plasma is more

specific but varies depending on the method and the

particular laboratory. In adults, a concentration of 150

pmol/L (200 pg/mL) is considered the lowest level for an

adequate supply. In a developing deficiency, serum con-

centrations are maintained by depleting stores of the vita-

min. Therefore, a concentration above the cutoff of 150

pmol/L does not inevitably reflect a sufficient vitamin B12

status as shown in some studies, indicating that the con-

centration is not a significant variable [17]. On the other

hand, if the cobalamin concentration is below this cutoff,

depleted stores can be assumed but are not necessarily

present [15,16]. Because of these results, a serum cobala-

min cutoff value of <220 pmol/L (<300 pg/mL) has been

proposed [18]. Based on studies with the more sensitive

indicators of cobalamin status, methylmalonic acid (MMA),

and homocysteine (see below), Lindenbaum et al. [19]

suggested a cutoff value of 258 pmol/L (350 pg/mL) in

elderly subjects. Subjects with low vitamin B12 concen-

trations exhibited significant elevations of MMA and

homocysteine concentrations. In the meanwhile, other

authors agree that the cutoff value of 150 pmol/L is too

low. For example, in a sample of elderly patients with

cobalamin concentrations below this value, 40% of the

subjects had increased serum MMA levels. In another

study, as many as 80% of the subjects aged 65 years with

cobalamin concentrations V148 pmol/L had increased

MMA and homocysteine values [18]. Thus, the limit

between sufficient and insufficient status is probably be-

tween serum cobalamin concentrations of 220–258 pmol/L

[18–20]. In the case of concentrations below 220 pmol/L,

further diagnostic measures are necessary. These early

markers of cobalamin deficiency could be elevated plasma

homocysteine, elevated serum MMA, and decreased serum

holotranscobalamin (holoTC) [21,22].

Elevated homocysteine is an important marker for vita-

min B12 and/or folate deficiency and it may also indicate a

low vitamin B6 status. In elderly people with normal folate

and vitamin B6 status, elevated homocysteine is generally a

consequence of cobalamin deficiency [23]. Homocysteine is

not a specific variable because it is not possible to differ-

entiate between a vitamin B12 and a folate deficiency.

Therefore, additional diagnostic measures such as the

MMA or the holoTC concentration are required (see below).

Homocysteine concentrations are also elevated in renal

insufficiency and hypovolemia [3]. Different levels of total

homocysteine in plasma have been suggested as normal:

<14 Amol/L [24], 5–13.6 Amol/L [25], and 4.9–11.7 Amol/

L [26]. Since results of many studies showed that the

prevalence and mortality of cardiovascular disease (CVD)

increased if a concentration of 10 Amol/L was exceeded

[27,28], this limit has been suggested as desirable [29].

Values of >12–30 Amol/L are classified as moderate hyper-

homocysteinemia [11].

A more specific and sensitive indicator of cobalamin

status is the serum methylmalonic acid (MMA) concentra-

tion. Elevated MMA is a direct metabolic consequence of

vitamin B12 deficiency, as shown in Fig. 1 [30]. Thus,

MMA is an important biochemical marker of cobalamin

status [3,25,31,32]. The reference range of serum MMA

concentrations in healthy adults is 73–271 nmol/L [33]. It

has to be considered that elevated MMA is also observed in

renal insufficiency and hypovolemia [3].

Beside MMA, which is an expensive measure, holo-

transcobalamin (holoTC) has been suggested to be an

early marker of cobalamin deficiency. holoTC contains

the biologically active vitamin B12 fraction bound to

transcobalamin II (TC II) because TC II promotes the

uptake of its vitamin B12 by all cells. Only 6–20% of total

serum cobalamin is present in the active form as holoTC

[21,34]. In recent studies, holoTC has been shown to be

the most sensitive marker of vitamin B12 deficiency

followed by MMA. However, in renal dysfunction, ho-

loTC increases and cannot be used as a marker of

cobalamin status [21].

Another indicator for vitamin B12 deficiency is the

increased amount of formiminoglutamic acid in the urine

following an orally administered dose of histidine. Since

formiminoglutamic acid excretion increases in folic acid

deficiency as well, this parameter lacks specificity for

cobalamin deficiency. In contrast, elevated propionate and

2-methylcitrate concentrations are specific markers of vita-

min B12 deficiency because both rise in cobalamin-deficient

subjects. However, both methods are not applied frequently

in routine laboratories [3,15].

Herbert (1994) suggested four stages of negative cobal-

amin balance in vitamin B12 deficiency: The first stage is

serum depletion indicated by low vitamin B12 on trans-

cobalamin II (i.e., low holoTC) [35]. The second stage is

cell depletion, which is also shown by decreased holoTC as

well as by low holohaptocorrin and low erythrocyte cobal-

Table 1

Causes of cobalamin deficiency [13,16,21]

Dietary deficiency

Strict vegetarian diet

Poor diet

Low intake

Malabsorption

M. Wolters et al. / Preventive Medicine 39 (2004) 1256–1266 1259

amin concentrations. The third stage is biochemical defi-

ciency with slowed DNA synthesis, elevated serum homo-

cysteine, and methylmalonic acid concentrations; and

finally, the fourth stage is anemia, the clinical deficiency.

Late clinical signs of vitamin B12 deficiency are megalo-

blastic anemia and neuropsychiatric disorders [21,35].

Pernicious anemia (type A chronic atrophic gastritis)

Gastrectomy

Type B chronic atrophic gastritis (reduced release of cobalamin from its

bound form in food)

Zollinger–Ellison syndrome

Intestinal diseases, especially of the ileum (celiac disease, Crohn’s disease,

ileitis)

Resection of the ileum

Pancreatic insufficiency

Parasitism (broad tapeworm Diphyllobothrium latum)

Bacterial overgrowth

Antiepileptic agents (carbamazepine, phenytoin, primidone)

Proton pump inhibitors (omeprazole)

Histamine (H2) receptor antagonists (cimetidine, ranitidine)

Antidiabetic drug metformin

Antibiotics (chloramphenicol, neomycin)

Cholestyramine

Increased requirement

MTHFR mutation

Hyperthyroidism

Diabetes mellitus

Renal insufficiency

Smokers

Regular alcohol intake

Prevalence of cobalamin deficiency in the elderly

In elderly subjects, the prevalence of subnormal cobala-

min concentrations varies between 10% and 43% depending

on the diagnostic criteria [3,36–41]. If the previously

considered threshold of 150 pmol/L (200 pg/mL) for a

normal vitamin B12 status is used, only 10–15% of the

elderly subjects are classified as cobalamin deficient. Clas-

sical deficiency symptoms such as megaloblastic anemia

often fail to appear [42]. Today, however, a threshold of

220–258 pmol/L (300–350 pg/mL) is recognized as a

marker for a desirable status in the elderly [4,19,20] or

otherwise more sensitive markers such as the blood con-

centration of homocysteine or methylmalonic acid are used.

Then the prevalence of cobalamin deficiency rises to up to

43% [3,4]. As observed in several studies, cobalamin

deficiency appears in most cases together with insufficient

folate status [24,38,43–45]. For example, in 66% of the

participants of the Framingham study who exhibited low

serum folate and elevated homocysteine concentrations,

MMA was also increased [41].

We performed a study with healthy women aged 60–70

years (n = 176) who did not use supplements. Women with

serum cobalamin below 258 pmol/L exhibited significantly

higher methylmalonic acid concentrations than those with

higher serum cobalamin. In total, 9.6% of the women had

elevated MMA concentrations [36].

Aetiopathogenesis of cobalamin deficiency

There is a variety of reasons for inadequate cobalamin

status (Table 1) in the elderly. The main problems are

impaired absorption, and thus an increased need of vitamin

B12 whereas other reasons like dietary insufficiency are less

important.

Impaired absorption

In elderly subjects, decreased gastric secretion due to

type B chronic atrophic gastritis is the major cause of

vitamin B12 deficiency [3,46–48]. Studies suggest that

20–50% of elderly people are subject to chronic atrophic

gastritis, depending on the definition used [2]. As shown in

the Framingham Heart Study, the disease is highly prevalent

in very old people. Prevalence of chronic atrophic gastritis

in subjects aged 60–69 years was 24% and rose to 37% in

subjects aged 80 years and over [49]. Similar findings of an

age-dependent development have been found previously

[50–54] and have been confirmed by subsequent studies

[55,56]. The main characteristics of chronic atrophic gastri-

tis are reduced gastric secretion of HCl and pepsinogen, in

an advanced stage the secretion of intrinsic factor is also

diminished [2,3]. These changes have severe consequences

for the intestinal release of vitamin B12 from food. As

shown by Doscherholmen and Swaim [57] as well as

Bradford and Taylor [58], the bioavailability of dietary

cobalamin is low in atrophic gastritis. Normally, protein-

bound cobalamin is released by gastric acid and proteolytic

pepsin and is for the most part subsequently bound to

haptocorrins [59]. Cobalamin is liberated by pancreatic

proteases in the intestinal lumen and bound to IF, which

protects the vitamin from catabolism by intestinal bacteria.

This complex associates with cubilin, which initiates Ca2+-

dependent receptor-mediated endocytosis together with an-

other protein called megalin. Due to the low pH in the

endosomes, the release of cobalamin from its IF-B12 recep-

tor complex already starts here and continues in the emerg-

ing lysosomes. Afterwards, released cobalamin is bound to

transcobalamin II (TC-II) in secretory vesicles. (Fig. 2).

Subsequently, cobalamin transcytosis occurs with a 6- to 8-

h delay [60,61]. In inadequate gastric HCl and pepsinogen

secretion, the absorption process is impaired and cobalamin

absorption is limited [48]. Furthermore, reduced acid secre-

tion leads to an elevated pH in the small intestine, which

weakens the barrier protecting against microorganisms and

Fig. 2. Intestinal absorption mechanism of vitamin B12 [61].

M. Wolters et al. / Preventive Medicine 39 (2004) 1256–12661260

elevates small intestinal permeability. Thus, bacteria can

pass over from the colon and result in small intestinal

bacterial overgrowth, most frequently including Campylo-

bacter, Yersinia, and Clostridium spp. This leads to a

competition for uptake of vitamin B12 and further reduces

cobalamin availability [62].

The main cause of gastric atrophy is not aging itself, but

a chronic Helicobacter pylori infection [3,48]. It is estimated

that in the U.S. population, 10% of the subjects aged up to

30 years are infected, while about 60% of the elderly (>60

years) are infected [63]. Helicobacter infection is highly

prevalent in subjects with low socioeconomic status [64].

Type A atrophic gastritis (pernicious anemia) is mostly

diagnosed in the elderly but is uncommonly the cause of

the age-associated cobalamin deficiency [46]. However, in

practice, pernicious anemia is often disregarded in the

elderly as shown by Carmel [65]. In this study, 1.9% of

729 included subjects (>60 years) exhibited the typical

biochemical changes found in pernicious anemia (low

cobalamin, abnormal result in Schilling test, presence of

antibodies to IF), but the disease had not been previously

diagnosed. Chronic atrophic gastritis is characterized by an

intensive gastric mucosa atrophy, which is associated with

the destruction of the parietal cells. This chronic autoim-

mune gastritis develops with antibodies to gastric parietal

cells (APCA) and leads to an achlorhydric stomach as well

as a loss of IF. Thus, cobalamin malabsorption ensues

[66].

Changes in gastric physiology can also be induced by

several drugs, which consequently impair cobalamin me-

tabolism [67]. Elderly people and especially multimorbid

seniors are at risk because they often take different drugs.

Absorption of vitamin B12 is predominantly reduced by

proton pump inhibitors such as omeprazole and lansopra-

zole (Table 1). These drugs are used in the treatment of

Zollinger–Ellison syndrome, reflux esophagitis, and peptic

ulcer. They inhibit gastric acid secretion and reduce the

release of cobalamin from food [58,68,69]. In this case of

drug–nutrient interaction, only the absorption of protein-

bound vitamin B12 is reduced while the absorption of

crystalline forms of cobalamin is not impaired. Furthermore,

histamine (H2) receptor antagonists such as cimetidine or

ranitidine reduce vitamin B12 release from food, but the

vitamin status seems to be almost unaffected by these drugs

[69]. Other drugs with negative influence on the vitamin B12

absorption are the cholesterol-lowering drug cholestyr-

amine, the antibiotics chloramphenicol and neomycin, and

metformin [13,70]. The latter reduces the intestinal avail-

ability of free calcium ions, which are required for vitamin

B12 absorption. However, the loss of vitamin B12 can be

prevented if foods rich in vitamin B12 are consumed

together with good calcium sources such as milk and milk

products [71].

Dietary insufficiency

In contrast to the abovementioned problems, nutritional

deficiency of vitamin B12 plays a minor role in reduced

cobalamin status. Studies show that the dietary intake of the

vitamin from food in the United States exceeded the RDA of

2.4 Ag/day [15]. In Germany, women aged over 60 years

consumed 4.8 Ag on average, while the average intake in

men was about 5.9 Ag/day [72]. This agrees with our own

investigations in 174 women aged 60–70 years, who had a

mean dietary cobalamin intake of 5.1 Ag/day [36]. There-

fore, in elderly people, dietary intake of vitamin B12 does

not significantly influence the prevalence of cobalamin

deficiency. Howard et al. [73] investigated dietary cobala-

min intake in elderly subjects with abnormal cobalamin

status and concluded that the high frequency of mildly

abnormal cobalamin status in the elderly cannot be attrib-

uted to poor intake of the vitamin. However, vitamin B12

intake is a problem in strict vegans who avoid meat, eggs,

and dairy products. This group develops signs of cobalamin

deficiency if the diet is consumed for several years [74–77].

Our own investigations confirm these findings. In the

German Vegan Study, 26% of the 149 participants ingesting

purely vegetarian diets exhibited an insufficient vitamin B12

M. Wolters et al. / Preventive Medicine 39 (2004) 1256–1266 1261

status [78]. Because of long-term storage of vitamin B12 in

the liver, deficiency normally only develops after some

years of a vegan diet. However, in elderly subjects, defi-

ciency can develop sooner if absorption is impaired because

vitamin B12 is continually secreted in the bile and most of it

is reabsorbed in healthy individuals. Enterohepatic circula-

tion is important and vitamin B12 losses are much larger in

individuals who malabsorb B12 [13]. As shown in a recent

study, even lactovegetarians and lacto-ovo-vegetarians ex-

hibit metabolic features indicating vitamin B12 deficiency

[77].

Increased requirement of vitamin B12

Cobalamin deficiency in older adults is mostly due to

food cobalamin malabsorption. Since older people with low

cobalamin and elevated serum MMA mostly do not have

true pernicious anemia, they should be able to absorb free or

synthetic cobalamin. Screening of MMA, holoTC, and

homocysteine concentrations as well as cobalamin, folate,

and B6 concentrations in elderly adults indicated that

elevated concentrations of the metabolites are related to

subnormal vitamin status and decreased renal function.

Thus, elderly subjects may require higher circulating B

vitamin concentrations to maintain concentrations of

MMA and homocysteine within the normal range [79].

Moreover, individuals homozygous for methylenetetrahy-

drofolate reductase (MTHFR) polymorphism 677 may have

increased vitamin B12 and folate requirements [80]. Two

studies showed that high supplemental doses of cobalamin

are necessary to normalize serum MMA in older people

[20,81]. In 23 older cobalamin-deficient subjects, daily

intake of 25 or 100 Ag oral cobalamin for a 6-week period

was not sufficient to normalize serum MMA in all elderly

subjects whereas the concentrations were reduced by 1000

Ag daily. Since in screening studies doses of 30 Ag cobal-

amin daily decreased prevalence of increased MMA, a

longer treatment period might be necessary to normalize

serum MMA concentrations. Most elderly subjects with

cobalamin deficiency need larger doses than available in

usual cobalamin supplements [81]. This is confirmed by a

study with oral daily supplementation with 500 Ag cyano-

cobalamin, 800 Ag folic acid, and 3 mg vitamin B6 for 4

months, which was effective in normalizing plasma homo-

cysteine and serum MMA levels in 70- to 93-year-old

community-dwelling subjects [82].

Pathophysiological consequences of vitamin B12

deficiency and hyperhomocysteinemia in the elderly

Atherosclerotic vascular diseases

Even moderately elevated homocysteine concentrations

are associated with an increased risk for atherosclerotic [83]

and thrombotic events [11,84] and seem to be a risk factor

for congestive heart failure [85]. It is estimated that about

10% of atherosclerotic diseases is related to moderately

elevated homocysteine concentrations. A mild elevation of

plasma homocysteine can be found in about 5–7% of the

general population [86], whereas 20–50% of the subjects

with atherosclerotic diseases exhibit a mild homocysteine

elevation [87]. However, recent studies have shown contra-

dictory results. In some trials, highly significant associations

between cardiovascular diseases and homocysteine concen-

trations were found whereas in other studies no association

could be discovered [88]. A meta-analysis that evaluated the

results of 30 studies including 5,073 cases of ischemic heart

disease and 1,113 cases with stroke showed that elevated

homocysteine levels are a moderate independent predictor

for these diseases in healthy populations [88]. After data

correction for various confounders such as age, blood

pressure, smoking, and cholesterol concentration, it was

concluded that a 25% homocysteine reduction (about 3

Amol/L) was associated with 11% risk reduction for ische-

mic heart disease and with 19% risk reduction for stroke.

This result shows that decreasing the mean homocysteine

level in the population can significantly reduce important

health risks [88]. Another meta-analysis also yields strong

evidence that the association between homocysteine and

cardiovascular disease is causal. According to this study,

lowering homocysteine concentrations by 3 Amol/L would

reduce the risk of ischemic heart disease by 16%, deep vein

thrombosis by 25%, and stroke by 24% [89]. Furthermore,

treatment with homocysteine lowering B vitamins (folic

acid, vitamin B12, and vitamin B6) significantly decreases

the rate of restenosis and the need for revascularization of

the target lesion after coronary angioplasty [90].

Despite this empirical evidence, to date it is not definitely

known whether hyperhomocysteinemia is a cause of ath-

erosclerosis or only a result of the disease [5,83]. However,

in vitro studies and results of experimental animal studies

confirm the hypothesis that homocysteine plays a role in the

pathogenesis of atherosclerosis since it initiates various

atherogenetic mechanisms [4]. Fig. 3 gives some examples

for atherogenic effects of homocysteine [29].

Many clinical studies were able to show that supplemen-

tation with vitamin B12 and folic acid efficiently reduces

homocysteine concentrations [91]. In most individuals, folic

acid is the more effective substance because in the adult

population insufficient folic acid status is highly prevalent,

whereas vitamin B12 status is generally sufficient in young

adults. However, elderly people often exhibit vitamin B12

deficiency; thus, cobalamin supplementation may play a

major role in lowering homocysteine in this group.

Neuropsychiatric symptoms

Cognitive impairments are often associated with insuffi-

cient cobalamin status or elevated homocysteine or methyl-

malonic acid concentrations [4]. Plasma homocysteine

seems to be an important predictor for mental performance

Fig. 3. Examples for atherogenic effects of homocysteine [based on data of 29].

M. Wolters et al. / Preventive Medicine 39 (2004) 1256–12661262

[92]. In cognitively normal elderly community dwellers,

elevated plasma homocysteine and elevated serum levels of

methylcitric acid indicating insufficient cobalamin status

had an independent association with cognitive impairment

[93,94]. It is estimated that, independent of the intelligence,

homocysteine is responsible for 11% of the variance of

cognitive performance [95].

Furthermore, vitamin B12 can influence mood as shown

in an epidemiological study involving 700 persons aged >65

years. In the group with vitamin B12 deficiency, persons

with depression were twice the number than in the group

with normal cobalamin values [96]. An association had also

been found in a study with 3,884 seniors in the Netherlands.

The prevalence of depressive symptoms was associated with

vitamin B12 and homocysteine concentration in blood. This

association was especially pronounced in hospitalized

seniors. In this group, about 30% of all depressive patients

were classified as cobalamin deficient [97].

It is assumed that an insufficient vitamin B12 status may

also be involved in the pathogenesis and the progression of

dementia (e.g., Alzheimer’s dementia). In patients diag-

nosed with Alzheimer or vascular dementia, elevated homo-

cysteine concentrations were highly prevalent [98–103].

This observation is confirmed by the data of the Framing-

ham population, which shows that the risk of developing

Alzheimer’s dementia nearly doubles with plasma homo-

cysteine concentrations above 14 Amol/L [104]. In several

studies, an inverse correlation between plasma homocys-

teine concentrations and cognitive performance has been

assessed [105–108].

To date there is a lack of large interventional studies

showing a benefit of vitamin B12 supplementation in neuro-

cognitive impairment or dementia [109]. One effect of

supplemental vitamin B12, B6, and folate seems to be the

improvement of blood–brain barrier function [110]. Since

cobalamin metabolism is closely related to folic acid me-

tabolism and deficiency of both vitamins leads to elevated

homocysteine concentrations, the effects of both vitamins

can hardly be distinguished. Clinical studies evaluating the

effect of a combined therapy with folic acid and vitamin B12

have led to contradictory results. In some studies, an

improvement of cognitive performance was detected after

supplementation with both vitamins [111–113], whereas

other investigators found no positive results [114–116].

Results of a clinical study with high-dose cobalamin sup-

plementation indicated a prominent correlation between

duration of cognitive symptoms and response to therapy

[117]. It is assumed that for a successful therapy, an early

intervention plays a major role [118].

While the exact reasons for the correlations between

cobalamin deficiency and cognitive impairments are un-

known to date, there are some experimental findings that

may explain a relation between the metabolites S-adenosyl-

methionine (SAM) and homocysteine (Fig. 1). SAM is an

important methyl group donator in many neurophysiologi-

cally relevant reactions. Decreased SAM values in spinal

fluid have been observed in patients with Alzheimer’s

dementia and depression [119].

SAM-dependent reactions are the methylation of phos-

pholipids as well as the synthesis of various neurotrans-

mitters (e.g., acetylcholine). The demethylation of SAM

leads to S-adenosylhomocysteine (SAH), which is an

inhibitor of the SAM-dependent transmethylation reac-

tions [2,8,120]. Therefore, transmethylation reactions re-

quire a SAM concentration above the SAH concentration

[121]. In the case of insufficient vitamin B12 and folate

status, the vitamin-dependent remethylation of homocys-

teine to methionine is inhibited and as a consequence less

Fig. 4. Modified food pyramid for people >70 years [122].

M. Wolters et al. / Preventive Medicine 39 (2004) 1256–1266 1263

methionine is available for SAM synthesis. Thus, cerebral

SAM-dependent transmethylation reactions are inhibited

and homocysteine increases [121]. The resulting hypome-

thylation is seen as a responsible factor in various

neurological and psychiatric diseases such as dementia

and depression [2,8,121]. Furthermore, elevated homocys-

teine may contribute to the development and progression

of vascular dementia due to its involvement in athero-

sclerosis (see above).

Recommendations

Because of the problem of insufficient vitamin B12

status in the elderly, many institutions generally recom-

mend supplementation with cobalamin for elderly subjects.

For example, the food pyramid based on the Dietary

Guidelines for the Americans has been modified for people

aged 70 years and over (Fig. 4). In this pyramid for the

elderly, daily supplementation with vitamins B12, D, and

calcium is recommended, while folate fortified foods

should be used (flour has had to be fortified with folic

acid in the United States since 1998) [122]. The U.S. Food

and Nutrition Board recommends the use of supplements

and/or the intake of fortified food (e.g., grain products) for

elderly people as well because absorption of crystalline

vitamin B12 is not influenced by atrophic gastritis type B

[3]. However, studies have shown that the use of supple-

ments or enriched foods reduces the prevalence of cobal-

amin deficiency in the elderly, but there still remains the

risk of deficiency due mostly to low dosages

[19,20,123,124]. In a sample of elderly aged 65–100

years, 46% indicated regular consumption of cobalamin

supplements or enriched foods. Nevertheless, 13% was

classified as vitamin B12 deficient because of serum

cobalamin concentrations V221 pmol/L and MMA con-

centrations >271 nmol/L [20]. In the elderly, supplemen-

tation with up to 50 Ag/day vitamin B12 seems to be

insufficient to avoid poor cobalamin status [20]. Because

of the high prevalence of vitamin B12 deficiency and its

association with neurocognitive diseases, the daily use of

cobalamin supplements of >50 Ag/day can be recommen-

ded for elderly people aged 60 years and over. This

preventive measure assumes no side effects and would

be useful in respect to a risk–benefit analysis. Due to

insecure cobalamin supply, it is necessary to monitor the

vitamin B12 status regularly in elderly subjects (z60

years). Since serum vitamin B12 is no reliable marker of

subclinical cobalamin deficiency, measurement of more

sensitive markers like MMA and holoTC should be

considered.

In patients with diagnosed cobalamin deficiency, the

abovementioned preventive doses of cobalamin are insuffi-

cient. Therefore, it must be strictly distinguished between

preventive and therapeutic vitamin supplementation. For

therapy, oral doses of 1000–2000 Ag cyanocobalamin are

required, which can be used instead of parenteral therapy for

treatment in most cobalamin-deficient patients [125].

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