Professional Documents
Culture Documents
2007; 35: 1 19
There has been much media speculation grade the evidence. The searches confirmed
(often sensationalist and conflicting) that the water-soluble vitamins (B group
regarding the potential influence of and C), together with the minerals,
micronutrients on cognitive function and calcium, magnesium and zinc, are most
performance. Our aim was to identify the relevant to cognitive performance.
micronutrients specifically implicated in Clinical evidence revealed that marginal
cognitive function and to review the deficiencies of one or more of these micro-
literature to identify original sources nutrients are not uncommon, even in the
underlying the media coverage. Literature developed countries, and that such
searches were carried out to identify deficiencies may affect cognitive perform-
recent clinical trials, reviews, editorials ance, especially in vulnerable groups such
and meetings describing the biochemical as the elderly and those individuals who
and physiological role of individual are exposed to occupational pressures and
micronutrients. No attempt was made to a stressful lifestyle.
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E Huskisson, S Maggini, M Ruf
Influence of micronutrients on cognitive function and performance
notes the potential role of excessive alcohol In the first part of this article, the current
intake as well as dietary deficiency in the knowledge of the physiological roles of the
causation of vitamin deficiencies. micronutrients most closely associated with
Two groups of people in the western world cognitive performance will be reviewed, with
are particularly at risk of developing micro- particular reference to the central nervous
nutrient deficiency: (i) individuals who are system (CNS). In the second part of this
exposed to occupational pressure and a article, the consequences of deficiencies are
stressful lifestyle, accompanied by a poor discussed with reference to clinical data.
diet, and (ii) the elderly. Both these groups
are booming. ROLE OF WATER-SOLUBLE VITAMINS
This review highlights evidence of the IN THE CNS
effects of vitamin and mineral supplements In this section the physiological roles of all
on behaviour and mental performance; the water-soluble vitamins and their roles in the
ability to concentrate, to be clear-headed, to nervous system are briefly described (for
be alert, composed and energetic and to feel more detailed information, please refer to
good. It may make doctors think again about publications such as those of the Institute of
the importance of vitamins in their everyday Medicine3,4).
work. Their patients will be reassured by the
hard evidence, although many will have Vitamin B1 (thiamine)
already noticed that vitamin and mineral The principal physiological role of
supplements make them feel better. thiamine is as a coenzyme in carbohydrate
metabolism. The thiamine coenzyme
Biochemistry, physiology thiamine pyrophosphate is required for
several stages in the breakdown of glucose to
and mechanisms provide energy. It also plays a role in the
WHICH MICRONUTRIENTS ARE conduction of nerve impulses. The brain and
ESSENTIAL FOR COGNITIVE the peripheral nerves contain significant
PERFORMANCE? amounts of thiamine, which has numerous
The micronutrients that have been most roles within nerve tissue.
closely associated with cognitive performance
are listed in Table 1 and include all the water- Vitamin B2 (riboflavin)
soluble vitamins, as well as some minerals. After intestinal absorption, riboflavin is
The inter-relationships between diet, the converted to the coenzymes flavin
brain and behaviour are complex. However, mononucleotide and flavin adenine
these micronutrients are known to have a dinucleotide. Physiologically, riboflavin acts
direct influence on cognitive function as an intermediary in numerous
through their involvement in the energy oxidationreduction reactions. Thus, it is
metabolism of neurons and glia cells, the essential for the metabolism of
synthesis of neurotransmitters, receptor carbohydrates, fats and proteins, and in
binding and the maintenance of membrane energy production. Importantly, riboflavin is
ion pumps.2 Marginal deficiency of these essential for the conversion of pyridoxine
micronutrients results in a number of non- (vitamin B6) and folic acid into their
specific symptoms, many of which are coenzyme forms, and for the transformation
related to cognitive performance. of tryptophan to niacin.
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Influence of micronutrients on cognitive function and performance
TABLE 1:
Micronutrients that are most closely associated with cognitive performance*
Vitamins Minerals
Vitamin B1 (thiamine) Calcium
Vitamin B2 (riboflavin) Magnesium
Niacin Zinc
Vitamin B6 (pyridoxine)
Folic acid
Vitamin B12 (cobalamin)
Biotin
Pantothenic acid
Vitamin C (ascorbic acid)
*The term performance has been used to include those aspects of cognitive function, such as concentration,
learning, memory and reasoning, that do not involve psychiatric or neurological diagnoses.
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Influence of micronutrients on cognitive function and performance
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Influence of micronutrients on cognitive function and performance
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and muscular excitability. The Mgadenosine magnesium and calcium for absorption in
triphosphate (MgATP) complex is involved the intestine. Calcium supplementation does
in all-important biosynthetic processes: not decrease magnesium absorption9 and an
glycolysis, formation of cyclic adenosine intake of up to 800 mg magnesium does not
monophosphate (cAMP), energy-dependent affect intestinal calcium absorption.10
membrane transport and transcription of the
genetic code. Zinc
Many of these enzymes also require a Zinc is required as a component of more
B vitamin as a cofactor. Specifically, than 200 enzymes and as a structural
magnesium is essential for all enzymes component of many proteins, hormones,
requiring vitamin B1 as a cofactor. Both hormone receptors and neuropeptides.11 In
magnesium and vitamin B2 are required for the CNS, zinc has an additional role as a
the conversion of vitamin B6 into its active neurosecretory product and cofactor. In this
form. Extra-cellular magnesium is critical for role, zinc is highly concentrated in the
the maintenance of nerve and muscle synaptic vesicles of the so-called zinc-
membranes and for the transmission of containing neurons. These neurons are
impulses across neuromuscular junctions. found almost exclusively in the forebrain.12
There are also a number of antagonistic While the precise role of zinc in the brain still
and synergistic interactions between remains to be discovered, it has been
magnesium and calcium. Of particular established that neuropsychological impair-
relevance here is the interaction between ment is one major health consequence of
magnesium and calcium in the regulation of zinc deficiency.13
the permeability of nerve and muscle cells, Zinc is absorbed mainly in the proximal
which governs neuromuscular excitability. small intestine by an active transport
So constant is this relationship that mechanism. Absorbed zinc is bound to
mathematical formulae have been derived albumin and transported to the liver in the
that allow excitability to be calculated from portal system. From the liver, zinc is
the concentration of electrolytes in the distributed to all tissues, with the highest
surrounding intercellular fluid: concentrations found in skeletal muscle.
Turnover is rapid and, although the liver
Excitability = (K+)(Na+) may retain zinc, there are no specific stores.
(Ca+)(Mg2+)(H+) A marked reduction in dietary zinc is quickly
followed by signs of zinc deficiency. It is
Since excitability is related to the reciprocal thought that even in developed countries
of the magnesium and calcium concen- many people are zinc deficient. In a recent
trations, it can be seen that deficiency of either study of rural, community-dwelling elderly
or both micronutrient leads to an increase in people in the USA, it was estimated that
excitability. Clinically, deficiency of either ion more than 25% were zinc deficient.14 Black15
may lead to muscle disturbances (e.g. cramps, cites evidence that zinc deficiency is a major
tetany), cardiac abnormalities, neurological public health problem in the USA.
system symptoms (e.g. paraesthesias, Besides the impairment of cognitive
irritability) or to psychiatric disturbances. function, zinc deficiency causes an impaired
Contrary to widespread belief, data show collagen formation, skin changes, delayed
that no competition exists between wound healing and susceptibility to infection.16
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Influence of micronutrients on cognitive function and performance
HOW MICRONUTRIENTS INFLUENCE requires vitamin B2, vitamin B6, vitamin B12,
COGNITIVE PERFORMANCE nicotinamide, folate and vitamin C. Synergy
No other organ system of the body depends between vitamin C and B vitamins also
more intimately on its nutrient supply occurs in the breakdown of histamine and
than the CNS. Individual micronutrients tryptophan in the brain (Table 2).
are especially important for cognitive In animal studies, thiamine deficiency
performance and mood because the effective has been shown to lead to a fall in GABA
functioning of the CNS depends, in part, on concentrations in the brain and to a
an adequate and constant nutrient supply. reduction in the pool size and turnover of
In his comprehensive review, Haller2 acetylcholine.17 Pyridoxine deficiency also
identified three main mechanisms two leads to reduced synthesis of GABA and can
direct and one indirect by which lead to convulsions in infants.
micronutrients affect cognitive function. In
the past decade, it has become clear that a 2. Neuronal membrane and receptor
fourth indirect mechanism, mediated by modification
Hcy, is also important. One of the metabolites of thiamine,
thiamine triphosphate, is found exclusively
1. Neurotransmitter synthesis in the neuronal membrane and appears to
B complex vitamins and vitamin C are be involved in the maintenance of the
required for the synthesis of amino acids, transmembrane potential difference. In
biogenic amines, neurotransmitters and isolated nerve preparations, destruction of
steroids. Specifically within the CNS, the thiamine by ultraviolet light leads to a loss
metabolism of dopamine and noradrenaline of membrane potential and no action
TABLE 2:
Some examples of the impact of water-soluble vitamins on neurotransmitter synthesis via
their involvement in amino acid metabolism
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Influence of micronutrients on cognitive function and performance
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Influence of micronutrients on cognitive function and performance
impairment and that lowering homo- of these micronutrients could have direct
cysteine by B vitamin supplementation may physiological effects on brain function and
protect cognitive function.30 therefore on cognition (Table 3).
Ellinson et al.31 carried out a systematic That frank vitamin deficiency can have a
review of all studies in English on the profound effect on cognitive function has
association between low serum vitamin been known for many years. The
B12/folate and raised total Hcy with cognitive WernickeKorsakoff syndrome as a result of
impairment. It was found that total Hcy was thiamine deficiency is characterized by
significantly higher in all cases of cognitive symptoms ranging from mild confusion and
impairment when compared with controls, depression to psychosis and coma. If
but there was wide variation for both serum treatment is delayed, the memory may be
vitamin B12 and folate. permanently impaired. In vitamin B6
In cohort studies, the total Hcy but not deficiency, the signs and symptoms include
serum folate or B12 could predict the rate of electroencephalogram abnormalities, nerve
decline in cognitive function, although one degeneration and peripheral neuritis.
study from the USA32 reported a significantly Pellagra, as a result of niacin deficiency, is
higher risk of Alzheimers when both folate associated with the three Ds, diarrhoea,
and B12 levels were low. In addition, this dermatosis and dementia. However, it is only
study found that both high Hcy and low in the past 20 years or so that a potential
B vitamins were predictive of cognitive link between borderline vitamin deficiencies
decline in a group of 321 ageing men and cognitive function has been explored.
followed over 3 years.32 The concept of marginal vitamin deficiencies
was first proposed by Pietrzik.34 He suggested
Micronutrients and that there are in fact five stages of deficiency.
The first stage is characterized by a lowering of
cognitive performance tissue vitamin content; the second by reduced
evidence overview synthesis of vitamin metabolites followed by
CONSEQUENCES OF DEFICIENCIES depressed activity of vitamin dependent
FOR COGNITIVE PERFORMANCE enzymes and hormones (stage three). The
The water-soluble B vitamins, vitamin C and fourth stage is characterized by morphological
the mineral micronutrients magnesium and or functional disturbances, followed by the
zinc are stored in the body only to a limited emergence of clinical symptoms (the fifth and
extent, and upon any reduction of intake, final stage). Pietrzik proposed that marginal
impairment of absorption or increase in deficiency be represented by the transition from
requirements, the body status begins to fall the third to the fourth stages and that
and may become deficient. Isolated biologically based functional parameters
deficiency of individual B vitamins seems to should be established for its assessment.
be rare since all members of the complex Following from this work, Chom et al.35
tend to occur in similar foods. investigated the effects of suboptimal vitamin
The role of the B vitamin and mineral status on behaviour, concluding that an
cofactors in the synthesis of brain neuro- insufficient supply of vitamins, especially of
transmitters and in the maintenance of thiamine, riboflavin, vitamin B12 and vitamin
neuron cell function has been discussed C, adversely affects different psychological and
above. Deficiency of all or any of a number behavioural functions.
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Influence of micronutrients on cognitive function and performance
TABLE 3:
Consequences of water-soluble vitamin deficiencies on cognitive performance3,4,27,33
Vitamin Consequence
Vitamin B1 Fatigue, mental changes (e.g. apathy, decrease in short-term memory,
confusion and irritability), visual difficulties
Frank deficiency: beriberi, WernickeKorsakoff syndrome
Vitamin B2 B2 deficiency is most often accompanied by other micronutrient deficiencies
Severe B2 deficiency may impair the metabolism of vitamin B6 and the
conversion of tryptophan to niacin
Vitamin B6 Depressed mood and neurological disturbances
Frank deficiency: peripheral neuropathy, convulsions, depression and
confusion
Vitamin B12 Fatigue and weakness, irritability, depressed mood, loss of concentration to
memory loss, mental confusion, disorientation
Frank deficiency: peripheral neuropathy, subacute combined system
degeneration, frank dementia
Folic acid Symptoms of folate deficiency include depression, insomnia, forgetfulness
and difficulty in concentrating, irritability, apathy, fatigue and anxiety
Biotin Irritability, depressed mood, central nervous system abnormalities
Nicotinamide Marginal deficiency: irritability, weakness, mental confusion and dizziness
Frank deficiency: pellagra, dementia
Panthotenic acid Irritability and restlessness, fatigue, apathy and malaise, neurobiological
symptoms, such as numbness, muscle cramps. Myelin degeneration
Vitamin C Weakness, fatigue, depression
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Influence of micronutrients on cognitive function and performance
TABLE 4:
Factors responsible for the reduced absorption of micronutrients
TABLE 5:
Factors responsible for the increased requirements for micronutrients
As well as the risk caused by medical unhealthy food choices, chronic or periodical
conditions like digestive disorders or dieting, and stress-related behaviour like
infection, the risk groups for micronutrient smoking, excessive alcohol and coffee
deficiencies can be classified into two main consumption. The link between micro-
categories: those at risk as a result of what nutrients and cognitive performance is of
might be called lifestyle and those at risk special interest in this group, because the
because of lifestage. combination of stressful lifestyle and risk for
The lifestyle category includes the large marginal micronutrient deficiency may
group of individuals who are at risk because cause a vicious circle.
of increased needs and/or insufficient intake The lifestage group comprises older adults
of micronutrients because of a demanding who are at risk of micronutrient deficiency
lifestyle. This category mainly includes because of their changing needs and life
young to middle-aged adults with high situation. Surveys have shown that even in
occupational pressure or the double burden affluent societies up to 40% of older persons
of family and work, for whom time is always living in single households consume
in short supply. In this group, deficiencies insufficient amounts of one or more essential
are likely to occur as a result of lifestyle nutrients.41 Therefore it is not surprising that
associated behaviour like snatched meals, this group is widely recognized as one of the
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E Huskisson, S Maggini, M Ruf
Influence of micronutrients on cognitive function and performance
most important risk groups.46 In the light of stress does manifest in ways that are
the current demographic revolution and the measurable: changes in mood, memory,
alarmingly increasing numbers of persons concentration and problem-solving. It has
suffering from age-related cognitive decline, been suggested that there may be a vicious
the clinical data exploring the link between cycle of stress (Fig. 1), whereby external stress
micronutrients and cognitive performance factors trigger the release of stress hormones.
become highly relevant.47 These in turn lead to increased micronutrient
In the following paragraphs, the review requirements which, if unmet, lower the
will focus on two major risk groups that resistance to stress and at the same time com-
regularly present to general practitioners: promise cognitive and physical well-being.
middle-aged adults with high occupational Because of greater interest in the role of
pressure and the elderly. The signs and micronutrients in cognitive development of
symptoms of marginal micronutrient children and in the maintenance of cognitive
deficiencies are often non-specific and performance in the elderly, fewer studies
therefore difficult to diagnose. It is therefore have been carried out in younger adults.
important for primary care health workers to However, in the past decade a number of
be alert to the particular risk of these groups preliminary studies have been published.
and to know about the potential of In Hallers review of the effects of vitamins
multivitamin supplementation as a and other nutrients on the brain,2 the author
preventive measure. concluded that many studies show specific
effects, particularly on cognitive function
Lifestyle and micronutrient deficiencies and mood, and that vitamins in high doses
Although the level of psychological stress have a pharmacological action which may
itself is difficult to measure and individual only become apparent many months after
ability to deal with stress is very variable, blood levels have risen to a higher level.
Vitamin and
Metabolism mineral
requirements
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E Huskisson, S Maggini, M Ruf
Influence of micronutrients on cognitive function and performance
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E Huskisson, S Maggini, M Ruf
Influence of micronutrients on cognitive function and performance
30.70 31.55
30.00 28.55
27.16
20.43
20.00 17.81
10.00
0.00
BSI HARS VAS PGWS
BSI P = 0.0344 HARS P = 0.0148 VAS = P = 0.0044 PGWS P = 0.0136
Reduction of Reduction in
concentration problems rated tiredness
(P 0.05) (P 0.06)
3.79
3.76
Main rating
Main rating
3.26
3.54
3.05
2.92
3.34
2.61
D 1
28
D 1
28
D 1
28
D 1
28
ay
ay
ay
ay
ay
ay
ay
ay
D
14
E Huskisson, S Maggini, M Ruf
Influence of micronutrients on cognitive function and performance
whether this age-related decline is associated that have reported success61 have
with the decline in nutritional status often subsequently been criticized for poor
found in elderly people, or is independent of methodology. Nevertheless, an editorial in
it. The weight of recent evidence suggests The American Journal of Clinical Nutrition
that there is indeed an association. Ortega (B vitamins and cognitive function: do we
et al.56 found that subjects with higher scores need more and larger trials?)62 concluded
in two tests of cognitive function had higher that, although no randomized trials of
intakes of total food, fruit, carbohydrate and B vitamin supplementation have provided
micronutrients than subjects with lower evidence for improvement of cognition,
scores. It was concluded that a diet with further trials are warranted because the
more carbohydrate, fibre and micronutrients suggested mechanisms are plausible and
is beneficial, not only to improve the strong associations have been established
general health of the elderly, but also to between these mechanisms and cognitive
improve cognitive function. A number of dysfunction in several high quality
recent studies have demonstrated that epidemiological studies.
micronutrient supplementation may help to Micronutrient supplementation in an
maintain cognitive performance in the attempt to prevent cognitive decline must
elderly. Gray et al.57 carried out a long-term lead to discussion of neurological deficits such
study of antioxidant vitamins plus minerals as dementias, rather than the psychological
supplementation in 2082 community- deficits that were the original remit of this
dwelling elderly people. After 7 years, it was review. However, two studies published in
found that supplement users had a 34% 2005 have caused such interest that they
lower risk of developing cognitive should be mentioned. The first study was
impairment than non-users. A Spanish study presented by a Dutch group at the
of institutionalized elderly people showed International Conference on Prevention of
that dietary deficiency of vitamin B12 and Dementia held in Washington DC, USA in
folic acid was associated with a higher risk of June 2005.63 The authors selected 818 healthy
cognitive impairment.58 older adults (aged 50 75 years), none of
A review of B vitamins, cognition and whom was suffering from dementia, and
ageing concluded that recent studies randomized them to receive a daily tablet
had confirmed an association between containing 800 g folic acid (approximately
B vitamins and many aspects of cognitive twice the European recommended dietary
performance and that even subclinical allowance [RDA]) or placebo. After 3 years,
differences in nutritional status could have the subjects taking the folic acid had scores on
subtle effects on cognition19. The same memory tests that were similar to those of
review also concluded that the evidence persons 5 years younger. They also had scores
supported the effectiveness of micronutrient of information processing and muscle speed
supplementation in enhancing cognitive that were similar to someone 2 years younger.
performance in older adults. However, in Supporting evidence came in a further study
elderly people not affected by micro-nutrient published in July 2005 from the Johns
deficiency, studies aimed at improving Hopkins University.64 A total of 579 non-
cognitive performance by means of demented men and women (who were part of
micronutrient supplementation have the ongoing Baltimore Longitudinal Study of
generally proved unsuccessful59,60 and those Aging) provided detailed dietary diaries over
15
E Huskisson, S Maggini, M Ruf
Influence of micronutrients on cognitive function and performance
a period of 6 years. Ultimately, 57 of the zinc are required as cofactors for numerous
original 579 participants developed vitamin-dependent enzymes and also play a
Alzheimers disease, but the researchers found direct and crucial role in membrane
that those with higher intakes of folates, excitability and neurotransmission. With
vitamin E and vitamin B6 had lower the exception of calcium, none of these
comparative rates of the disease. But, when micronutrients is stored in the body in
the three vitamins were analysed together, significant quantities and it is therefore
only folates were associated with a essential that the daily consumption
significantly decreased risk. No association is adequate.
was found between vitamin C, beta carotene Four major mechanisms can be identified
or vitamin B12 intake and decreased risk of by which micronutrients influence cognitive
Alzheimers disease. Professor Corrada function: through their role in
commented that, participants who had neurotransmitter synthesis; by neuronal
intakes at or above the 400 g RDA of folates membrane and receptor modification; by
had a 55% reduction in risk of developing influencing brain energy requirements; and
Alzheimers, but most people who reached via their role in Hcy metabolism.
that level did so by taking folic acid Review of the clinical evidence leads to the
supplements, which suggests that many conclusion that:
people do not get the recommended (a) Even in developed countries, large
amounts of folates in their diets. sections of the population are at risk for
marginal micronutrient deficiencies.
Conclusions Major risk groups are the young to
Two main groups of micronutrients essential middle-aged adults with demanding
for optimum cognitive performance can be lifestyles and too little time, and the
differentiated: the water-soluble vitamins elderly.
(B complex and C), as well as the minerals (b) Micronutrient deficiencies can impair
calcium, magnesium and zinc. cognitive performance in all stages of
Because of their metabolic interdependence, life and are associated with age-related
the B complex vitamins have to be regarded as cognitive decline.
a functional unit whose individual members Micronutrient supplementation can
act like links in a chain of biochemical help prevent deficiencies in those at risk
reactions. Within intermediate metabolism, and may therefore help to maintain
transformations exist which require all eight cognitive performance.
B vitamins as cofactors for the various Doctors confronted with stressed or elderly
enzymes.65 Many interactions are also known patients complaining of non-specific,
between the different members of the complex. especially cognitive, symptoms should
Although vitamin C is essential for collagen consider the possibility of marginal
synthesis in the skin, it is noteworthy that the micronutrient deficiency and the potential
highest concentrations of this vitamin are benefits of micronutrient supplementation.
found in brain tissue. Brain vitamin C is known
to interact synergistically with B complex Conflicts of interest
vitamins in the maintenance of several aspects Silvia Maggini and Michael Ruf are
of cognitive function and performance. employed by Bayer Consumer Care, a
The minerals calcium, magnesium and manufacturer of multivitamins.
16
E Huskisson, S Maggini, M Ruf
Influence of micronutrients on cognitive function and performance
Received for publication 9 October 2006 Accepted subject to revision 21 October 2006
Revised accepted 3 November 2006
Copyright 2007 Cambridge Medical Publications
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Influence of micronutrients on cognitive function and performance
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Influence of micronutrients on cognitive function and performance
61 Chandra RJ: Effect of vitamin and trace- Association First International Conference on
element supplementation on cognitive the Prevention of Dementia, Washington DC,
function in elderly subjects. Nutrition 2001; 17: USA. 18 21 June 2005. Presentation Number:
709 712. HT-002
62 Vollset SE, Ueland PM: B vitamins and cognitive 64 Corrada MM, Kawas CH, Hallfrisch J, Muller D,
function: do we need more and larger trials? Brookmeyer R: Reduced risk of Alzheimers
Am J Clin Nutr 2005; 81: 951 952. disease with high folate intake: The Baltimore
63 Durga J, van Boxtel MPJ, Schouten EG, Kok FJ, Longitudinal Study of Aging. Alzheimers Dement
Jolles J, Katan MB, et al: Effect of 3-year folic 2005 1: 11 18.
acid supplementation on cognitive function in 65 Bayer W, Schmidt K: Vitamin C. In: Vitamine in
older adults. A randomized, double blind, Pravention und Therapie. (Bayer W, Schmidt K, eds).
controlled trial. Presented at the Alzheimers Stuttgart: Hippokrates Verlag, 1991; pp 237 264.
19