The New England Journal of Medicine
Original Article
Volume 346:476-483
February 14, 2002
Number 7
Plasma Homocysteine as a Risk Factor for Dementia and Alzheimer's Disease
Sudha Seshadri, M.D., Alexa Beiser, Ph.D., Jacob Selhub, Ph.D., Paul F.
Jacques, Sc.D., Irwin H. Rosenberg, M.D., Ralph B. D'Agostino, Ph.D., Peter
W.F. Wilson, M.D., and Philip A. Wolf, M.D.
ABSTRACT
Background In cross-sectional studies, elevated plasma homocysteine levels
have been associated with poor cognition and dementia. Studies of newly
diagnosed dementia are required in order to establish whether the elevated
homocysteine levels precede the onset of dementia or result from
dementia-related nutritional and vitamin deficiencies.
Methods A total of 1092 subjects without dementia (667 women and 425 men;
mean age, 76 years) from the Framingham Study constituted our study sample.
We examined the relation of the plasma total homocysteine level measured at
base line and that measured eight years earlier to the risk of newly
diagnosed dementia on follow-up. We used multivariable proportional-hazards
regression to adjust for age, sex, apolipoprotein E genotype, vascular risk
factors other than homocysteine, and plasma levels of folate and vitamins
B12 and B6.
Results Over a median follow-up period of eight years, dementia developed in
111 subjects, including 83 given a diagnosis of Alzheimer's disease. The
multivariable-adjusted relative risk of dementia was 1.4 (95 percent
confidence interval, 1.1 to 1.9) for each increase of 1 SD in the
log-transformed homocysteine value either at base line or eight years
earlier. The relative risk of Alzheimer's disease was 1.8 (95 percent
confidence interval, 1.3 to 2.5) per increase of 1 SD at base line and 1.6
(95 percent confidence interval, 1.2 to 2.1) per increase of 1 SD eight
years before base line. With a plasma homocysteine level greater than 14
µmol per liter, the risk of Alzheimer's disease nearly doubled.
Conclusions An increased plasma homocysteine level is a strong, independent
risk factor for the development of dementia and Alzheimer's disease.
_____
Alzheimer's disease accounts for more than 70 percent of all cases of
dementia, so it is important to identify modifiable risk factors for the
disease. 1 <http://content.nejm.org/cgi/content/full/346/7/#R1> During the
past decade, there has been growing interest in vascular factors that may
underlie Alzheimer's disease. It is now recognized that subjects with
cardiovascular risk factors and a history of stroke have an increased risk
of both vascular dementia and Alzheimer's disease. 2
<http://content.nejm.org/cgi/content/full/346/7/#R2> , 3
<http://content.nejm.org/cgi/content/full/346/7/#R3> , 4
<http://content.nejm.org/cgi/content/full/346/7/#R4> Plasma total
homocysteine has recently emerged as a major vascular risk factor. Elevated
total homocysteine levels have been associated with an increased risk of
atherosclerotic sequelae, including death from cardiovascular causes, 5
<http://content.nejm.org/cgi/content/full/346/7/#R5> , 6
<http://content.nejm.org/cgi/content/full/346/7/#R6> coronary heart
disease, 6 <http://content.nejm.org/cgi/content/full/346/7/#R6> , 7
<http://content.nejm.org/cgi/content/full/346/7/#R7> carotid
atherosclerosis, 8 <http://content.nejm.org/cgi/content/full/346/7/#R8> and
clinical stroke. 9 <http://content.nejm.org/cgi/content/full/346/7/#R9> , 10
<http://content.nejm.org/cgi/content/full/346/7/#R10> These observations
led to the hypothesis that elevated plasma homocysteine may be a risk factor
for dementia and Alzheimer's disease. If this hypothesis is valid, it points
to a modifiable risk factor, since plasma homocysteine levels can be lowered
by supplementation with folic acid. 11
<http://content.nejm.org/cgi/content/full/346/7/#R11>
Previous studies have reported an inverse association between plasma total
homocysteine levels and simultaneously assessed cognitive function. 12
<http://content.nejm.org/cgi/content/full/346/7/#R12> , 13
<http://content.nejm.org/cgi/content/full/346/7/#R13> , 14
<http://content.nejm.org/cgi/content/full/346/7/#R14> , 15
<http://content.nejm.org/cgi/content/full/346/7/#R15> , 16
<http://content.nejm.org/cgi/content/full/346/7/#R16> Two case–control
studies have found higher plasma homocysteine levels in persons with
Alzheimer's disease. 17
<http://content.nejm.org/cgi/content/full/346/7/#R17> , 18
<http://content.nejm.org/cgi/content/full/346/7/#R18> However, in a
prospective study plasma homocysteine levels were not related to cognitive
decline during follow-up in a community-based sample. 19
<http://content.nejm.org/cgi/content/full/346/7/#R19> Elevated plasma
homocysteine levels in subjects with cognitive impairment or dementia might
be the result of poor nutrition and vitamin deficiencies. 20
<http://content.nejm.org/cgi/content/full/346/7/#R20> A prospective study
should be able to show whether elevated plasma homocysteine in cognitively
intact adults is associated with an increased risk of dementia and
Alzheimer's disease on follow-up. We therefore examined plasma total
homocysteine in relation to newly diagnosed dementia and Alzheimer's disease
in the elderly, population-based cohort of Framingham Study participants.
Methods
Subjects
The Framingham Study cohort has been evaluated biennially since 1948.
Between 1976 and 1978, a total of 2611 subjects were enrolled in a
dementia-free cohort. 21
<http://content.nejm.org/cgi/content/full/346/7/#R21> , 22
<http://content.nejm.org/cgi/content/full/346/7/#R22> At the 20th biennial
examination (between 1986 and 1990), 1592 subjects from this cohort were
alive and free of dementia and had follow-up data for at least one year. Of
these subjects, 1229 (77 percent) underwent the 20th examination, and in
1092 participants (89 percent of those examined), plasma total homocysteine
levels were measured. These 1092 subjects constituted our study sample.
There were 667 women and 425 men, and their mean (±SD) age was 76±6 years
(range, 68 to 97). Informed consent was obtained from all study subjects
with the use of a consent form approved by the institutional review board
for human research at the Boston University School of Medicine.
Diagnosis of New Cases of Dementia and Alzheimer's Disease
Subjects in the cohort that was free of dementia at inception have been
monitored with published surveillance techniques since 1978 for the
development of stroke or dementia. 21
<http://content.nejm.org/cgi/content/full/346/7/#R21> , 22
<http://content.nejm.org/cgi/content/full/346/7/#R22> Methods have included
a screening Folstein Mini–Mental State Examination 23
<http://content.nejm.org/cgi/content/full/346/7/#R23> at each biennial
evaluation, followed by annual neurologic and neuropsychological assessment
of subjects with suspected cognitive impairment.
The final diagnosis of dementia was made by a committee, comprising at least
two neurologists and a neuropsychologist, that determined the type of
dementia and the date of diagnosis. All available information was used to
evaluate participants with suspected dementia, including serial neurologic
and neuropsychological assessments, a telephone interview with a family
member or care giver, medical records, imaging studies, and autopsy data
when available. The review committee was unaware of the subjects' plasma
homocysteine levels. The diagnosis of dementia was made according to the
criteria of the Diagnostic and Statistical Manual of Mental Disorders,
fourth edition 24 <http://content.nejm.org/cgi/content/full/346/7/#R24> ;
our definition also required a duration of symptoms greater than six months,
and a score for severity of dementia of 1 or higher on the Clinical Dementia
Rating scale. 25 <http://content.nejm.org/cgi/content/full/346/7/#R25>
Alzheimer's disease was diagnosed when subjects met the criteria of the
National Institute of Neurological and Communicative Disorders and Stroke
and the Alzheimer's Disease and Related Disorders Association for definite,
probable, or possible Alzheimer's disease. 26
<http://content.nejm.org/cgi/content/full/346/7/#R26>
Plasma Homocysteine
Plasma total homocysteine levels were measured in all subjects at the 20th
biennial examination (base line). An earlier measure from the 16th biennial
examination (performed between 1979 and 1982, approximately eight years
before base line) was also available for 935 of the subjects (86 percent).
All plasma specimens were stored at or below –20°C. Homocysteine levels were
determined with the use of high-performance liquid chromatography with
fluorometric detection. 27
<http://content.nejm.org/cgi/content/full/346/7/#R27> The coefficient of
variation for this assay was 9 percent. 28
<http://content.nejm.org/cgi/content/full/346/7/#R28>
Apolipoprotein E Genotypes
Data on the apolipoprotein E (APOE) genotype were available for 1012 of the
subjects (93 percent). The presence of particular alleles was determined by
means of isoelectric focusing of the plasma and confirmed by DNA genotyping.
29 <http://content.nejm.org/cgi/content/full/346/7/#R29> , 30
<http://content.nejm.org/cgi/content/full/346/7/#R30> Participants were
divided into two groups, one comprising persons with an APOE {epsilon}4
allele ({epsilon}2/{epsilon}4, {epsilon}3/{epsilon}4, or
{epsilon}4/{epsilon}4 genotype) and another comprising those without an APOE
{epsilon}4 allele.
Vitamin Levels
Plasma concentrations of folate, cyanocobalamin (vitamin B12), and
pyridoxal-5'-phosphate (the coenzyme form of vitamin B6) were estimated at
the 20th biennial examination. Plasma folate was measured by a microbial
(Lactobacillus casei) assay with a 96-well plate and manganese
supplementation 31 <http://content.nejm.org/cgi/content/full/346/7/#R31> ;
plasma vitamin B12 levels were estimated with the use of a radioassay kit
(Magic, Ciba–Corning, Medfield, Mass.); and pyridoxal-5'-phosphate was
measured by the tyrosine decarboxylase apoenzyme method. 32
<http://content.nejm.org/cgi/content/full/346/7/#R32> Coefficients of
variation for these assays were 13 percent for plasma folate, 7 percent for
cyanocobalamin, and 16 percent for pyridoxal-5'-phosphate. 28
<http://content.nejm.org/cgi/content/full/346/7/#R28> Because of
insufficient plasma samples, the vitamin levels were not determined for all
patients. Of the subjects with measurements of plasma homocysteine, 85
percent had measurements of vitamin B12, 92 percent had measurements of
vitamin B6, and 98 percent had measurements of folate.
Definition of Additional Risk Factors
Risk factors that could potentially confound the relation between plasma
homocysteine and dementia or Alzheimer's disease were defined with the use
of data collected at the 20th biennial examination. When appropriate, data
from earlier biennial examinations were also used. Educational status was
dichotomized at the level of high-school completion. We adjusted the
analyses for cigarette smoking using two variables: current smoking status
(smoker or nonsmoker) and lifetime exposure to cigarette smoke (<5.0
pack-years, 5.0 to 29.9 pack-years, or >=30.0 pack-years). Alcohol intake
was categorized in terms of the number of drinks per day: zero, less than
one, one to two, or more than two. 33
<http://content.nejm.org/cgi/content/full/346/7/#R33> Diabetes mellitus was
defined by a recorded casual blood glucose level of at least 200 mg per
deciliter (11.1 mmol per liter), a previous diagnosis of diabetes mellitus,
or the use of a hypoglycemic agent or insulin. Systolic blood pressure and
body-mass index (the weight in kilograms divided by the square of the height
in meters) were treated as continuous variables.
Statistical Analysis
The distribution of plasma homocysteine levels in the population was
positively skewed. The use of natural-log–transformed values provided the
best-fitting model for analyses in which the plasma homocysteine level was
treated as a continuous variable. Plasma homocysteine levels were also
evaluated with a quartile-based analysis. Since homocysteine levels increase
markedly with age, 28 <http://content.nejm.org/cgi/content/full/346/7/#R28>
, 34 <http://content.nejm.org/cgi/content/full/346/7/#R34> , 35
<http://content.nejm.org/cgi/content/full/346/7/#R35> the quartiles were
defined in an age-specific manner for each of several five-year age
categories.
Cox proportional-hazards regression models 36
<http://content.nejm.org/cgi/content/full/346/7/#R36> were used to examine
the relation between the homocysteine level and the incidence of dementia
and Alzheimer's disease during follow-up, after adjustment for age (in
one-year increments), sex, and APOE genotype (with or without an APOE
{epsilon}4 allele). 37 <http://content.nejm.org/cgi/content/full/346/7/#R37>
In supplementary analyses, we also adjusted for vitamin levels and other
covariates. Subjects were followed for new cases of dementia from the date
of their 20th biennial examination until December 31, 2000. For the analysis
of new cases of Alzheimer's disease, data for subjects in whom other types
of dementia developed were censored at the date of the diagnosis of
dementia, since the diagnostic categories were mutually exclusive. Subjects
who had a stroke during the study period were not excluded, since such an
event could be part of the causal chain between an elevated plasma
homocysteine level and the development of dementia. All statistical analyses
were performed with the use of SAS software (SAS Institute, Cary, N.C.).
Results
Base-Line Characteristics
The base-line characteristics of the subjects are presented in Table 1
<http://content.nejm.org/cgi/content/full/346/7/#T1> (further information
may be found in Supplementary Appendix 1
<http://content.nejm.org/cgi/content/full/346/7/#T5> , available with the
full text of this article at http://www.nejm.org). Mild-to-moderate
elevation of the plasma homocysteine level (>14 µmol per liter) was present
in 30 percent of the subjects. None of the subjects had severe
hyperhomocysteinemia (plasma homocysteine, >100 µmol per liter). The mean
plasma homocysteine level within each of the five-year age groups is shown
in Table 2 <http://content.nejm.org/cgi/content/full/346/7/#T2> . The
correlation between the base-line plasma homocysteine level in a given
subject and the level measured eight years earlier was calculated for the
935 subjects (571 women and 364 men) for whom both measurements were
available (Pearson r=0.47, P<0.001).
View this table:
[in this window] <http://content.nejm.org/cgi/content/full/346/7/476/T1>
[in a new window] <http://content.nejm.org/cgi/content-nw/full/346/7/476/T1>
Table 1. Base-Line Characteristics of Study Subjects at the 20th Biennial
Examination.
View this table:
[in this window] <http://content.nejm.org/cgi/content/full/346/7/476/T5>
[in a new window] <http://content.nejm.org/cgi/content-nw/full/346/7/476/T5>
Supplementary Appendix 1. Distribution of Base-Line Characteristics of
Subjects According to Age-Specific Quartiles of Plasma Homocysteine Levels.
View this table:
[in this window] <http://content.nejm.org/cgi/content/full/346/7/476/T2>
[in a new window] <http://content.nejm.org/cgi/content-nw/full/346/7/476/T2>
Table 2. Distribution of Base-Line Plasma Homocysteine Levels within
Five-Year Age Groups.
Dementia, Alzheimer's Disease, and Plasma Homocysteine
Over a median follow-up period of 8 years (range, 1 to 13), dementia
developed in 111 subjects (10.2 percent; 74 women and 37 men), and 83 of
these subjects (62 women and 21 men) were given a diagnosis of Alzheimer's
disease. In five subjects, the clinical diagnosis of Alzheimer's disease was
confirmed at autopsy (definite Alzheimer's disease). The diagnosis was
probable Alzheimer's disease for 67 subjects and possible Alzheimer's
disease for 11 subjects. Other types of dementia diagnosed in the study
population included vascular dementia in 11 subjects, non-Alzheimer's
degenerative dementias in 11 subjects, and other types of dementia in 6
subjects. The absence of Alzheimer's disease was confirmed at autopsy in 14
subjects.
The overall results relating the plasma homocysteine level to the
development of any dementia and to the development of Alzheimer's disease
are shown in Table 3 <http://content.nejm.org/cgi/content/full/346/7/#T3>
and Table 4 <http://content.nejm.org/cgi/content/full/346/7/#T4> and in
Figure 1 <http://content.nejm.org/cgi/content/full/346/7/#F1> . After
adjustment for the age, sex, and APOE genotype, the relative risks of
dementia and Alzheimer's disease, for each increase of 1 SD in
log-transformed base-line homocysteine value, were 1.3 (95 percent
confidence interval, 1.1 to 1.6) and 1.4 (95 percent confidence interval,
1.2 to 1.7), respectively. Hyperhomocysteinemia (plasma homocysteine, >14
µmol per liter) 8 <http://content.nejm.org/cgi/content/full/346/7/#R8> , 18
<http://content.nejm.org/cgi/content/full/346/7/#R18> was correspondingly
associated with an increased risk of dementia (relative risk, 1.9; 95
percent confidence interval, 1.3 to 2.8) and Alzheimer's disease (relative
risk, 1.9; 95 percent confidence interval, 1.2 to 3.0). An increase in the
plasma homocysteine level of 5 µmol per liter increased the
multivariable-adjusted risk of Alzheimer's disease by 40 percent (P<0.001).
We did not find evidence of modification of this effect by age or sex.
View this table:
[in this window] <http://content.nejm.org/cgi/content/full/346/7/476/T3>
[in a new window] <http://content.nejm.org/cgi/content-nw/full/346/7/476/T3>
Table 3. Multivariable Cox Proportional-Hazards Regression Models Examining
the Relation between the Plasma Total Homocysteine Level and the Risk of
Dementia and Alzheimer's Disease.
View this table:
[in this window] <http://content.nejm.org/cgi/content/full/346/7/476/T4>
[in a new window] <http://content.nejm.org/cgi/content-nw/full/346/7/476/T4>
Table 4. Multivariable Cox Proportional-Hazards Regression Models for the
Risk of Dementia and Alzheimer's Disease According to Age-Specific Quartile
of Plasma Total Homocysteine Level.
<http://content.nejm.org/cgi/content/full/346/7/476/F1>
View larger version (6K):
[in this window] <http://content.nejm.org/cgi/content/full/346/7/476/F1>
[in a new window] <http://content.nejm.org/cgi/content-nw/full/346/7/476/F1>
Figure 1. Crude Cumulative Incidence of Dementia among Subjects with
Base-Line Plasma Homocysteine Levels in the Highest Age-Specific Quartile
and among All Other Subjects.
The 75th percentile of the plasma homocysteine level (the cutoff point for
quartile 4) was 13.2 µmol per liter for subjects 65 to 69 years old, 13.8
µmol per liter for subjects 70 to 74 years old, 14.5 µmol per liter for
subjects 75 to 79 years old, 16.5 µmol per liter for subjects 80 to 84 years
old, 19.3 µmol per liter for subjects 85 to 89 years old, and 26.6 µmol per
liter for subjects 90 to 95 years old.
Effect of Vitamin Levels
Low serum levels of certain B vitamins (folate and vitamins B12 and B6) have
been associated with elevated plasma homocysteine levels in several studies
and with an increased risk of dementia in a few investigations. 38
<http://content.nejm.org/cgi/content/full/346/7/#R38> , 39
<http://content.nejm.org/cgi/content/full/346/7/#R39> , 40
<http://content.nejm.org/cgi/content/full/346/7/#R40> , 41
<http://content.nejm.org/cgi/content/full/346/7/#R41> , 42
<http://content.nejm.org/cgi/content/full/346/7/#R42> In our study, the
observed association between plasma homocysteine and risk of dementia was
not significantly altered by adjustment for the plasma levels of these
vitamins ( Table 3 <http://content.nejm.org/cgi/content/full/346/7/#T3> ).
Furthermore, after adjustment for age, sex, and APOE genotype, none of these
vitamin levels were independently related to the risk of dementia or
Alzheimer's disease (data not shown).
Additional Covariates
The observed association between the plasma homocysteine level and dementia
or Alzheimer's disease was not diminished by adjustment for educational
status, systolic blood pressure, smoking status, alcohol intake, presence or
absence of diabetes, body-mass index, or presence or absence of a history of
stroke ( Table 3 <http://content.nejm.org/cgi/content/full/346/7/#T3> ).
Serum creatinine was measured at the 15th biennial examination, and
cholesterol and thyrotropin were measured at the 20th biennial examination.
Adjustment for these additional variables did not alter our results (data
not shown).
Varying the Diagnostic Criteria for Alzheimer's Disease
Higher plasma homocysteine levels have been related to an increased risk of
stroke. 8 <http://content.nejm.org/cgi/content/full/346/7/#R8> , 10
<http://content.nejm.org/cgi/content/full/346/7/#R10> To address the
possibility that the association we observed between plasma homocysteine and
Alzheimer's disease resulted from the inclusion of subjects who might have
vascular dementia rather than Alzheimer's disease, we evaluated separately
the association between base-line plasma homocysteine levels and a diagnosis
of definite or probable Alzheimer's disease after excluding subjects with a
diagnosis of possible Alzheimer's disease. The relative risk per increment
of 1 SD in the log-transformed base-line homocysteine value remained
essentially unchanged at 1.4 (95 percent confidence interval, 1.2 to 1.7).
Association with Earlier Homocysteine Levels
Unlike stroke or myocardial infarction, clinical dementia begins
insidiously. It may therefore be difficult to exclude subjects in whom the
disease is incipient at base line. However, subjects who were free of
clinical dementia at base line were most likely free of even incipient
disease eight years earlier, at the examination from which we derived the
previous plasma homocysteine measurement. We examined the relation between
the plasma homocysteine level eight years before base line and the risk of
newly diagnosed dementia or Alzheimer's disease during the follow-up period
between the base-line examination and December 31, 2000. Again, we found a
strong association ( Table 3
<http://content.nejm.org/cgi/content/full/346/7/#T3> ), indicating that the
elevation of the plasma homocysteine level occurred well before the onset of
clinical manifestations.
Quartile-Specific Analysis
Examination of the risks of dementia and Alzheimer's disease in age-specific
quartiles of plasma homocysteine levels suggested that subjects with levels
in the highest quartile (according to the cutoff points in Table 2
<http://content.nejm.org/cgi/content/full/346/7/#T2> ) had the highest risk
of dementia and Alzheimer's disease. When both measurements of plasma
homocysteine were considered, this subgroup had about twice the risk of all
other subjects ( Table 4
<http://content.nejm.org/cgi/content/full/346/7/#T4> and Figure 1
<http://content.nejm.org/cgi/content/full/346/7/#F1> ). Although the effect
of the homocysteine level was smaller in the second and third quartiles, we
did not find evidence of a specific threshold. When the subjects whose
base-line levels were in the lowest age-specific quartile were used as the
reference group, the relative risk of Alzheimer's disease was 1.2 (95
percent confidence interval, 0.6 to 2.2) for subjects in the second
quartile, 1.3 (95 percent confidence interval, 0.6 to 2.5) for subjects in
the third quartile, and 2.2 (95 percent confidence interval, 1.2 to 4.1) for
subjects in the fourth quartile. Subjects whose plasma homocysteine levels
were consistently high (in the fourth quartile at both the 16th and 20th
examinations) had the highest risk.
Population Attributable Risk
In our population, the risk of Alzheimer's disease attributable to a plasma
homocysteine level in the highest age-specific quartile was estimated, with
the use of standard techniques, 43
<http://content.nejm.org/cgi/content/full/346/7/#R43> at 16 percent. In the
same population, 21 percent of subjects had at least one APOE {epsilon}4
allele, and the age- and sex-adjusted relative risk of Alzheimer's disease
associated with the presence of this allele was 2.3 (95 percent confidence
interval, 1.5 to 3.7); thus, there was a 21 percent risk of Alzheimer's
disease attributable to the presence of an APOE {epsilon}4 genotype.
Discussion
The results of our prospective, observational study indicate that there is a
strong, graded association between plasma total homocysteine levels and the
risk of dementia and Alzheimer's disease. An increment in the plasma
homocysteine level of 5 µmol per liter increased the risk of Alzheimer's
disease by 40 percent. A plasma homocysteine level in the highest
age-specific quartile doubled the risk of dementia or Alzheimer's disease. A
similar result was found when the single criterion of hyperhomocysteinemia
(base-line plasma homocysteine, >14 µmol per liter) was used. The magnitude
of this effect is similar to the magnitude of the increases in the risks of
death from cardiovascular causes and stroke associated with a similar
increment in the plasma homocysteine level, which have been previously
described in the Framingham cohort. 6
<http://content.nejm.org/cgi/content/full/346/7/#R6> , 10
<http://content.nejm.org/cgi/content/full/346/7/#R10>
The observed association appeared to be independent of age, sex, APOE
genotype, plasma vitamin levels, and other putative risk factors for
dementia and Alzheimer's disease. The prospective nature of this study and
the strong association between newly diagnosed dementia and Alzheimer's
disease and plasma homocysteine levels measured eight years before base line
suggest that the elevation in the homocysteine level preceded the onset of
dementia. Finally, subjects with a sustained elevation of plasma
homocysteine had the greatest risk of dementia.
Two case–control studies have specifically addressed the relation between
homocysteine levels and the risk of Alzheimer's disease. 17
<http://content.nejm.org/cgi/content/full/346/7/#R17> , 18
<http://content.nejm.org/cgi/content/full/346/7/#R18> Both studies found a
significant elevation of the serum homocysteine level in patients with
Alzheimer's disease as compared with age-matched controls. A report from the
Rotterdam Study did not show an association between the base-line
homocysteine level and a decline in the score on the Mini–Mental State
Examination, perhaps because the follow-up period was only 2.7 years. 19
<http://content.nejm.org/cgi/content/full/346/7/#R19> In our study
population, an elevated homocysteine level at base line was related to a
decline in the scores on the Mini–Mental State Examination, but only after a
follow-up period of at least four years (data not shown).
Elevated plasma homocysteine levels are associated with carotid
atherosclerosis and an increased risk of stroke. 8
<http://content.nejm.org/cgi/content/full/346/7/#R8> , 10
<http://content.nejm.org/cgi/content/full/346/7/#R10> Atherosclerosis and
stroke, in turn, increase the risk of clinical Alzheimer's disease. 2
<http://content.nejm.org/cgi/content/full/346/7/#R2> , 4
<http://content.nejm.org/cgi/content/full/346/7/#R4> Hyperhomocysteinemia
has been related to cerebral microangiopathy, 44
<http://content.nejm.org/cgi/content/full/346/7/#R44> endothelial
dysfunction, 45 <http://content.nejm.org/cgi/content/full/346/7/#R45>
impaired nitric oxide activity, 46
<http://content.nejm.org/cgi/content/full/346/7/#R46> and increased
oxidative stress 47 <http://content.nejm.org/cgi/content/full/346/7/#R47> —
all factors associated with the aging of the brain. 48
<http://content.nejm.org/cgi/content/full/346/7/#R48> , 49
<http://content.nejm.org/cgi/content/full/346/7/#R49> Increased
concentrations of homocysteic acid, an N-methyl-D-aspartate receptor agonist
and a metabolite of homocysteine, may result in excitotoxic damage to
neurons. 50 <http://content.nejm.org/cgi/content/full/346/7/#R50>
Homocysteine promotes copper-mediated and {beta}-amyloid-peptide–mediated
toxic effects in neuronal cell cultures 51
<http://content.nejm.org/cgi/content/full/346/7/#R51> and induces apoptosis
in hippocampal neurons in rats. 52
<http://content.nejm.org/cgi/content/full/346/7/#R52>
The strengths of our investigation include its prospective design, the large
community-based sample, the long follow-up period, and the availability of
prestudy plasma homocysteine levels and base-line values for plasma B
vitamins and other covariates. A limitation of this study is the lack of
racial diversity in the overwhelmingly white Framingham cohort. It is
possible that our use of samples obtained from nonfasting subjects resulted
in estimates of plasma homocysteine levels that were up to 20 percent higher
than they would have been in fasting subjects, 53
<http://content.nejm.org/cgi/content/full/346/7/#R53> but any increase in
the variability in plasma homocysteine values caused by this approach is
likely to be random and is unlikely to have altered the results.
Vitamin therapy with folic acid, alone or in combination with vitamins B6
and B12, and dietary supplementation with enriched cereal-grain products and
breakfast cereals containing folate can reduce plasma homocysteine levels.
54 <http://content.nejm.org/cgi/content/full/346/7/#R54> , 55
<http://content.nejm.org/cgi/content/full/346/7/#R55> , 56
<http://content.nejm.org/cgi/content/full/346/7/#R56> The U.S. government
now mandates folic acid fortification of the food supply. 55
<http://content.nejm.org/cgi/content/full/346/7/#R55> Current plasma
homocysteine levels in the Framingham Study population are significantly
lower than those that were estimated at the 16th and 20th biennial
examinations. 56 <http://content.nejm.org/cgi/content/full/346/7/#R56>
However, only 20 cases of dementia were diagnosed between 1997 and the time
the levels were remeasured, and therefore it is not possible to assess the
effect of recent increases in folic acid fortification on the risk of
dementia in this cohort. Furthermore, since there have been no prospective
trials of the effect of vitamin supplementation on the incidence of
dementia, our findings cannot be used as a basis for setting health policy
or treatment recommendations.
The relation between elevated plasma homocysteine levels and dementia must
be evaluated in other cohort studies. If such studies confirm our findings,
proof of a causal association between plasma homocysteine and the
development of dementia and Alzheimer's disease will require further
elucidation of the pathophysiologic mechanisms and direct evidence from
controlled clinical trials in humans that interventions that reduce plasma
homocysteine levels can reduce the risk of clinical dementia and Alzheimer's
disease.
Supported by the Framingham Heart Study's National Heart, Lung, and Blood
Institute contract (N01-HC-38038) and by grants (NIA-5R01-AG08122-11 and
NIA-5R01-AG16495-02) from the National Institute on Aging and a grant
(NINDS-5R01-NS17950-19) from the National Institute of Neurological
Disorders and Stroke.
Source Information
From the Department of Neurology (S.S., P.A.W.) and the Department of
Medicine (P.W.F.W.), Boston University School of Medicine; the Department of
Epidemiology and Biostatistics, Boston University School of Public Health
(A.B.); the Jean Mayer U.S. Department of Agriculture Human Nutrition
Research Center on Aging, Tufts University (J.S., P.F.J., I.H.R.); and the
Department of Mathematics and Statistics, Boston University (R.B.D.) — all
in Boston.
Address reprint requests to Dr. Wolf at the Department of Neurology
(Neurological Epidemiology and Genetics), Boston University School of
Medicine, 715 Albany St., B-608, Boston, MA 02118-2526, or at [log in to unmask]
<mailto:[log in to unmask]> .
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Edward E. Rylander, M.D.
Diplomat American Board of Family Practice.
Diplomat American Board of Palliative Medicine.