Homocysteine, folate, and vitamin B-12 and cognitive performance
in older Chinese adults: findings from the Singapore Longitudinal
Ageing Study13
Lei Feng, Tze-Pin Ng, Lisa Chuah, Mathew Niti, and Ee-Heok Kua
ABSTRACT
Background: The relations of elevated homocysteine, low folate,
and vitamin B-12 with cognitive performance in nondemented el-
derly are not well established. Limited research data suggest differ-
ential effects of homocysteine and folate on specific cognitive do-
mains.
Objective: The aim was to examine the independent associations of
homocysteine, folate, and vitamin B-12 with cognitive performance
in high-functioning elderly Chinese.
Design: Homocysteine, folate, and vitamin B-12 concentrations
were measured in fasting blood samples of 451 Chinese aged 55 y
with Mini-Mental State Examination scores 24 and who were
considered fully independent based on Activities of Daily Living
score. Cognitive functions were assessed by a neuropsychological
test battery. Independent associations (standardized ) were deter-
mined in multiple linear regression models that simultaneously con-
trolled for potential confounders.
Results: Log-transformed homocysteine was inversely associated
with performance on Block Design ( 0.319, P 0.006) and the
written Symbol Digit Modality Test ( 0.129, P 0.031).
Log-transformed folate was significantly associated with Rey Au-
ditory Verbal Learning Test delayed recall ( 0.139, P 0.010),
verbal learning ( 0.112, P 0.038), percentage of forgetting
( 0.139, P 0.013), and the Categorical Verbal Fluency test
( 0.104, P 0.042). Vitamin B-12 was not significantly asso-
ciated with any cognitive test score.
Conclusions: In this high-functioning elderly Chinese population,
elevated homocysteine is associated with deficits in constructional
ability and processing speed and folate is associated with measures
of episodic memory and language. Our results provide support for
differential effects of homocysteine and folate on specific cognitive
functions. Am J Clin Nutr 2006;84:1506 12.
KEY WORDS Homocysteine, folate, vitamin B-12, cognitive
function, Chinese
INTRODUCTION
Recent research has investigated the link between plasma ho-
mocysteine, folate, and vitamin B-12 and the risk of dementia
and cognitive impairment in older adults. The thiol-containing
amino acid homocysteine links the methionine cycle with the
folate cycle and is a sensitive marker for folate and vitamin B-12
deficiency (1, 2). To date, studies of the associations of elevated
1506 Am J Clin Nutr 2006;84:1506 12. Printed in USA. 2006 American Society for Nutrition
concentrations of homocysteine and decreased folate and vita-
min B-12 with cognitive function in the elderly have yielded
inconsistent findings.
Previous studies have observed that dementia patients have
elevated homocysteine or decreased folate and vitamin B-12
concentrations compared with control subjects (35). Longitu-
Downloaded from ajcn.nutrition.org by guest on March 11, 2017
dinal studies have reported positive findings linking elevated
concentrations of homocysteine or lowered concentrations of B
vitamins with cognitive decline and dementia (6 11); however,
negative findings have also been reported (1214). Randomized
controlled trials have shown that supplements of folic acid or
vitamin B-12 have no apparent efficacy in improving cognitive
function (15, 16).
In studies conducted in nondemented, healthy elderly popu-
lations, some investigators have reported an association of ele-
vated homocysteine or decreased B vitamins with lowered cog-
nitive performance (1731). Limited data from a few studies also
suggest that homocysteine and folate may be associated differ-
entially with specific cognitive domains (17, 25, 30). However,
many studies had a limited sample size (17, 18, 21, 23, 27) or
measured only a limited range of cognitive domains (20, 24, 26,
31). Furthermore, some studies did not measure B vitamins and
homocysteine simultaneously (18, 19, 21, 22, 28), and thus could
not examine the differential contributions of each of these closely
associated micronutrients. In a triethnic population, Wright (26)
reported that an association between homocysteine and Mini-
Mental State Examination (MMSE) score was observed only in
white and Hispanic subjects but not in black subjects. This sug-
gests that ethnicity may also have a modulating effect, either by
itself or as a surrogate of ethnicity-related factors. In the present
study, we aimed to determine the independent association be-
tween homocysteine, folate, and vitamin B-12 and cognitive
1
From the Gerontological Research Programme, Faculty of Medicine,
National University of Singapore, Singapore (LF, T-PN, LC, and MN); the
Department of Psychological Medicine, National University of Singapore,
Singapore (LF, T-PN, and E-HK); and the Cognitive Neuroscience Labora-
tory, Singapore Health Service, Singapore (LC).
2
Supported by a research grant (no. 03-1-21-17-214) from the Biomedical
Research Council, Agency for Science, Technology and Research (ASTAR).
3
Reprints not available. Address correspondence to T-P Ng, Gerontologi-
cal Research Programme, National University of Singapore, Department of
Psychological Medicine, National University Hospital, 5 Lower Kent Ridge
Road, Singapore 119074. E-mail: pcmngtp@nus.edu.sg.
Received June 26, 2006.
Accepted for publication July 17, 2006.
 HOMOCYSTEINE, FOLATE, VITAMIN B-12, AND COGNITION
function in a group of community-dwelling Singapore Chinese
elderly with generally good cognitive and physical functioning.
SUBJECTS AND METHODS
Subjects
The subjects in the present study were identified from partic-
ipants of the Singapore Longitudinal Ageing Study, a
community-based epidemiologic study of aging and health.
Briefly, a whole population of all residents (Singapore citizens
and permanent residents) in contiguous precincts within 5 dis-
tricts in the South East region of Singapore who were aged 55
y were identified from a door-to-door census and invited to par-
ticipate in the study. The study was approved by National Uni-
versity of Singapore Institutional Review Board. All participants
signed an informed consent letter before participating. The re-
sponse rate was 78.2%.
An exhaustive neuropsychological assessment was performed
on a 1-in-3 random sample of the respondents who had the suf-
ficient visual, language, and motor abilities that are required to
complete the tests. The study was conducted on Chinese elderly
subjects, because the numbers of Malay and Indian subjects were
small. Because demented elderly persons are grossly impaired on
cognition and may hence be prone to malnutrition, their inclusion
may overestimate the potential associations and render the inter-
pretations of cause-and-effect difficult. Thus, only respondents
with a MMSE score of 24 and who were fully independent
based on the Activity of Daily Living (ADL) test were selected
for the study.
Laboratory measurements
Venous blood samples after overnight fasting were drawn
from 0900 to 0930 according to standard procedures. Blood
samples were transported to Singapore National University Hos-
pital Referral Laboratory on ice within 2 h, and the plasma or
serum was isolated and stored at 80 C before analysis. Plasma
total homocysteine was measured by automated chemilumines-
cent enzyme immunoassay method (Diagnostic Products Cor-
poration, Los Angeles, CA); the CV ranged from 4.1% to 10.4%.
Folate and vitamin B-12 was measured in serum by radioassay
with an Elecsys Folate II reagent kit (CVs ranged from 6.1%
to 13.8%) and an Elecsys Vitamin B-12 reagent kit (CVs
ranged from 3.2% to 7.6%; Roche Diagnostic, Indianapolis,
IN), respectively.
Cognitive tests
Trained research assistants administered a comprehensive
neuropsychological test battery that assesses a wide range of
cognitive domains, including attention and working memory
(Digit Span and Spatial Span), verbal learning and memory (Rey
Auditory Verbal Learning Test; RAVLT), visual memory (Vi-
sual Reproduction), language (Categorical Verbal Fluency), ex-
ecutive function (Design Fluency), information processing
speed (Symbol Digit Modality Test; SDMT), visual conceptual
ability, visual-motor tracking and mental flexibility (Trail Mak-
ing test A and B), and visual spatial and constructional ability
(Block Design). The assessment was administered in English,
Mandarin, or Chinese dialects according to the subjects habitual
language. The entire battery took 1.52 h to complete.
1507
Digit Span
In Digit Span Forward (32), the examiner reads strings of
numbers in series with increasing length, and the examinee is
asked to repeat the string in the exact order. In Digit Span Back-
wards, the examinee is asked to say the strings in reverse order.
Spatial Span
A computerized version of the Spatial Span test (33) was used;
Spatial Forward was performed by having the examinee touch
the same square on the computer screen in the same order as they
were flashed up (changing from blue to red). In Spatial Back-
wards, the subject is asked to touch the squares in the reverse
order.
Rey Auditory Verbal Learning Test
In the RAVLT (34), the examiner reads a semantically unre-
lated word list (list A) to the examinee in a series of 5 trials. After
each learning trial, the examinee is asked to repeat all the words
he or she can remember. A second distracter word list (list B) is
then presented. Thirty minutes later, the examinee is asked to
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recall all the words he or she can remember from list A again.
Visual Reproduction
In the Visual Reproduction test (33), the examinee is allowed
10 s to observe each of 5 design cards (3 cards with one design
and 2 cards with 2 designs) and reproduce them from memory.
Thirty minutes later, the examinee is asked to reproduce the
designs again.
Categorical Verbal Fluency
In this test, the examinee is asked to produce as many words as
possible in one minute from 3 categories (animal, vegetable, and
fruit) respectively.
Design Fluency
For the Design Fluency test (35), the examinee is asked to
connect dots to make different designs with 4 straight lines in
60 s. In condition 1, there are only black dots presented. In
condition 2, there are black and empty dots and the subject is
asked to only use the empty dots. In condition 3, the subject is
asked to alternate between black and empty dots.
Symbol Digit Modality Test
In the written version of the SDMT(36), the examinee is asked
to write as many numbers as he or she can in the boxes below a
series of symbols according to the key provided at the top of the
page within 90 s. In the oral version, the examiner records the
numbers spoken by the subjects.
Trail Making Test A and B
In part A of this test (37), the examinee is timed to connect the
numbers in sequence as fast as possible with a pencil. In Part B,
the subjects is asked to switch between number and letters.
Block Design
For the Block Design test (32), the examinee is asked to rep-
licate models or pictures of two-color designs with blocks. The
designs progress in difficulty from simple two-block designs to
more complex, nine-block designs.
1508 FENG ET AL

Related data TABLE 1

Demographic and laboratory test characteristics of the study subjects1
A detailed interview conducted by research nurses at the first
visit collected information on related variables that included Variable Value
sociodemographic information (age, sex, and education), sub- Age (y) 64.2 6.7 (5586)2
stance use (cigarette smoking and alcohol consumption), medi- Sex (% women) 60.2
cal conditions, weight, and height. The Geriatric Depression Education (y) 6.9 4.4 (020)
Scale (38) was administered as a measure of depression. The BMI (kg/m2) 23.7 3.5 (12.540.6)
MMSE (39) was administered as a global measure of cognitive Exsmoker or current smoker (%) 15.2
function. Functional status was assessed by the respondents Regular alcohol drinker (%) 10.3
level of dependency in performing basic ADL found in the Bar- Hypertension (%) 45.7
thel Index (40). Only subjects fully independent on all 10 ADL Diabetes mellitus (%) 12.3
Cardiovascular disease (%) 10.5
items were included.
GDS total score 2.6 3.0 (015)
Total cholesterol (mmol/L) 5.5 1.0 (2.99.3)
Statistical analysis Creatinine (mol/L) 79.9 24.2 (42235)
After omitting a small number of respondents with missing or Homocysteine (mol/L) 13.0 4.6 (5.550)
extreme outlier data for smoking (1 respondent), alcohol con- Folate (nmol/L) 24.9 12.4 (6.790)
sumption (1 respondent), Geriatric Depression Scale (1 respon- Vitamin B-12 (pmol/L) 397.8 174.2 (351350)
dent), homocysteine (1 respodent), folate (2 respondents), vita- 1
n 451. GDS, Geriatric Depression Scale.
min B-12 (1 respodent), and creatinine (1 respondent), data were 2
x SD; range in parentheses (all such values).
analyzed for the remaining 451 elderly Chinese subjects aged

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55 y who had MMSE scores 24, who were fully independent
based on ADL scores, and who completed cognitive assessment and there were only small proportions of regular daily drinkers
and homocysteine, folate, and vitamin B-12 measurements be- (10.3%) and smokers (exsmokers and current smokers: 15.2%).
tween September 2003 and June 2005. Because not all subjects Nearly one-half of the population had a history of hypertension
completed the whole test battery and some tests (ie, Trail (45.7%), and 12.3% of them had diabetes. Altogether, 10.5% of
Making Test and Block Design) were subsequent additions to the respondents had a history of heart failure, heart attack, atrial
the test battery, the results for different neuropsychological fibrillation, or stroke.
measures were based on varying numbers of subjects (ranging
from 72 to 451).
Multiple linear regression was used to examine the relations TABLE 2
Cognitive performance of the study subjects1
between neurocognitive performance and homocysteine, folate,
and vitamin B-12 concentrations, with control for potential con- Test score n x SD (range)
founding variables to evaluate whether the relations were altered
MMSE total score 27.9 1.7 (2430)
by these other variables. We first modeled the relation between Digit span total raw score 451 15.9 4.0 (829)
cognitive test scores and homocysteine, folate, or vitamin B-12 Spatial span total raw score 386 12.0 3.7 (221)
individually in base models (model 1), which controlled for age, RAVLT
sex, and the number of years of education. In a higher-order Immediate recall2 402 43.4 9.8 (1370)
model (model 2), we added, as covariates, cardiovascular disease Delayed recall 383 8.9 3.3 (015)
risk factors (including cigarette smoking, alcohol consumption, Verbal learning3 402 7.2 2.0 (213)
body mass index, and total cholesterol); chronic diseases includ- Percentage of forgetting4 382 24.4 21.3 (0100)
ing hypertension, diabetes, and cardiovascular disease (heart VR
attack, heart failure, atrial fibrillation, or stroke); renal function Immediate recall total raw score 390 66.6 18.4 (11102)
Delayed recall total raw score 375 41.2 20.9 (0100)
(by measuring the serum creatinine concentration); and depres-
Categorical Verbal Fluency 385 42.5 9.4 (1682)
sion (measured by using the Geriatric Depression Scale). In the Design Fluency
final model (model 3), we included homocysteine, folate, and Condition 1 337 7.0 3.2 (118)
vitamin B-12 into the regression models simultaneously with all Condition 2 335 7.7 3.6 (119)
the covariates tested in model 2. Because homocysteine, folate, Condition 3 335 5.1 2.9 (015)
vitamin B-12, and creatinine data were highly skewed to the SDMT
right, they were natural logarithmtransformed before data anal- Written version 232 33.8 13.9 (466)
ysis. To facilitate meaningful comparisons of results across dif- Oral version 232 41.4 14.6 (774)
ferent cognitive tests with varying metrics, standardized coef- Trail Making Test A (s) 92 49.4 23.3 (22136)
ficient estimates are presented. All data analyses were done with Trail Making Test B (s) 72 108.4 55.0 (43333)
Block Design total raw score 103 24.4 9.7 (668)
SPSS version 13.0 (SPSS Inc, Chicago, IL).
1
MMSE, Mini-Mental State Examination; RAVLT, Rey Auditory Ver-
bal Learning Test; VR, Visual Reproduction; SDMT, Symbol Digit Modality
RESULTS Test.
2
The sum of words correctly recalled from trial 1 to trial 5.
The characteristics of the study population are summarized in 3
The maximum of words correctly recalled from trial 1 to trial 5
Table 1 and Table 2. The mean (SD) age of the respondents words correctly recalled at trial 1.
was 64.2 6.7 y, and a larger proportion were women (60.2%). 4
100 (words correctly recalled at trial 5 words correctly recalled
The mean (SD) number of years of education was 6.9 4.4 y, at delayed recall)/words correctly recalled at trial 5.
 HOMOCYSTEINE, FOLATE, VITAMIN B-12, AND COGNITION 1509
TABLE 3
Associations between natural log-transformed homocysteine, folate, vitamin B-12 and cognitive test scores (model 1)1

Homocysteine Folate Vitamin B-12

Cognitive test Standardized P Standardized P Standardized P

MMSE total score 0.080 0.073 0.076 0.063 0.056 0.17

Digit span total raw score 0.054 0.252 0.041 0.339 0.067 0.12
Spatial span total raw score 0.022 0.647 0.052 0.236 0.029 0.51
RAVLT
Immediate recall 0.083 0.101 0.110 0.017 0.007 0.89
Delayed recall 0.074 0.188 0.149 0.003 0.045 0.37
Verbal learning 0.020 0.726 0.110 0.030 0.015 0.76
Percentage of forgetting 0.051 0.373 0.140 0.008 0.069 0.19
VR
Immediate recall 0.006 0.905 0.069 0.103 0.045 0.29
Delayed recall 0.015 0.752 0.065 0.142 0.070 0.12
Categorical Verbal Fluency 0.094 0.073 0.125 0.009 0.049 0.31
Design Fluency
Condition 1 0.080 0.127 0.013 0.786 0.054 0.26
Condition 2 0.143 0.006 0.103 0.031 0.048 0.32
Condition 3 0.096 0.073 0.002 0.961 0.026 0.59

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SDMT
Written version 0.115 0.028 0.030 0.526 0.073 0.13
Oral version 0.074 0.187 0.000 0.997 0.069 0.18
Trail Making Test A 0.062 0.501 0.048 0.564 0.006 0.95
Trail Making Test B 0.057 0.642 0.062 0.575 0.041 0.72
Block Design total raw score 0.296 0.003 0.075 0.426 0.059 0.53
1
Model 1 covariates were the following: age, sex, and number of years of education. MMSE, Mini-Mental State Examination; RAVLT, Rey Auditory
Verbal Learning Test; VR, Visual Reproduction; SDMT, Symbol Digit Modality Test.

Homocysteine was significantly correlated with folate (Pear-
son correlation r 0.235, P 0.001), vitamin B-12 (r
0.210, P 0.001), and creatinine (r 0.494, P 0.001);
the correlation (r) between folate and vitamin B-12 was 0.161
(P 0.001).
In base models (model 1), log-transformed homocysteine was
inversely and significantly associated with Design Fluency con-
dition 2 ( 0.143), SDMT written version ( 0.115), and
Block Design total raw score ( 0.296) (Table 3). In mul-
tivariable models that controlled for other covariates, homocys-
teine was significantly associated with 2 cognitive measures:
Block Design ( 0.319) and SDMT written version (
0.129), independent of a wide range of potential confounders
as well as folate and vitamin B-12 (model 3, Table 4).
Log-transformed folate was significantly associated with
RAVLT immediate recall, RAVLT delayed recall, RAVLT ver-
bal learning, RAVLT percentage of forgetting, and Categorical
Verbal Fluency in both base model 1 and model 2 (Table 3 and
Table 5). In model 3, which controlled additionally for homo-
cysteine and vitamin B-12, independent associations of folate
with these cognitive scores remained significant, except for
RAVLT immediate recall [RAVLT delayed recall 0.139,
RAVLT verbal learning 0.112, RAVLT percentage of
forgetting 0.139, and Categorical Verbal Fluency
0.104 (Table 5)]. Log-transformed vitamin B-12 was not as-
sociated significantly with any cognitive measure in all 3
regression models.
DISCUSSION
Our results, which were based on a community sample of older
Chinese adults with generally well global cognitive and physical
functioning, suggest that homocysteine and folate may have in-
dependent and differential associations with specific domains of

TABLE 4
Associations between natural log-transformed homocysteine and cognitive test scores, adjusted for confounding in multivariate models1

Model 12 Model 23 Model 34

Cognitive test Standardized P Standardized P Standardized P

SDMT written version 0.115 0.028 0.125 0.025 0.129 0.031

Block Design total raw score 0.296 0.003 0.299 0.005 0.319 0.006
Design Fluency (condition 2) 0.143 0.006 0.140 0.013 0.113 0.062
1
SDMT, Symbol Digit Modality Test.
2
Covariates were age, sex, and number of years of education.
3
Covariates were age, sex, number of years of education, cigarette smoking, alcohol consumption, BMI, total cholesterol, hypertension, diabetes,
cardiovascular disease, log-transformed creatinine, and Geriatric Depression Scale total score.
4
Covariates were folate and vitamin B-12 entered simultaneously with all covariates in Model 2.
1510
TABLE 5
Associations between natural log-transformed folate and cognitive test scores, adjusted for confounding in multivariate models1
Model 12
Cognitive test Standardized
RAVLT
Immediate recall 0.110
Delayed recall 0.149
Verbal learning 0.110
Percentage of forgetting 0.140
Categorical Verbal Fluency 0.125
Design Fluency (condition 2) 0.103
1
RAVLT, Rey Auditory Verbal Learning Test.
2
Covariates were age, sex, and number of years of education.
3
Covariates were age, sex, number of years of education, cigarette smoking, alcohol consumption, BMI, total cholesterol, hypertension, diabetes,
cardiovascular disease, log-transformed creatinine, and Geriatric Depression Scale total score.
4
Covariates were natural log-transformed homocysteine and vitamin B-12 entered simultaneously with all covariates in Model 2.
cognitive function. Homocysteine appeared to be specifically
associated with constructional ability and information process-
ing speed; folate appeared to be associated specifically with
episodic memory and language ability. These associations were
independent of a wide range of confounding factors and also of
each other.
With regard to executive control function measured with De-
sign Fluency, no clear statistically significant associations with
homocysteine or folate were observed, although the marginally
significant associations shown in several models do not rule out
this possibility. No significant association with Categorical Ver-
bal Fluency was observed. With regard to vitamin B-12, there
was no observable significant association with performance on
any cognitive test.
Our findings in a Chinese population support similar associ-
ations of homocysteine and folate with cognitive performance
reported in Western studies, even though there may be subtle
differences between different ethnic populations. A few previous
studies have also reported patterns of specific cognitive domains
that are differentially associated with homocysteine and folate.
In a small group of 70 male elderly subjects, the Normative
Aging Study found that a higher concentration of homocysteine
was specifically associated with poorer spatial copying skills,
whereas B vitamins were more strongly associated with memory
performance (17). The Sacramento Area Latino Study on Aging
also found that, in elderly Latinos, homocysteine was inversely
associated with performance on the modified mini-mental state
examination (3MSE), picture association, verbal attention span,
and pattern recognition, whereas folate was associated with
3MSE and delayed recall (25, 30). However, individual neuro-
psychological tests may assess overlapping cognitive domains to
varying extents, and studies that use different test batteries make
cross comparison of results difficult.
Because of our strict exclusion criteria and rigorous control for
potential confounding, our results may possibly be biased by
overadjustment toward showing null associations. Hence, mar-
ginally significant associations should not be dismissed. On the
other hand, with numerous neuropsychological variables and
multiple significance testings, several statistical tests may be
expected to result in spurious significance at the conventional
level of P 0.05. Lastly, the cross-sectional design of our study
FENG ET AL
Model 23 Model 34
P Standardized P Standardized P
0.017 0.096 0.039 0.089 0.067
0.003 0.138 0.008 0.139 0.010
0.030 0.103 0.047 0.112 0.038
0.008 0.142 0.008 0.139 0.013
0.009 0.119 0.016 0.104 0.042
0.031 0.096 0.050 0.068 0.175
cannot firmly establish cause-and-effect relation. Additional
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longitudinal studies are warranted.
In our study, the lack of an observable association between
vitamin B-12 and performance on any cognitive test suggests a
less important role for vitamin B-12 than for homocysteine and
folate. However, the assessment of cobalamin status by using
serum vitamin B-12 may have limitations. Methylmalonic acid
and holotranscobalamin are proposed to be more sensitive mark-
ers for vitamin B-12 deficiency (2, 41). In the study conducted by
Refsum et al (42), low holotranscobalamin was associated with
Alzheimer disease even though total cobalamin was not. Hence,
our study does not exclude a possible association with vitamin
B-12.
It is interesting to discuss why homocysteine and folate can
exert separate effects on cognitive function. Although homocys-
teine is viewed as a marker of folate deficiency, its concentration
is affected by multiple factors (1). In our study population, the
correlation between homocysteine and folate was moderate (r
0.235), making it possible to analyze their differential effects.
Folate provides the methyl group for the conversion of methio-
nine to S-adenosylmethionine, which is the major methyl donor
for most methyltransferase reactions; thus, folate deficiency can
cause hypomethylation (43). Elevated homocysteine is postu-
lated to affect the brain through vascular or neurotoxic mecha-
nisms (44, 45). Folate deficiency, on the other hand, may affect
brain function through high homocysteine (as an intermediary),
through decreased S-adenosylmethionine, or both (45). Our re-
sults favor the involvement of both pathways and the differential
effect of each mechanism. Protein synthesis in the brain is an
essential process for the encoding of information in episodic
memory, and it is conceivable that the B vitaminrelated memory
deficits could be due to changes in brain protein metabolism (46).
We noted that, with a wide range of cognitive domains measured,
the association between folate and cognition appears confined to
episodic memory performance; thus, our results suggest that this
is plausible.
Although conclusive evidence from randomized controlled
trials is still lacking, it is nevertheless possible that modification
of homocysteine and B vitamin status could delay cognitive
decline or even enhance cognitive function in elderly persons.
Observational studies of community-dwelling elderly showed
 HOMOCYSTEINE, FOLATE, VITAMIN B-12, AND COGNITION
that the rate of change of homocysteine concentrations was sig-
nificantly correlated with the rate of change of the Stroop scores
(47). More recently, the Hordaland Homocysteine Study found
that a favorable change in folate or homocysteine concentra-
tions over time was associated with better memory performance
(31). Large scale clinical trials with a longer interventional pe-
riod are needed
In conclusion, we found that in high-functioning Chinese
older adults, there were differential associations of homocys-
teine, folate, and vitamin B-12 with specific domains of cognitive
performance. Homocysteine was specifically associated with
constructional ability and information processing speed,
whereas folate was associated specifically with episodic memory
and language ability. Vitamin B-12 did not appear to be associ-
ated with any cognitive performance, but additional studies are
warranted.
LF formulated the hypothesis, performed the literature review and statis-
tical data analysis, and drafted and revised the manuscript. T-PN conceptu-
alized and designed the study, formulated the hypothesis, reviewed statistical
analysis and results, and drafted and revised the manuscript. LC designed and
formulated the neuropsychological testing and reviewed the manuscript. MN
participated in the study design, statistical analysis, interpretation of the
results, and review of the manuscript. E-HK participated in the study design,
interpretation of the results, and review of the manuscript. No commercial
company sponsored or played any role in the design and methods of the study,
subject recruitment, data collection and analysis, and preparation of this
article.
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