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Homocysteine and cognition - A historical perspective

Article  in  Journal of Alzheimer's disease: JAD · September 2006

DOI: 10.3233/JAD-2006-9402 · Source: PubMed


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Andrew McCaddon
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Journal of Alzheimer’s Disease 9 (2006) 361–380 361
IOS Press

Homocysteine and cognition – A historical

Andrew McCaddon
Wales College of Medicine, Gardden Road Surgery, Rhosllanerchrugog, Wrexham, Wales, LL142EN, UK
Tel.: +44 (0) 1978 842177; Fax: +44 (0) 1978 845782; E-mail:

Abstract. The discovery of a relationship between homocysteine and cognition stems from clinical observations of an association
between vitamin B12 and folate deficiency and cognitive dysfunction. This retrospective details the history of vitamin B12 and
folic acid and the conceptual evolution of their association with dementia. The hematological and neuropsychiatric manifestations
of these deficiencies are discussed, together with the nature of their relationship with dementia, generalized cognitive decline
and discrete neuropsychological function. An evaluation of the potential of reversing ‘homocysteine-associated’ and/or ‘vitamin-
associated’ cognitive decline raises questions as to whether current interventions can unequivocally determine if homocysteine
independently impacts on cognitive function. Alternative approaches specifically designed to address this issue are discussed.

Keywords: Homocysteine, cognition, vitamin B12 , folic acid

1. Introduction are specifically related to discrete neuropsychological

The fascinating story of the discovery of a relation- The retrospective concludes by evaluating the po-
ship between homocysteine and cognition is closely tential of reversing homocysteine-associated and/or
related to observations made during the last century vitamin-associated cognitive decline. The evolving
concerning the potential role of vitamin B 12 and folate concepts of the relationship between homocysteine and
deficiencies in the development of cognitive disorders. cognition raise questions as to whether current inter-
In the last few decades clinicians began to speculate ventions can unequivocally determine if homocysteine
that such deficiencies might actively contribute to cog- per se independently contributes to cognitive decline.
nitive decline and occur in association with the specific Alternative approaches specifically designed to address
dementia of Alzheimer’s disease (AD). Prior to this, the this issue are briefly discussed.
prevailing view was that they arose simply as a result
of dementia-related malnutrition.
This retrospective details the history of vitamin B 12
2. Vitamin B12 , folic acid and homocysteine
and folic acid, and aims to demonstrate the conceptual
evolution of their association with AD and cognition.
Interest in this field has exploded with confirmation that 2.1. Vitamin B 12
metabolic evidence of these deficiencies co-exists with
AD as well as vascular dementia. The paper addresses: A fatal form of anaemia associated with stomach de-
the distinct and common features of disrupted vitamin generation was first described in 1824 by J.S. Combe
B12 , folate and homocysteine metabolism; the relation in Edinburgh and later by Thomas Addison in 1849, a
between the hematological, neuropsychiatric and vas- physician at Guy’s Hospital [1,2]. In 1872 Biermer, in
cular manifestations of these conditions; the nature of Switzerland, coined the concept of pernicious anaemia
their relationship with AD versus generalized cogni- (PA) based on the inevitably fatal outcome of this dis-
tive decline; and whether homocysteine, folate and B 12 order [3]. In the 1880’s, Ehrlich added that patients

ISSN 1387-2877/06/$17.00 © 2006 – IOS Press and the authors. All rights reserved
362 A. McCaddon / Homocysteine and cognition – A historical perspective

with this anaemia had giant peripheral blood cells, so 2.3. Homocysteine
called megaloblasts [4].
This disease remained incurable until 1926 when two Homocysteine was discovered in 1932 at the Uni-
American physicians, Minot and Murphy, described a versity of Illinois by Butz and du Vigneaud, who
raw liver diet that cured PA [5]. Their discovery was were originally studying the nature of sulphur in in-
prompted by experiments conducted six years earlier sulin [15]. During their studies they heated methion-
by George Whipple. Whipple had found that inges- ine in sulfuric acid and isolated a compound with sim-
tion of raw liver regenerated hemoglobin in dogs made ilar chemical properties to cysteine and cystine, which
anaemic by bleeding [6]. Liver extracts were able to they initially termed ‘bis-(γ-amino-γ-carboxypropyl)
reverse PA in dogs and humans. The discovery and disulfide’ (see [16] for review). They suggested it be
application of this anti-pernicious or ‘extrinsic’ factor called homocystine, since it had the structure of the
is one of the most fascinating events in the history of ‘next higher symmetrical homolog of cystine.’ Du Vi-
medicine. Minot, Murphy and Whipple shared the No- gneaud went on to win the 1955 Nobel Prize in Chem-
bel Prize in Physiology and Medicine in 1934 for their istry for his work on these biochemically important sul-
work. Liver contains an appreciable concentration of phur compounds, as well as for the first synthesis of a
vitamin B12 and it served for the next two decades as polypeptide hormone.
the main source of this curious extrinsic factor. Castle Over the next few decades a clearer picture emerged
observed that gastric juice contained a protein he called of methionine metabolism, with homocysteine now
‘intrinsic factor’ which enhanced the curative effects of identified as the key branch-point intermediate in the
extrinsic factor [7]. methionine cycle. The discovery and identification of
In 1948 two independent teams in the United States inborn errors of homocysteine metabolism (the ‘homo-
and England isolated the mysterious extrinsic factor in cystinurias’) provided considerable insight into the role
crystalline form [8,9]. Folkers called it ‘vitamin B 12 ’. of the various enzymatic co-factors involved, includ-
In 1955 Dorothy Crowfoot Hodgkin, a British chemist, ing vitamin B12 and folate. These metabolic disorders
elucidated the unique and complex chemical structure are rare; the commonest is cystathionine β-synthase
of this large molecule, in its cyanocobalamin form, us- (CBS) deficiency. The first cases of CBS deficiency
ing X-Ray crystallography [10]. She was awarded the
were reported in 1963 [17], and in 1964 Mudd and col-
Nobel Prize for Chemistry in 1964 for this monumental
leagues identified the enzyme defect [18]. There are
achievement, and for determining the structure of peni-
four major hallmarks of the disease: lens dislocation,
cillin. The production of vitamin B 12 on an industrial
skeletal abnormalities, mental retardation, and throm-
scale in the early fifties enabled its worldwide medical
boembolic disease. The relationship between throm-
application to treat PA.
boembolic disease and homocysteine is relevant to the
2.2. Folic acid later discovery of a role for homocysteine in cognitive
disorders, and will be briefly discussed here.
The related story of the discovery of folic acid by In 1965 a nine-year-old mentally retarded girl with
Lucy Wills, Consultant Pathologist at the Royal Free dislocated lenses was found to have homocystine in her
Hospital, is detailed elsewhere [11]. Briefly, whilst urine and blood. She was diagnosed as having CBS de-
working in India, Wills discovered that the addition ficiency. The girl’s uncle had died of a similar disease
of yeast or its extract corrected macrocytic anaemia in 1933. Her uncle was an eight-year-old mentally re-
in pregnancy [12]. Folic acid received its name some tarded boy who also had dislocated lenses; he later de-
years later, following its isolation from spinach (from veloped hemiplegia and coma. At postmortem he was
the Latin ‘folium’ meaning leaf) [13]. found to have carotid artery thrombosis with cerebral
After the synthesis of folic acid in 1945 [14] it infarction and stroke. The pathologist commented that
became apparent that it was effective in treating all the thickening of his carotid arteries had the appearance
types of megaloblastic anaemia, but especially those of arteriosclerosis in the elderly [19].
that proved refractory to liver preparations such as the In 1968 a second case of homocystinuria was re-
megaloblastic anaemia of sprue, coeliac disease, preg- ported in a two-month-old infant with homocystine
nancy and malnutrition. Although it was temporarily and cystathionine in urine and blood, clearly showing
effective in curing Addisonian PA, it became apparent a different etiology of the homocystinuria. This boy
that, unlike vitamin B 12 , it did not improve the associ- had an abnormality of methionine synthase (cobalamin
ated neurological damage. C disease) [20]. In reviewing this case, the patholo-
A. McCaddon / Homocysteine and cognition – A historical perspective 363

Table 1
Homocysteine and cognition: A ‘timeline.’ Significant events in the history of the discovery
of an association between homocysteine and cognition1
1849 Addison notes that ‘the mind occasionally wanders’ in pernicious anaemia [2]
1930 Folic acid identified [12]
1932 Homocysteine identified as a biologically important amino acid [15]
1945 Folic acid synthesized [14]
1948 Vitamin B12 isolated [8]
1956 Dementia reported in vitamin B12 deficient patients [41]
1959 Significantly lower blood vitamin B12 levels in senile dementia patients [42]
1963 Mental retardation in first cases of homocystinuria due to CBS deficiency [17]
1966 Homocysteic acid identified [183]
1967 Dementia reported in folate deficient patients [44]
1969 McCully proposes a role for homocysteine in arteriosclerosis [19]
1970 Cortical neurones found to be sensitive to homocysteine [184]
1973 Low blood folic acid reported in patients with dementia [46]
1978 Oxidative sensitivity of methionine synthase noted [185]
1980 Importance of phospholipid methylation for signal transmission noted [186]
1980 Activity and importance of brain methionine synthase activity noted [187]
1982 Hippocampal neurones found to be sensitive to homocysteic acid [188]
1983 Low CSF vitamin B12 levels found in patients with AD [50]
1983 Association between nutritional status and cognition in healthy elderly noted [52]
1984 Low serum vitamin B12 levels in patients with SDAT [56]
1986 Homocysteic acid is an endogenous agonist of NMDA receptors [189]
1986 White matter changes observed in AD [190]
1987 Absence of anaemia in patients with low serum B12 and dementia [57]
1988 Neuropsychiatry and hematology of low B12 frequently dissociated [70]
1989 Low B12 and folate in dementia patients is independent of nutritional intake [58]
1990 B12 /folate status correlates with cognitive score in elderly psychiatric patients [59]
1990 Hyperhomocysteinaemia in patients with early onset cerebrovascular disease [191]
1990 Elevated plasma homocysteine in primary degenerative dementia [61]
1991 Homocysteic acid mediates hippocampal synaptic transmission [192]
1992 Serum B12 levels correlate with cognitive scores in AD [97]
1992 ‘Homocysteine hypothesis of AD’ proposed [90–92]
1992 Homocysteine correlates with cognitive scores in depressed elderly [98]
1993 Elevated serum MMA and low B12 in AD patients [99]
1994 Low serum vitamin B12 in early-onset familial AD [89]
1996 AD is associated with changes in remethylation status in brain [107,108]
1996 Raised plasma homocysteine in ‘psychogeriatric’ patients [109]
1997 Elevated serum homocysteine and methylmalonic acid in AD patients [113]
1998 Serum homocysteine correlates with cognitive scores in AD patients [116]
1998 Serum homocysteine is elevated in histologically-confirmed AD [120]
1999 Serum homocysteine is elevated in mild cognitive impairment [121]
2000 Homocysteine correlates with cognitive scores in healthy elderly [130]
2000 Homocysteine correlates with white matter changes in dementia [136]

gist Kilmer McCully again discovered arteriosclerotic tion [21,22]. Later studies revealed that injection of
plaques widely distributed in the infant’s arteries. This homocysteine, or feeding of homocysteine in an ex-
suggested that, at least in these rare inherited metabolic perimental diet, caused arteriosclerotic plaques in rab-
diseases, elevation of blood homocysteine, common to bits, and vascular injury, plaques and thrombosis in
both disease processes, might cause arterial lesions by baboons [23,24].
a direct effect on the cells and tissues of the arteries It is important to note that these observations, al-
regardless of the underlying enzymatic abnormality. though persuasive, do not conclusively demonstrate
Identical arteriosclerotic plaques in a child with
a third type of homocystinuria caused by methylene
tetrahydrofolate reductase deficiency lent additional 1 Historical developments relating specifically to AD can be found

support to a potential causative role of homocysteine in “Alzheimer and the Dementias.” Eds: Berrios G.E. and Freeman
H.L. Royal Society of Medicine Services Limited, 1991 (ISBN 1-
in relation to arteriosclerosis. McCully suggested that
85315-156-4) and “Alzheimer’s Disease. A Medical Companion.”
mild-moderate elevation of homocysteine might also Eds: Burns A. Howard R. and Pettit W. Blackwell Science Limited,
contribute to arteriosclerosis in the general popula- 1995 (ISBN 0-632-03731-8).
364 A. McCaddon / Homocysteine and cognition – A historical perspective

causality; rather, they show that different disruptions of B12 deficiency is perhaps easier to investigate than
intracellular metabolism leading to the export of homo- folate deficiency, which is often accompanied by mal-
cysteine into blood can also cause occlusive vascular nutrition and malabsorption of other nutrients, but pure
pathology. The mechanisms remain unclear and there folate deficiency due to inborn errors of metabolism
remains considerable debate over the relation of ho- also causes neurological manifestations [28]. Folate is
mocysteinemia to arteriosclerotic or thrombo-occlusive actively transported across the blood-brain barrier and
pathology [25]. is present in a greater concentration in cerebrospinal
Nevertheless, many case-control studies have since fluid (CSF) than serum, an unusual observation imply-
confirmed that elevated blood levels of homocysteine ing an important functional role [29]. Folate-related
are associated with an increased risk of cardiovascular enzymes involved in purine and pyrimidine synthesis
disease, and there are numerous suggestions as to how decline almost ten-fold in adulthood, again indicating
homocysteine might contribute to the development of that provision of methyl groups for SAM, coupled with
such disease [26]. These include the pro-coagulant recycling of homocysteine, is probably the dominant
activity of homocysteine toward platelets and vascular function of adult brain folate metabolism [30].
endothelium and the pro-oxidant activity of homocys- Because vitamin B12 and folate are so closely in-
teine. Homocysteine might also induce gene expres- terrelated, their associations with cognitive disturbance
sion, and interact with specific targets such as cellular are presented chronologically.
receptors, intracellular proteins, and small molecules
such as nitric oxide. Regardless of whether or not it 3.1. 1849 to 1950
plays a direct causal role, it will be seen that the recog-
Mental disturbance associated with vitamin B 12 defi-
nition of a relationship between homocysteine and vas-
ciency was first documented in 1849 in Thomas Addis-
cular disease was of later significance for the discov-
on’s initial description of PA when he noted that, “. . .
ery of its relationship to cognitive impairment in the
the mind occasionally wanders” [2]. At the beginning
of the last century there were several early reports of
‘cerebral symptoms’ in patients with PA [31,32].
In 1900, Russell, Batten and Collier published the
3. Cognition, B12 and folate deficiency first full pathological description of ‘subacute com-
bined degeneration of the spinal cord’ which occurs
The literature concerning an association between in untreated PA [33]. The dominant lesions affect the
these two vitamins and cognition is extensive. It pre- cervical and upper thoracic spinal cord, but they also
dates reports of homocysteine as a ‘risk factor’ for de- found that the cerebrum is affected, being mildly at-
mentia by nearly 150 years (Table 1). Vitamin B 12 rophic. The white matter of spinal cord, especially in
and folate are intimately related, reflected in the fact the dorso-lateral columns, appears grey and sponge-
that deficiency of either leads to a morphologically in- like because of demyelination. Vacuoles surrounded
distinguishable anaemia. The neuropsychiatry of their by myelin-laden macrophages occur. This appearance
deficiency is less clearly understood than the haema- was termed a ‘lachen felden’ (field of holes) by Ger-
tology. Nevertheless, nearly thirty years ago Reynolds man physicians describing the condition in the mid-
suggested that the ‘mechanism’ of these neurological nineteenth century [34].
changes may not differ greatly from the mechanism of In 1944 Adams and Kubik confirmed that cerebral
haematological changes [27]. lesions, almost identical to the spinal lesions, occur in
Both folate and B12 are required for the synthesis of PA [35]. The following year Ferraro et al. reported
purines and pyrimidines, but the high cellular turnover on five patients whose autopsies had accidentally re-
in blood compared with brain implies that such path- vealed PA in the course of psychosis and/or dementia
ways are relatively less important in brain. The role of praecox [36]:
these vitamins in methylation is probably of more rele- “The nerve cells presented acute, severe, chronic,
vance in neurological tissue. They are both required for ischaemic, oedematous and fatty changes in vary-
the synthesis of S-adenosylmethionine (SAM), the sole ing degree. The small blood vessels appeared to be
methyl-donor in brain for numerous reactions involv- increased in number and presented a mild endar-
ing nucleoproteins, proteins, membrane phospholipids teritis in all cases. The distribution of the glia of the
and neurotransmitters. white matter was markedly irregular. Often the glia
A. McCaddon / Homocysteine and cognition – A historical perspective 365

nuclei gathered around the blood vessels, so that the acid was associated with marked cognitive improve-
course of the latter was well outlined even when the ment in one patient and a complete return to normality
vascular walls were at a different level, and could in the second. They suggested that, contrary to the pre-
not be seen. Frequently between the conglomera- vailing view at the time, folate deficiency could cause
tion of the glia nuclei and the blood vessels a small such neuropsychiatric abnormalities.
area of white matter, which frequently underwent Further reports of an association between cognition
a process of demyelination, was interposed. These and folate status soon followed. In 1972 Pincus et
areas of demyelination at times had the tendency to al. described a disorientated and dyscalculic patient
coalesce.” with low serum folate; almost total remission of the
There have since been many excellent reviews of the dementia occurred within two weeks of commencing
neurology of B 12 deficiency [37–39]. The neurological folate therapy [45]. The following year Sneath et al.
features are usually chronic and progressive [40]. Typ- examined serum folate levels in 113 elderly inpatients
ical symptoms include a symmetrical paraesthesiae of and found that the 14 individuals with dementia had
extremities and gait ataxia. Some patients also develop lower levels than the group as a whole [46]. They
memory impairment, personality change, psychosis, also found a positive correlation between red-cell folate
anosmia, urinary or faecal incontinence and impotence, and cognitive performance in patients with low folate
although the latter are rare. Signs include loss of cu- levels.
taneous sensation in a ‘glove and stocking’ distribu- At this time, affective disorders were still considered
tion, and impaired vibration sense and proprioception. the commonest neuropsychiatric feature of folate defi-
Romberg’s sign is frequently positive. ciency [47]. However, towards the end of the 1970’s
there were several reports of chronic folate deficiency
3.2. 1950–1980 in which ‘intellectual fatigue’ featured as a symptom.
In a study of 16 patients with folic acid responsive
Dementia per se in association with B 12 deficiency neuropsychiatric disorders, Botez et al. found that all
was initially reported in a few studies in the 1950’s [41, displayed abnormal intellectual functioning on assess-
42]. In 1959 Droller and Dossett investigated a series ment [48]. There was a striking improvement after 6–
of confusional states and non-organic dementias in el- 12 months of folic acid supplementation. In addition,
derly patients. They found significantly lower serum the correlations between neuropsychological findings,
B12 levels in patients compared to controls [42]. In- computerized transaxial tomography findings and ra-
terestingly, they found no difference in bodyweight be- dionuclide cisternograms led Botez et al. to conclude
tween cases and controls, suggesting that malnutrition that chronic folate deficiency could induce cerebral at-
was an unlikely cause of these low values. rophy.
During the 1950’s the strikingly successful treatment
of the haematological features of PA with B 12 con- 3.3. 1980–1990
trasted sharply with the less successful treatment of its
associated neurological disturbances. In all instances In 1982 Inada et al. performed one of the few post-
in the 1950’s, cognitive impairment did not respond to mortem tissue studies of vitamin B 12 levels in relation
B12 replacement and it was unclear whether the vita- to dementia [49]. They measured vitamin B 12 content
min deficiency simply co-existed with dementia or was of brains in 12 autopsy cases of senile dementia, and
of etiological significance (see [39] for review). Nev- found a decrease in B 12 and its binder in those brains
ertheless, vitamin B12 deficiency became included in with severe neuronal loss, myelin degeneration, atro-
many medical textbooks as a reversible cause of de- phy, ventricular dilatation and vascular lesions com-
mentia, despite the lack of definitive evidence at this pared with controls. They also studied autopsy cases
time. of vascular dementia and noticed a markedly decreased
In 1965 Strachan and Henderson described three in- B12 temporal lobe content in association with atrophy,
teresting patients with organic mental deterioration in ventricular dilatation, and vascular lesions.
the face of low serum B 12 , but normal blood and mar- In 1983 Cees Van Tiggelen suggested that cerebral
row, and no spinal cord findings [43]. Two years later B12 deficiency might sometimes occur specifically in
they described two other patients presenting with ad- association with AD [50]. He observed that 24 of his
vanced dementia and megaloblastic anaemia, but this AD patients had pathologically low CSF B 12 levels de-
time due to folate deficiency [44]. Treatment with folic spite normal serum levels, perhaps suggesting abnor-
366 A. McCaddon / Homocysteine and cognition – A historical perspective

mal blood-brain barrier function in AD patients. His and B12 , in 22 patients with SDAT and 41 cognitively
observations were later confirmed by Ikeda et al. [51]. normal elderly control subjects [58]. The two groups
Goodwin et al. noted that low B 12 values were as- did not differ in intake of these vitamins, although the
sociated with poorer cognitive scores in 260 healthy SDAT group had lower levels of red cell folate and
non-institutionalized elderly patients [52]. Curiously, serum B12 . They extended their study to a retrospec-
cognitive function did not correlate with daily intake of tive survey of 154 dementia patients and 49 healthy
the vitamin. Others had previously attributed the high controls, in which they confirmed lower folate and B 12
prevalence of B 12 and folate deficiency in psychiatric values in the patient group independently of estimates
patients (and dementia patients in particular) to mal- of nutritional intake.
nutrition because apathy, loss of appetite and general In 1990 Bell et al. conducted a retrospective review
global decline in these patients results in nutritional of the relationship between cognitive scores and serum
neglect, and hence poor vitamin intake [53–55]. folate and B12 in 102 elderly psychiatric inpatients [59].
Two other key studies in the mid 1980’s confirmed Although participants’ records indicated satisfactory
that serum vitamin B12 levels were significantly lower, nutritional status, correlation analyses indicated that
and B12 deficiency more frequent, in subjects with se- those with below average values for both serum folate
nile dementia of Alzheimer-type (SDAT) [56,57]. Typ- and B12 had significantly lower mini-mental state ex-
ical haematological findings of this deficiency were amination (MMSE) scores than those with higher lev-
often absent in these patients. Karnaze and Carmel els of these vitamins. They concluded that lower lev-
prospectively studied two such patients with dementia els of folate and B12 , even within the normal range,
and low B12 levels, neither of whom had megaloblastic may interact to produce CNS metabolic abnormalities
anemia; one had a normal Schilling test while the oth- affecting cognition.
er’s was borderline [57]. Despite this absence of ex- Nijst et al. measured vitamin B 12 and folate concen-
pected findings, the deoxyuridine suppression test gave
trations in CSF, as well as serum, in 293 neurological
unequivocal biochemical evidence of B 12 deficiency in
patients [60]. The median serum vitamin B 12 concen-
both cases. These findings indicated that low serum
tration of the AD group was significantly lower than
B12 levels in patients with dementia were associated, in
that of a control group. Lower median CSF vitamin B 12
at least some cases, with an ‘atypical’ deficiency state
concentrations were found in groups of patients with
rather than with ‘classical’ disorders such as PA.
multiple sclerosis and AD. Five patients with heteroge-
Despite these reports, debate remained as to whether
neous clinical pictures had unexplained low serum and
there was convincing evidence for an association be-
tween B12 deficiency and dementia. An extensive re- CSF B12 concentrations without macrocytosis. Two
view by Hector and Burton covered almost all the rele- patients had very high serum levels of B 12 but low CSF
vant papers from 1903 to 1986 concerning the psychi- concentrations, suggesting a blood-brain barrier (BBB)
atric manifestations of B 12 deficiency [39]. They noted transport defect. Serum and CSF folate concentrations
that the symptoms most frequently reported were slow did not differ significantly between the various groups.
cerebration and confusion with memory loss. How- Regland suggested that low CSF B 12 levels in de-
ever, in their review of papers published between 1959 mentia patients might be explained by inactive B 12 ana-
and 1986, they found only 3 cases of established de- logues interfering with BBB transport of the vitamin.
mentia that improved with supplementation. They con- He found a lower ratio of active B 12 / inactive analogues
cluded that vitamin B 12 deficiency caused psychiatric in patients with dementia [61]. Further evidence of
disorders of several types: delirium with slow menta- disturbed CSF B12 metabolism was demonstrated by
tion, fear, memory change, delusions, depressive ill- Bottiglieri et al., who discovered surprisingly low lev-
ness, paranoid psychosis, and in rare cases secondary els of CSF SAM in AD compared with patients with
mania [39]. However, they found ‘. . . no convincing other neurological disorders, an observation recently
evidence at all that vitamin B 12 deficiency was a re- confirmed by Eto et al. [62,63]. Bottiglieri concluded
versible cause of dementia’ and challenged this pre- that impaired methylation perhaps contributes to some
vailing concept. They suggested that the association forms of dementia [64].
between B12 deficiency and dementia was simply the
chance occurrence of two unrelated clinical entities, 3.4. 1990–1995
both common in an ageing population.
In 1989 Renvall et al. reported on dietary intake By the early 1990’s the literature encompassed sev-
and several nutritional blood assays including folate eral interesting and contrasting opinions. Were B 12
A. McCaddon / Homocysteine and cognition – A historical perspective 367

and folate deficiencies really associated with dementia, teristics to express B12 deficiency largely in one way,
and more specifically with AD? Should these deficien- whereas others express it largely in another [71].
cies still be considered as ‘exclusion criteria’ for the Early studies utilizing these new metabolic markers
diagnosis of AD [65], or were they perhaps somehow revealed that the prevalence of tissue deficiencies of B 12
intimately related to the AD process itself? and folate were substantially higher than estimates us-
An interesting parallel was also developing for these ing vitamin concentrations alone, especially within the
two separate disorders (B vitamin deficiencies and AD). elderly population [72,73]. An increased prevalence
Both were increasingly recognised as being gradually of moderately low serum B 12 levels in healthy elderly
progressive, with subtle and previously undetectable people had been reported in most [74–76], but not all
pre-clinical stages. Braak and Braak proposed a se- studies [77], but it now became apparent that this was
quence of events in the development of AD pathol- associated with biochemical evidence of deficiency [78,
ogy, suggesting a long time course as the pathological 79]. A high prevalence of vitamin B 12 and folate de-
changes slowly spread throughout the brain [66]. AD is ficiencies in the elderly population was recently con-
therefore preceded by a prodromal phase characterized firmed in two European studies [80,81], and there are
by mild cognitive impairment. Similarly, the late Vic- several reviews of the relevant literature [82–84].
tor Herbert proposed a disease model that ‘reframed’ There are conflicting views concerning the cause of
the concept of vitamin B 12 and folate deficiencies as low blood B12 levels in the elderly population. Elsborg
gradually progressive disorders [67]. He suggested that suggested that the deficiency arises as a result of an
they might best be considered as a ‘continuum’, pro- insufficient dietary supply of vitamin B 12 due to poor
gressing from negative vitamin balance, via depletion dietary habits of the elderly [53]. However Howard
to a ‘classical’ clinical deficiency. The development et al. convincingly showed that poor dietary intake
of new metabolic markers of deficiency, such as blood could not be implicated and suggested that non-dietary
causes must always be sought to explain this common
assays of methylmalonic acid (MMA) and homocys-
metabolic insufficiency state [85]. The most commonly
teine, now meant that early ‘sub-clinical’ deficiencies
suggested factor to account for low vitamin B 12 status
were potentially identifiable [68]. Homocysteine was
in the elderly is the increased prevalence of atrophic
of particular interest in view of its recognised associ-
gastritis with aging [86,87].
ation with an increased risk of vascular disease (see
It was also becoming apparent that not only were B 12
and folate deficiencies more common than previously
The advent of these assays made it clear that the clin-
recognized in the elderly, they also seemed to be asso-
ical spectra of these deficiencies were far broader than ciated with the specific dementia of AD. However, the
previously recognized. The concept of mild preclini- nature of this association remained unclear. If the as-
cal deficiency developed – a state in which metabolic sociation was genuine, several explanations were pos-
evidence of deficiency exists in the absence of symp- sible. The deficiencies might reflect a chance occur-
toms or hematological signs [69]. Nevertheless, there rence of disorders that become increasingly frequent
remained some reluctance to accept that neurological with age, or (at least in the case of folate deficiency)
dysfunction could be the sole expression of deficiency. be a consequence of malnutrition secondary to demen-
This absence, or near absence, of anemia remained tia, or perhaps be due to an age-related decline in ab-
widely unaccepted until 1988 when Lindenbaum re- sorptive function. Alternatively, the deficiencies them-
ported that 40 of 141 patients with neuropsychiatric selves might contribute to cognitive changes via their
disorders attributable to B 12 deficiency had no macro- effects on neurotransmitter metabolism.
cytic anaemia whatsoever [70]. Following this, pa- There is a difficulty in interpreting reports regarding
tients with predominantly neurological manifestations clinically diagnosed AD cases (i.e. ‘SDAT’) since it is
became increasingly recognized [38]. impossible to be certain that these patients have genuine
Some of the reluctance to accept the absence of AD neuropathology. AD is essentially a histopatho-
anaemia was perhaps due to the misleading term ‘PA’ logical diagnosis; only around 70% of clinically diag-
for the gastroenterological entity of B 12 malabsorption nosed AD cases have characteristic AD neuropathol-
due to lack of intrinsic factor. It had been assumed ogy at post-mortem. Patients with a clinical diagnosis,
that megaloblastosis was an ‘early’ phenomenon with together with low blood levels of B 12 or folate, might
neurological involvement occurring somewhat later. simply represent a previously undetected ‘sub-group’
Carmel suggested that it is more likely that some peo- of patients with dementia secondary to B-vitamin defi-
ple are ‘programmed’ by genetic or acquired charac- ciency.
368 A. McCaddon / Homocysteine and cognition – A historical perspective

It was against this background that, in 1990, I met a evated blood levels of homocysteine in 22 patients with
59-year old patient with a nine-year history of memory a primary degenerative dementia [61]. His pioneering
problems and a family history of early-onset dementia studies confirmed that a substantial number of patients
affecting six of his ten siblings, his father, an uncle, and with dementia disorders had co-existing B 12 deficiency,
a cousin. In addition, he had a profoundly low level and he suggested that such deficiencies might play a
of vitamin B12 (50 pmol/L), but a normal Schilling contributory role in the development of dementia [91].
test and no anaemia. The family were later identified Along similar lines, Rosenberg and Miller reviewed
as having Familial AD, due to a mutation in the amy- the evidence for nutritional factors that might influence
loid precursor protein gene [88]. Whilst collating their cognition in older people [92]. They noted that dis-
medical records, I noticed that other affected members turbances of single-carbon metabolism would lead to
of the family also had low blood levels of vitamin B 12 an accumulation of homocysteine in blood, and that
and confirmed this by taking assays at the same time as this might adversely impact cognition as a result of
collecting blood for genetic studies [89]. This was the its relationship to cerebrovascular disease. They also
first example of vitamin B 12 deficiency co-existing in commented that hypomethylation associated with B-
individuals with confirmed AD pathology. vitamin deficiency might adversely affect myelin, neu-
By 1992, there was sufficient evidence to suggest rotransmitter and membrane phospholipid metabolism.
that poor B vitamin status might at least be partially Levitt and Karlinsky considered alternative hypothe-
responsible for cognitive decline in some patients with ses [97]. The ‘low intake’ hypothesis proposed that
dementia. Three groups independently postulated that, cognitively impaired individuals have a reduced capac-
if this were the case, blood levels of homocysteine ity for self-care and nutrition,and consequently develop
should be elevated in patients with late onset AD [90– vitamin deficiency. If this were the case, then cogni-
92]. These papers constitute the ‘homocysteine hy- tive impairment should be associated with deficiencies
pothesis of AD’ [93]; collectively they describe nearly in a wide range of nutritional indices. Their second
all of the mechanisms currently believed to underpin hypothesis was the ‘etiologic’ hypothesis, whereby B
the relationship between homocysteine and cognitive vitamins play a specific role in the development and
impairment. severity of cognitive deficits. If this were the case, then
We suggested that deficiency of these vitamins, par- the relationship between B vitamins and cognitive per-
ticularly vitamin B12 , might contribute to the neuro- formance should exist for all types of dementias. They
transmitter and structural changes of AD [90]. One tested these two hypotheses by examining the relation-
observation supporting this idea was that homocysteic ship between nutritional indices and severity of cogni-
acid, an oxidized form of homocysteine, was an en- tive impairment among people with AD and those with
dogenous agonist of the NMDA receptor [94], with other forms of dementia. They found that serum B 12 ,
an anatomical distribution correlating with that of neu- but not folate status, correlated with MMSE scores only
rofibrillary tangles and senile plaques [95]. It seemed for the group with AD. They concluded that their results
possible that homocysteine might account for the char- did not support the ‘low intake’ hypothesis, because al-
acteristic distribution of neuropathological lesions in though B12 was related to cognitive impairment, none
AD. We also suggested that B12 can be functionally of the other nutritional indices, including folate, were.
inactive (although present in normal serum concentra- However, the ‘etiologic’ hypothesis was not supported
tion), as a result of increased oxidative damage known either, as a relationship between B 12 and cognition was
to occur in AD [96], and that in these situations serum only seen in those patients with AD. They therefore
homocysteine concentrations may prove a more accu- proposed a third hypothesis, the ‘common pathophysi-
rate indicator of B 12 tissue status. ology’ hypothesis, to account for the association. They
Regland investigated the prevalence of vitamin B 12 suggested that the disease process in AD might affect
deficiency in patients with dementia disorders by an- cellular function in a way that is somehow associated
alyzing blood and CSF samples using novel mark- with a decrease in the ability to utilize vitamin B 12 [97].
ers of B12 status, including homocysteine and holo- In the same year, Bell et al. observed that ‘de-
transcobalamin saturation [61]. He confirmed earlier pression among elderly people with reversible cogni-
reports of an association between B 12 deficiency and tive loss often manifests with concomitant vascular dis-
SDAT, finding that low serum B 12 levels were nearly ease.’ Because homocysteine is a vascular disease risk
five times more frequent in these patients compared factor (see above), they speculated that it might play
with an age-matched population. He also discovered el- a role in the pathophysiology of such individuals. In
A. McCaddon / Homocysteine and cognition – A historical perspective 369

a study of 27 depressed elderly inpatients they found In 1995 Carmel and colleagues evaluated neuropsy-
significantly higher plasma homocysteine levels and chological and electrophysiological indices in thirteen
lower cognitive screening test scores than 15 depressed older adults with dementia and low serum B 12 levels
young adult inpatients [98]. Homocysteine was high- before and after B 12 supplementation [103]. Improve-
est in older patients with concomitant vascular disease, ments were found for homocysteine and haemoglobin
and lowest in older depressives who had neither vascu- levels, neuropathological symptoms, EEG abnormali-
lar disease nor dementia, compared to the young adult ties, and visual evoked and somatosensory abnormali-
depressives. Higher homocysteine correlated signif- ties, although none were found for neuropsychological
icantly with poorer cognition only in the nonvascu- tests of cognitive performance.
lar geriatric patients. Their findings extended earlier Teunisse et al. investigated the effects of treating
work from general medical populations demonstrating B12 deficient patients with dementia, specifically with
higher plasma homocysteine levels in vascular patients, regard to its effects on cognition, activities of daily liv-
and suggested that elevated homocysteine might be a ing, behavioural problems, and caregiver burden [104].
metabolic factor in certain dementias, at least in those They studied 170 consecutive referrals and found low
associated with late-life depression. B12 in 26 (15%), all but one fulfilling diagnostic crite-
In 1993 Kristensen et al. evaluated vitamin B 12 sta- ria for possible AD. These patients were treated with
tus in AD, other dementias, various gerontopsychiatric monthly intramuscular B 12 and reassessed 6 months
disorders, and healthy controls [99]. They measured later, but supplementation did not slow the progression
serum B12 and MMA levels. The mean B 12 concentra- of dementia. They concluded that, contrary to widely
tion was significantly lower in AD than in age-matched accepted beliefs, subnormal serum B 12 is not a quanti-
controls and the other patient groups. Correspondingly, tatively important cause of reversible dementia.
the mean MMA level was higher in AD than any other More recently, Eastley et al. identified 125 B 12
diagnostic group. Comparing AD to the other groups
deficient patients out of 1,432 attending a memory
as a whole the elevation was highly significant. Their
clinic [105]; 66 had a dementia and 22 were cognitively
findings further confirmed that AD patients appeared
impaired. There was no change in the dementia group
particularly prone to B 12 deficiency.
after B12 supplementation, but patients in the cogni-
Conversely, in the same year Crystal et al. presented
tively impaired group improved on measures of verbal
the results of a five-year follow up study of 410 elderly
subjects [100]. They found no difference in the inci-
Larner and Rakshi summarized this intervention lit-
dence of dementia between subjects who were B 12 de-
ficient compared with those with normal blood levels erature by concluding that “. . . low vitamin B 12 is not
of the vitamin. None of the three low B 12 subjects who an uncommon finding in patients with dementia or cog-
did develop a dementia responded to monthly B 12 in- nitive decline, but cases of dementia reversible with
jections. They concluded that a low B 12 level may not vitamin B12 therapy seem extremely rare” [106]. They
be a risk factor for dementia in general or AD in par- suggested that in most cases a low blood vitamin B 12
ticular. Vitamin B12 levels were also normal in AD pa- level in a patient with dementia was a coexistent rather
tients in another population study conducted the same than causal abnormality.
year [101].
Might the effects of B 12 supplementation in cogni- 3.5. 1996–2000
tively impaired deficient subjects shed light on these
discrepant observations? During the 1990’s, four such The closing years of the Millennium saw a dramatic
studies were conducted [102–105]. acceleration of research in this field, often using innova-
Martin et al. investigated the effects of six-months tive approaches. For example, Gomes-Trolin et al. de-
B12 supplementation on cognitive performance in a termined the influence of vitamin B 12 on the activity of
group of eighteen elderly participants with cognitive methionine adenosyltransferase (MAT) in postmortem
dysfunction and low serum B 12 [102]. Eleven partic- SDAT brains [107]. MAT activity in frontal cortex
ipants showed improvement on the Mattis Dementia was significantly increased in SDAT cases compared
Rating Scale. The best responses were seen in those to non-demented controls. Furthermore, this activity
symptomatic for less than 6 months, suggesting that was restored to normal in B 12 -treated SDAT patients.
cognitive impairment in B 12 deficiency might be re- The authors suggested that this change in activity might
versible only if supplementation is initiated at an early reflect the effect of chronic adaptation, as a result of a
stage. low supply of methionine due to deficient activity of
370 A. McCaddon / Homocysteine and cognition – A historical perspective

B12 dependent MS. Further support for disturbed CNS al. examined 137 healthy, independent, well educated
methylation reactions in AD came from Morrison et al., and well nourished cognitively intact elderly in a longi-
who showed that brain levels of SAM were severely de- tudinal follow up of the older adults originally studied
creased at post-mortem in patients with AD compared by Goodwin et al. [52,112]. Participants with higher
with Parkinson’s Disease [108]. levels of folate performed better on tests of abstraction,
In 1996 the accumulating reports of an association and a history of higher past intake of vitamin B 12 was
between reduced concentrations of B 12 , folate and related to better visuo-spatial recall and abstraction,
‘neuropsychiatric’ symptoms led Nilsson et al. to in- although these latter associations were relatively weak.
vestigate B12 and folate status using the new metabolic This led Joosten et al to examine whether AD patients
marker homocysteine in 741 consecutive psychogeri- were particularly prone to metabolically significant B 12
atric patients [109]. In this study, plasma homocysteine or folate deficiency compared to non-demented hos-
concentrations were significantly increased in both the pitalized controls and healthy elderly controls [113].
demented and non-demented patients, whereas only the They measured serum folate, B 12 , MMA and homo-
demented patients had lower blood folate and serum cysteine in 52 patients with AD, 50 non-demented hos-
creatinine concentrations compared with 163 control pitalized controls, and 49 healthy elderly subjects liv-
subjects. Almost all of the different diagnostic groups ing at home. They found that serum vitamin B 12 and
of demented and non-demented patients exhibited sig- folate levels were comparable between patients with
nificantly increased plasma homocysteine concentra- AD, hospitalized control patients, and subjects living
tions compared with control subjects. Significantly de- at home. However, patients with AD had the highest
creased blood folate concentrations were mainly found serum MMA and homocysteine levels, and the mean
in the different diagnostic sub-groups of demented pa- homocysteine level was significantly higher in AD pa-
tients. Plasma homocysteine concentrations in both de- tients compared to the other groups. They concluded
mented and non-demented patients with serum vitamin that the interpretation of the vitamin B 12 and folate
B12 and blood folate above the lower 20th percentile of status of patients with AD depended largely on the
these vitamins in the control subjects were also stud- methodology used (i.e., serum vitamin versus metabo-
ied. Despite these vitamin concentrations, both groups lite levels) and the selection of the control group. Al-
of patients still exhibited significantly higher plasma though patients with AD had the highest homocysteine
homocysteine concentrations than the control subjects. and MMA levels, they confirmed that metabolically
The authors suggested that this might indicate an im- significant vitamin B12 and folate deficiency is also a
paired capacity to metabolize homocysteine in these pa- substantial problem in non-demented elderly patients.
tients. Patients with either dementia of vascular cause Folate deficiency is probably as prevalent as vitamin
or a history of other occlusive arterial disease had sig- B12 deficiency in patients with cognitive impairment,
nificantly higher plasma homocysteine concentration although at this time it was perhaps more often over-
than those without a history of vascular disease. looked. In the Canadian Study of Health and Aging
Another noteworthy pioneering study was also con- in which serum folate was determined in 1,171 elderly
ducted in 1996, demonstrating the utility of these new subjects, those with low folate levels were more likely
metabolic markers in probing B-vitamin related cog- to be demented [114]. Those in the lowest folate quar-
nitive effects [110]. Riggs et al. found a relationship tile also had an increased risk of stroke, and were more
between spatial copying errors and elevated homocys- likely to be institutionalized and depressed. In the cog-
teine in seventy elderly males in the Normative Ageing nitively impaired but not demented group, individuals
Study [110]. In contrast to Nilsson’s findings, higher with low folate scored lower on the modified MMSE
homocysteine levels in these individuals were unrelated and had more short-term memory problems. Low fo-
to the presence of cerebrovascular disease. late levels were common in all types of dementia, and
By 1997, although there was now further evidence were associated with a history of weight loss, lower
for an association between AD and B 12 /folate defi- body mass index and lower serum albumin. The au-
ciency, it was still argued that, because both conditions thors felt that this might reflect the reduced ability of
occur commonly in the elderly, it was not surprising cognitively impaired individuals to eat adequately.
that many subjects had a combination of the two dis- Bernard et al. examined the effect of B 12 deficiency
orders [111]. However, intriguing observations con- with regard to general health and cognitive impairment
tinued to be made concerning a correlation between in 303 male elderly out-patients [115]. They used
B12 /folate status and cognition. For example, La Rue et two definitions of B12 deficiency: a ‘strict’ definition
A. McCaddon / Homocysteine and cognition – A historical perspective 371

(B12 < laboratory cut-off of 200 pg/ml) and a broader and apoE4 genotype. The corresponding odds ratio
‘metabolic’ classification (B 12 up to 300 pg/ml and for the lowest tertile compared with the upper tertile
MMA or homocysteine levels greater than 2 standard of serum folate distribution was 3.3 (95% CI, 1.8–6.3)
deviations above the mean). 6% of individuals were and for the vitamin B 12 distribution was 4.3 (95% CI,
B12 deficient by the strict definition, and 16% using the 2.1–8.8). Mean homocysteine levels were unaltered by
broader definition. There was a significant difference duration of symptoms. In a 3-year follow-up of a subset
between cognitive scores of B 12 -deficient subjects and of patients, radiological evidence of disease progres-
B12 -normal subjects with deficient individuals being sion was greater among those with higher homocys-
more impaired, but this only arose when the ‘strict’ teine levels at entry. The OPTIMA team concluded that
definition was used (MMSE 27.2 ± 2 versus 22.5 ± low blood levels of folate and vitamin B 12 and elevated
1.89). homocysteine levels were associated with definite AD
In 1998 we confirmed Joosten’s and Regland’s ear- pathology.
lier observations of elevated total serum homocysteine The OPTIMA study did not find a relationship be-
levels in patients with clinically diagnosed AD com- tween dementia duration and serum homocysteine,
pared to age matched healthy elderly controls. We again suggesting that hyperhomocysteinaemia cannot
also discovered a correlation between homocysteine solely be a consequence of the disease process and
and cognitive function scores in these patients [116] might be an important pathogenic element. Notably,
. This suggested that the patients might indeed har- individuals with higher homocysteine concentrations
bour the ‘subtle’ vitamin B 12 or folate deficiencies ini- showed a more rapid progression of their disease over
tially suggested by Karnaze and Carmel some ten years a three-year period.
earlier [57]. A secondary aim of our study was to The following year, Lehmann et al. confirmed and
determine whether these deficiencies were nutrition- extended these findings [121]. They evaluated 336 con-
ally independent. We assayed retinol binding protein, secutive patients attending a university-affiliated mem-
a vitamin A transport protein sensitive to dietary in- ory unit. The patients were diagnosed with early-onset
take [117]. Retinol binding protein values did not dif- AD, SDAT, VD, other dementias, minor cognitive im-
fer between groups, suggesting that malnutrition was pairment (dysmentia), and also included a group of
an unlikely cause of the hyperhomocysteinaemia. This patients with subjective symptoms only. Increases in
concurs with earlier studies of nutritional indices and vascular risk factors, serum homocysteine, ApoE4 load
intake [118,119], and suggests that metabolic evidence and neuroimaging pathology were found in dementia
of these deficiencies arises as a result of aberrant ab- but also in dysmentia patients, and in patients with sub-
sorption, metabolism, or transport of B vitamins rather jective symptoms only. Homocysteine levels correlated
than dementia-related malnutrition. inversely with cognitive performance. The authors con-
Confirmation of elevated homocysteine levels in as- cluded that the increases in serum homocysteine, which
sociation with definite AD came later that year from were pathological in vascular dementia and dysmentia
the Oxford Project to Investigate Memory and Aging as well as SDAT, perhaps indicate disturbed cerebral
(OPTIMA) [120]. Since recent studies had suggested one-carbon metabolism and might signal accelerated
that vascular disease might contribute to the develop- development of cognitive disease. Lehmann et al. also
ment of AD and that moderately elevated blood homo- showed that the thermolabile methylene tetrahydrofo-
cysteine was associated with vascular disease, the OP- late reductase variant was not over-represented in these
TIMA team measured homocysteine levels in 164 pa- patients, and could therefore not account for elevated
tients aged 55 years or older with a clinical diagnosis of homocysteine; subsequent studies have confirmed this
dementia of Alzheimer type, and 108 control subjects. observation [122].
A key feature of their work was that the patient group The Nun Study provided important additional infor-
included 76 patients with histologically confirmed AD. mation regarding folate status and AD [123]. This
They found that serum homocysteine levels were signif- study examined whether serum folate was inversely as-
icantly higher, and serum folate and B 12 levels lower in sociated with neocortical atrophy, which was measured
patients with dementia than in controls. The odds ratio in addition to various nutrients, in thirty elderly Nuns
of confirmed AD associated with a homocysteine level who had died between the ages of 78 and 101 years.
in the upper tertile compared with the lowest tertile of Folate correlated with neocortical atrophy, and among
the control distribution was 4.5 (95% CI, 2.2–9.2), after a subset of fifteen with significant Alzheimer pathol-
adjustment for age, sex, social class, cigarette smoking, ogy, this correlation was more marked. Snowdon et al.
372 A. McCaddon / Homocysteine and cognition – A historical perspective

concluded that atrophy might be specific to folate since ally exclusive; elevated levels of homocysteine might
correlations were not found with any other nutrients. have a multifactorial adverse impact on central ner-
This study is unique in that all individuals ate from the vous system function. A full discussion of such mech-
same kitchen, and were highly comparable with respect anisms is beyond the scope of this review, but can be
to their environmental and lifestyle factors. Many of read elsewhere in this Special Issue of the Journal (and
the participants with atrophy had serum folate in the see [146–148]).
normal range, suggesting that optimal folate concentra- The last few years have also seen an important emerg-
tion may in fact be higher in old age or when diseases ing story of the apparent impact of food folate fortifi-
such as AD are present. Snowdon et al. suggested cation in altering the epidemiological associations be-
that the relationship could be due to folate’s effects on tween folate and dementia [149]. Data from SALSA
the vascular system, via its influence on homocysteine and other studies have sparked debate that vitamin defi-
levels. However, folate was negatively correlated with ciency, rather than homocysteine itself, drives cognitive
atrophy even in subjects with minimal atherosclero- decline in the elderly [149,150]. However, as noted in
sis and without infarcts, suggesting that the correlation a recent editorial by Bottiglieri and Diaz-Arrastia, the
may not be entirely due to vascular disease. metabolic relations between homocysteine, folate and
B vitamins are intimate and complex, and it is probable
3.6. 2000 – present that multiple mechanisms underpin the pathophysio-
logic consequences of hyperhomocysteinaemia and B
The last five years have witnessed an explosion of vitamin deficiency [150]. It should also be noted that
interest in the relationship between homocysteine and ‘non-universal’ folate fortification leads to additional
cognitive disorders. Individuals with low serum lev- limitations of epidemiologic tools not only in address-
els of vitamin B12 and folate were confirmed to be at ing causality, but in referring only to specific popula-
greater risk of developing AD [124]. Several case- tions. This inevitably results in inconsistencies, where
control studies, but not all [125], confirmed a relation- differences of methods and populations may discrim-
ship between homocysteine and dementia [126–129], inate between groups where the true biological rela-
as well as a correlation between elevated plasma ho- tionship between homocysteine and vitamins to cog-
mocysteine and poor performance on neuropsychologi- nition are different (compare, for example, the study
cal tests, even in healthy elderly individuals [130–133]. populations in [110,141,151–154].
Most prospective studies also reported an association Many excellent reviews have recently detailed the
between baseline homocysteine and subsequent cog- now burgeoning literature concerning homocysteine
nitive decline in non-demented individuals [134,135]. and cognition [93,155–161]. In his review, Miller notes
Relationships between homocysteine and white matter that the impetus to this work for many research groups
lesions and brain atrophy have also been reported [136– stemmed from the increasing realization of a potential
138]. vascular component in AD pathology [155]. For exam-
Perhaps the most striking observations in the last ple, AD is associated with atherosclerosis, cerebral mi-
five years are that baseline hyperhomocysteinaemia in- crovascular abnormalities, hypertension, and ApoE4.
creases the risk of developing dementia and AD over From a historical viewpoint, there is some irony in
an 8 year follow-up period [139]. Although this finding the fact that the discovery of a relationship between ho-
was not initially replicated [140], a similar relationship mocysteine and AD partly relates to observations con-
was recently confirmed over a shorter follow-up period cerning the association of both with vascular disease.
of four years [141]. Alois Alzheimer first described his eponymous disease
Many groups are now exploring ways in which el- at the 37th Conference of Southwest German Psychi-
evated homocysteine levels might adversely influence atrists in Tübingen on November 3rd and 4th 1906.
cognition [142–145]. Several potential mechanisms His presentation was entitled “A peculiar disease of the
exist. These relate elevated levels of homocysteine to cerebral cortex.” [162]. He described a 51-year old
cerebrovascular disease and white matter lesions, im- woman, Auguste D, who had been admitted to the state
paired methylation, NMDA receptor antagonism, ox- asylum in Frankfurt [163]. She had become jealous
idative stress, apoptosis, amyloid accumulation (in- of her husband and subsequently developed memory
cluding the formation of senile plaques and vascular impairment. She was suffering from cognitive and lan-
Aβ deposits) and, more recently, to neurofibrillary tan- guage deficits, auditory hallucinations, delusions, para-
gle formation. None of these mechanisms are mutu- noia and aggressive behaviour. Mental regression ad-
A. McCaddon / Homocysteine and cognition – A historical perspective 373

vanced quite steadily and after four and half years of supplementation with folic acid, with or without B 12 ,
illness she died on the 8 th of April 1906. The day of on cognitive function in healthy elderly, or those with
Auguste’s death was not mentioned by Alzheimer but cognitive impairment or dementia [165,166]. However,
by his other two (unnamed) colleagues, who wrote the studies to date have included only a small number of
following report in her records [163]: participants over a short time period. Much larger in-
“April 8, 1906 tervention studies, over a longer period will be required
During the morning exitus letalis; cause of death: to assess the potential for such supplements to slow or
septicaemia due to decubitus; anatomical diagno- prevent cognitive impairment in later life.
sis: moderate hydrocephalus (external internal); Several such trials are now underway. The NIH-
cerebral atrophy; arteriosclerosis of the small cere- funded VITAL trial is a large double-blind placebo-
bral vessels; pneumonia of both inferior lobes; controlled trial to determine whether high-dose B sup-
nephritis.” plements slow cognitive decline over 18 months in sub-
Alzheimer asked for her records and brain to be sent jects with established AD [167]. The VITATOPS study
to Munich. He had moved there to work with Emil is a multi-center secondary stroke prevention trial to
Kraepelin, one of the foremost German Psychiatrists of determine whether the addition of B-supplements to
the time. He found an evenly affected brain without current best management reduces the incidence of re-
microscopic foci, and described fibrils in one quarter current vascular events in patients with stroke or TIA;
to one third of all neurons in the cerebral cortex and dementia is a secondary outcome measure [168]. VI-
large numbers of miliary foci representing the sites of TATOPS will recruit 8,000 patients with a follow-up
deposition of a peculiar substance in the cerebral cor- period of 2.5 years, and will complete in 2007. VI-
tex. He noted a disappearance of numerous neurons, TACOG is a UK-based placebo-controlled study of B
especially in the upper cell layer. In his original presen- supplements in 300 elderly participants with MCI to de-
tation of this case, Alzheimer also reported that he had termine effects on brain atrophy and cognitive function,
found arteriosclerotic changes in her brain. However, and will finish in 2008 (Smith A.D. – personal commu-
his description of arteriosclerosis was not mentioned in nication). Our own research continues with COBALZ
Kraepelin’s announcement of “Alzheimer’s Disease” a IV, a randomized controlled trial of B-vitamin and
few years later in the eighth edition of his Handbook antioxidant therapy in hyperhomocysteinaemic MCI
of Psychiatry. The reasons for this are not clear. One patients. The rationale for using an antioxidant is
possibility is that Kraepelin wished to emphasize only that oxidative stress adversely impacts B 12 and folate
the novel features of Alzheimer’s observations. metabolism [169,170]. 100 patients will receive stan-
These historical aspects of AD have been carefully dard dose B-vitamins or high-dose reduced forms of
documented by Berrios [164]. He describes two in- B-vitamins together with N-acetylcysteine, the primary
teresting metaphors concerning the classification of objective being to determine whether the latter slow
disease. He suggests that we could either consider brain atrophy over 12 months. Other closely related
Alzheimer, in describing these findings, as “. . . cata- ongoing, or recently completed, trials include a five-
loguing species in an exotic garden,” or alternatively year ancillary study of the cognitive benefits of high
behaving as “. . . a sculptor, carving a shape out of dose B vitamins in renal transplant recipients [171], the
formless matter and creating a clinical form.” Berrios Wageningen folate supplementation trial [172], a study
points out that AD continued to be ‘sculpted’ through- of the effects of vitamin treatment on movement and
out the last century. He notes that during the last cen- cognitive performance in elderly subjects [173], and
tury there was a clear move towards narrowing down a trial of homocysteine-lowering vitamin treatment in
the syndrome, and arteriosclerosis was quietly dropped elderly patients with vascular disease [174].
until it eventually became an exclusion criterion. In
Although epidemiological observations coupled with
historical terms, it is only relatively recently that this
plausible biological mechanisms suggest a causal role
overlap between AD and cerebrovascular disease has
for homocysteine in cognitive disorders, it may actually
been noted, or rather, ‘rediscovered.’
prove difficult to provide ultimate proof of such causal-
ity. In all of the ongoing trials a positive result will sim-
4. The Future? ply show that ‘homocysteine lowering therapy’ has cog-
nitive benefit. Since this is achieved through vitamin
Two recent systematic literature reviews concluded supplementation, this will demonstrate that such sup-
that there is as yet no evidence of benefit from dietary plementation, which ameliorates a functional metabolic
374 A. McCaddon / Homocysteine and cognition – A historical perspective

deficiency (i.e., is capable of lowering plasma homo- It is certainly true that there is still a great deal to
cysteine), has cognitive benefit. Whilst this will be be discovered concerning the relationship between this
good news for treatment, it will not provide definitive vitamin, folic acid and cognition.
evidence that homocysteine itself is causative. Con- It remains to be seen whether early detection and
versely, homocysteine lowering intervention trials may correction of the metabolic abnormalities associated
be negative (fail to reduce risk) even where homocys- with deficiency of these vitamins can slow, or even
teine is significantly associated with risk. For exam- halt, cognitive decline. Even so, despite considerable
ple, the Vitamin Intervention for Stroke Prevention trial debate in the literature over the last quarter-century, it
(VISP) showed no effect of homocysteine lowering on now appears that patients with low blood levels of these
the primary outcome of recurrent stroke, or on a sec- vitamins should not necessarily be excluded from a
ondary outcome of cognition and dementia, despite diagnosis of AD or vascular dementia [65,182]. These
strong associations of baseline homocysteine with in- disturbances may actually be an important component
creased risk of stroke [175]. Nevertheless, a recent re- of these fascinating but devastating diseases.
assessment of the trial showed that, when stratified by
baseline B12 levels and after exclusion of individuals
with probable malabsorption or extra supplement use,
treatment with a multivitamin containing B 12 produced
a significant reduction in risk [176].
It can be seen that, although there are plausible hy- This review is dedicated to the memory of Cees Van
potheses concerning homocysteine and cognition, the Tiggelen. AM is a shareholder in, and transferred a
complexities of its metabolism (as well as the com- patent to, Cobalz Limited, U.K.
plexity of the clinical entity of ‘dementia’ and of the
intangible outcome of ‘cognition’) make it difficult to
adequately test such hypotheses. None of the cur- References
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