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.
Methods A total of 1092 subjects without dementia (667 womenand 425 men; mean age, 76 years) from the Framingham Study constitutedour study sample. We examined the relation of the plasma totalhomocysteine level measured at base line and that measured eightyears earlier to the risk of newly diagnosed dementia on follow-up.We used multivariable proportional-hazards regression to adjustfor age, sex, apolipoprotein E genotype, vascular risk factorsother than homocysteine, and plasma levels of folate and vitaminsB12 and B6.
Results Over a median follow-up period of eight years, dementiadeveloped in 111 subjects, including 83 given a diagnosis ofAlzheimer's disease. The multivariable-adjusted relative riskof dementia was 1.4 (95 percent confidence interval, 1.1 to1.9) for each increase of 1 SD in the log-transformed homocysteinevalue either at base line or eight years earlier. The relativerisk 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 percentconfidence interval, 1.2 to 2.1) per increase of 1 SD eightyears before base line. With a plasma homocysteine level greaterthan 14 µmol per liter, the risk of Alzheimer's diseasenearly doubled.
Alzheimer's disease accounts for more than 70 percent of allcases of dementia, so it is important to identify modifiablerisk factors for the disease.1 During the past decade, therehas been growing interest in vascular factors that may underlieAlzheimer's disease. It is now recognized that subjects withcardiovascular risk factors and a history of stroke have anincreased risk of both vascular dementia and Alzheimer's disease.2,3,4Plasma total homocysteine has recently emerged as a major vascularrisk factor. Elevated total homocysteine levels have been associatedwith an increased risk of atherosclerotic sequelae, includingdeath from cardiovascular causes,5,6 coronary heart disease,6,7carotid atherosclerosis,8 and clinical stroke.9,10 These observationsled to the hypothesis that elevated plasma homocysteine maybe a risk factor for dementia and Alzheimer's disease. If thishypothesis is valid, it points to a modifiable risk factor,since plasma homocysteine levels can be lowered by supplementationwith folic acid.11
Previous studies have reported an inverse association betweenplasma total homocysteine levels and simultaneously assessedcognitive function.12,13,14,15,16 Two case–control studieshave found higher plasma homocysteine levels in persons withAlzheimer's disease.17,18 However, in a prospective study plasmahomocysteine levels were not related to cognitive decline duringfollow-up in a community-based sample.19 Elevated plasma homocysteinelevels in subjects with cognitive impairment or dementia mightbe the result of poor nutrition and vitamin deficiencies.20A prospective study should be able to show whether elevatedplasma homocysteine in cognitively intact adults is associatedwith an increased risk of dementia and Alzheimer's disease onfollow-up. We therefore examined plasma total homocysteine inrelation to newly diagnosed dementia and Alzheimer's diseasein the elderly, population-based cohort of Framingham Studyparticipants.
Methods
Subjects
The Framingham Study cohort has been evaluated biennially since1948. Between 1976 and 1978, a total of 2611 subjects were enrolledin a dementia-free cohort.21,22 At the 20th biennial examination(between 1986 and 1990), 1592 subjects from this cohort werealive and free of dementia and had follow-up data for at leastone year. Of these subjects, 1229 (77 percent) underwent the20th examination, and in 1092 participants (89 percent of thoseexamined), plasma total homocysteine levels were measured. These1092 subjects constituted our study sample. There were 667 womenand 425 men, and their mean (±SD) age was 76±6years (range, 68 to 97). Informed consent was obtained fromall study subjects with the use of a consent form approved bythe institutional review board for human research at the BostonUniversity School of Medicine.
Diagnosis of New Cases of Dementia and Alzheimer's Disease
Subjects in the cohort that was free of dementia at inceptionhave been monitored with published surveillance techniques since1978 for the development of stroke or dementia.21,22 Methodshave included a screening Folstein Mini–Mental State Examination23at each biennial evaluation, followed by annual neurologic andneuropsychological assessment of subjects with suspected cognitiveimpairment.
The final diagnosis of dementia was made by a committee, comprisingat least two neurologists and a neuropsychologist, that determinedthe type of dementia and the date of diagnosis. All availableinformation was used to evaluate participants with suspecteddementia, including serial neurologic and neuropsychologicalassessments, a telephone interview with a family member or caregiver, medical records, imaging studies, and autopsy data whenavailable. The review committee was unaware of the subjects'plasma homocysteine levels. The diagnosis of dementia was madeaccording to the criteria of the Diagnostic and StatisticalManual of Mental Disorders, fourth edition24; our definitionalso required a duration of symptoms greater than six months,and a score for severity of dementia of 1 or higher on the ClinicalDementia Rating scale.25 Alzheimer's disease was diagnosed whensubjects met the criteria of the National Institute of Neurologicaland Communicative Disorders and Stroke and the Alzheimer's Diseaseand Related Disorders Association for definite, probable, orpossible Alzheimer's disease.26
Plasma Homocysteine
Plasma total homocysteine levels were measured in all subjectsat the 20th biennial examination (base line). An earlier measurefrom the 16th biennial examination (performed between 1979 and1982, approximately eight years before base line) was also availablefor 935 of the subjects (86 percent). All plasma specimens werestored at or below –20°C. Homocysteine levels weredetermined with the use of high-performance liquid chromatographywith fluorometric detection.27 The coefficient of variationfor this assay was 9 percent.28
Apolipoprotein E Genotypes
Data on the apolipoprotein E (APOE) genotype were availablefor 1012 of the subjects (93 percent). The presence of particularalleles was determined by means of isoelectric focusing of theplasma and confirmed by DNA genotyping.29,30 Participants weredivided into two groups, one comprising persons with an APOE4 allele (2/4, 3/4, or 4/4 genotype) and another comprisingthose without an APOE4 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 folatewas measured by a microbial (Lactobacillus casei) assay witha 96-well plate and manganese supplementation31; plasma vitaminB12 levels were estimated with the use of a radioassay kit (Magic,Ciba–Corning, Medfield, Mass.); and pyridoxal-5'-phosphatewas measured by the tyrosine decarboxylase apoenzyme method.32Coefficients of variation for these assays were 13 percent forplasma folate, 7 percent for cyanocobalamin, and 16 percentfor pyridoxal-5'-phosphate.28 Because of insufficient plasmasamples, the vitamin levels were not determined for all patients.Of the subjects with measurements of plasma homocysteine, 85percent had measurements of vitamin B12, 92 percent had measurementsof vitamin B6, and 98 percent had measurements of folate.
Definition of Additional Risk Factors
Risk factors that could potentially confound the relation betweenplasma homocysteine and dementia or Alzheimer's disease weredefined with the use of data collected at the 20th biennialexamination. When appropriate, data from earlier biennial examinationswere also used. Educational status was dichotomized at the levelof high-school completion. We adjusted the analyses for cigarettesmoking using two variables: current smoking status (smokeror nonsmoker) and lifetime exposure to cigarette smoke (<5.0pack-years, 5.0 to 29.9 pack-years, or 30.0 pack-years). Alcoholintake was categorized in terms of the number of drinks perday: zero, less than one, one to two, or more than two.33 Diabetesmellitus was defined by a recorded casual blood glucose levelof at least 200 mg per deciliter (11.1 mmol per liter), a previousdiagnosis of diabetes mellitus, or the use of a hypoglycemicagent or insulin. Systolic blood pressure and body-mass index(the weight in kilograms divided by the square of the heightin meters) were treated as continuous variables.
Statistical Analysis
The distribution of plasma homocysteine levels in the populationwas positively skewed. The use of natural-log–transformedvalues provided the best-fitting model for analyses in whichthe plasma homocysteine level was treated as a continuous variable.Plasma homocysteine levels were also evaluated with a quartile-basedanalysis. Since homocysteine levels increase markedly with age,28,34,35the quartiles were defined in an age-specific manner for eachof several five-year age categories.
Cox proportional-hazards regression models36 were used to examinethe relation between the homocysteine level and the incidenceof dementia and Alzheimer's disease during follow-up, afteradjustment for age (in one-year increments), sex, and APOE genotype(with or without an APOE4 allele).37 In supplementary analyses,we also adjusted for vitamin levels and other covariates. Subjectswere followed for new cases of dementia from the date of their20th biennial examination until December 31, 2000. For the analysisof new cases of Alzheimer's disease, data for subjects in whomother types of dementia developed were censored at the dateof the diagnosis of dementia, since the diagnostic categorieswere mutually exclusive. Subjects who had a stroke during thestudy period were not excluded, since such an event could bepart of the causal chain between an elevated plasma homocysteinelevel and the development of dementia. All statistical analyseswere performed with the use of SAS software (SAS Institute,Cary, N.C.).
Results
Base-Line Characteristics
The base-line characteristics of the subjects are presentedin Table 1 (further information may be found in Supplementary Appendix 1,available with the full text of this article athttp://www.nejm.org). Mild-to-moderate elevation of the plasmahomocysteine level (>14 µmol per liter) was presentin 30 percent of the subjects. None of the subjects had severehyperhomocysteinemia (plasma homocysteine, >100 µmolper liter). The mean plasma homocysteine level within each ofthe five-year age groups is shown in Table 2. The correlationbetween the base-line plasma homocysteine level in a given subjectand the level measured eight years earlier was calculated forthe 935 subjects (571 women and 364 men) for whom both measurementswere available (Pearson r=0.47, P<0.001).
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 and37 men), and 83 of these subjects (62 women and 21 men) weregiven a diagnosis of Alzheimer's disease. In five subjects,the clinical diagnosis of Alzheimer's disease was confirmedat autopsy (definite Alzheimer's disease). The diagnosis wasprobable Alzheimer's disease for 67 subjects and possible Alzheimer'sdisease for 11 subjects. Other types of dementia diagnosed inthe study population included vascular dementia in 11 subjects,non-Alzheimer's degenerative dementias in 11 subjects, and othertypes of dementia in 6 subjects. The absence of Alzheimer'sdisease was confirmed at autopsy in 14 subjects.
The overall results relating the plasma homocysteine level tothe development of any dementia and to the development of Alzheimer'sdisease are shown in Table 3 and Table 4 and in Figure 1. Afteradjustment for the age, sex, and APOE genotype, the relativerisks of dementia and Alzheimer's disease, for each increaseof 1 SD in log-transformed base-line homocysteine value, were1.3 (95 percent confidence interval, 1.1 to 1.6) and 1.4 (95percent confidence interval, 1.2 to 1.7), respectively. Hyperhomocysteinemia(plasma homocysteine, >14 µmol per liter)8,18 was correspondinglyassociated with an increased risk of dementia (relative risk,1.9; 95 percent confidence interval, 1.3 to 2.8) and Alzheimer'sdisease (relative risk, 1.9; 95 percent confidence interval,1.2 to 3.0). An increase in the plasma homocysteine level of5 µmol per liter increased the multivariable-adjustedrisk of Alzheimer's disease by 40 percent (P<0.001). We did not find evidence of modification of this effect by age or sex.
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.
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.
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 vitaminsB12 and B6) have been associated with elevated plasma homocysteinelevels in several studies and with an increased risk of dementiain a few investigations.38,39,40,41,42 In our study, the observedassociation between plasma homocysteine and risk of dementiawas not significantly altered by adjustment for the plasma levelsof these vitamins (Table 3). Furthermore, after adjustment forage, sex, and APOE genotype, none of these vitamin levels wereindependently related to the risk of dementia or Alzheimer'sdisease (data not shown).
Additional Covariates
The observed association between the plasma homocysteine leveland dementia or Alzheimer's disease was not diminished by adjustmentfor 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). Serumcreatinine was measured at the 15th biennial examination, andcholesterol and thyrotropin were measured at the 20th biennialexamination. Adjustment for these additional variables did notalter our results (data not shown).
Varying the Diagnostic Criteria for Alzheimer's Disease
Higher plasma homocysteine levels have been related to an increasedrisk of stroke.8,10 To address the possibility that the associationwe observed between plasma homocysteine and Alzheimer's diseaseresulted from the inclusion of subjects who might have vasculardementia rather than Alzheimer's disease, we evaluated separatelythe association between base-line plasma homocysteine levelsand a diagnosis of definite or probable Alzheimer's diseaseafter excluding subjects with a diagnosis of possible Alzheimer'sdisease. The relative risk per increment of 1 SD in the log-transformedbase-line homocysteine value remained essentially unchangedat 1.4 (95 percent confidence interval, 1.2 to 1.7).
Association with Earlier Homocysteine Levels
Unlike stroke or myocardial infarction, clinical dementia beginsinsidiously. It may therefore be difficult to exclude subjectsin whom the disease is incipient at base line. However, subjectswho were free of clinical dementia at base line were most likelyfree of even incipient disease eight years earlier, at the examinationfrom which we derived the previous plasma homocysteine measurement.We examined the relation between the plasma homocysteine leveleight years before base line and the risk of newly diagnoseddementia or Alzheimer's disease during the follow-up periodbetween the base-line examination and December 31, 2000. Again,we found a strong association (Table 3), indicating that theelevation of the plasma homocysteine level occurred well beforethe onset of clinical manifestations.
Quartile-Specific Analysis
Examination of the risks of dementia and Alzheimer's diseasein age-specific quartiles of plasma homocysteine levels suggestedthat subjects with levels in the highest quartile (accordingto the cutoff points in Table 2) had the highest risk of dementiaand Alzheimer's disease. When both measurements of plasma homocysteinewere considered, this subgroup had about twice the risk of allother subjects (Table 4 and Figure 1). Although the effect ofthe homocysteine level was smaller in the second and third quartiles,we did not find evidence of a specific threshold. When the subjectswhose base-line levels were in the lowest age-specific quartilewere used as the reference group, the relative risk of Alzheimer'sdisease was 1.2 (95 percent confidence interval, 0.6 to 2.2)for subjects in the second quartile, 1.3 (95 percent confidenceinterval, 0.6 to 2.5) for subjects in the third quartile, and2.2 (95 percent confidence interval, 1.2 to 4.1) for subjectsin the fourth quartile. Subjects whose plasma homocysteine levelswere consistently high (in the fourth quartile at both the 16thand 20th examinations) had the highest risk.
Population Attributable Risk
In our population, the risk of Alzheimer's disease attributableto a plasma homocysteine level in the highest age-specific quartilewas estimated, with the use of standard techniques,43 at 16percent. In the same population, 21 percent of subjects hadat least one APOE4 allele, and the age- and sex-adjusted relativerisk of Alzheimer's disease associated with the presence ofthis allele was 2.3 (95 percent confidence interval, 1.5 to3.7); thus, there was a 21 percent risk of Alzheimer's diseaseattributable to the presence of an APOE4 genotype.
Discussion
The results of our prospective, observational study indicatethat there is a strong, graded association between plasma totalhomocysteine levels and the risk of dementia and Alzheimer'sdisease. An increment in the plasma homocysteine level of 5µmol per liter increased the risk of Alzheimer's diseaseby 40 percent. A plasma homocysteine level in the highest age-specificquartile 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 magnitudeof the increases in the risks of death from cardiovascular causesand stroke associated with a similar increment in the plasmahomocysteine level, which have been previously described inthe Framingham cohort.6,10
Two case–control studies have specifically addressed therelation between homocysteine levels and the risk of Alzheimer'sdisease.17,18 Both studies found a significant elevation ofthe serum homocysteine level in patients with Alzheimer's diseaseas compared with age-matched controls. A report from the RotterdamStudy did not show an association between the base-line homocysteinelevel and a decline in the score on the Mini–Mental StateExamination, perhaps because the follow-up period was only 2.7years.19 In our study population, an elevated homocysteine levelat base line was related to a decline in the scores on the Mini–MentalState Examination, but only after a follow-up period of at leastfour years (data not shown).
Elevated plasma homocysteine levels are associated with carotidatherosclerosis and an increased risk of stroke.8,10 Atherosclerosisand stroke, in turn, increase the risk of clinical Alzheimer'sdisease.2,4 Hyperhomocysteinemia has been related to cerebralmicroangiopathy,44 endothelial dysfunction,45 impaired nitricoxide activity,46 and increased oxidative stress47 — allfactors associated with the aging of the brain.48,49 Increasedconcentrations of homocysteic acid, an N-methyl-D-aspartatereceptor agonist and a metabolite of homocysteine, may resultin excitotoxic damage to neurons.50 Homocysteine promotes copper-mediatedand -amyloid-peptide–mediated toxic effects in neuronalcell cultures51 and induces apoptosis in hippocampal neuronsin rats.52
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 levelsand base-line values for plasma B vitamins and other covariates.A limitation of this study is the lack of racial diversity inthe overwhelmingly white Framingham cohort. It is possible thatour use of samples obtained from nonfasting subjects resultedin estimates of plasma homocysteine levels that were up to 20percent higher than they would have been in fasting subjects,53but any increase in the variability in plasma homocysteine valuescaused by this approach is likely to be random and is unlikelyto have altered the results.
Supported by the Framingham Heart Study's National Heart, Lung,and Blood Institute contract (N01-HC-38038) and by grants (NIA-5R01-AG08122-11and NIA-5R01-AG16495-02) from the National Institute on Agingand a grant (NINDS-5R01-NS17950-19) from the National Instituteof 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 pawolf{at}bu.edu.
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Homocysteine and Dementia
Shea T. B., Rogers E., Auer J., Berent R., Eber B., Seshadri S., Wolf P. A.
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N Engl J Med 2002;
346:2007-2008, Jun 20, 2002.
Correspondence
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60: 1017-1021
[Abstract][Full Text]
Shields, D. J., Lingrell, S., Agellon, L. B., Brosnan, J. T., Vance, D. E.
(200
4 allele (
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 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. 
-amyloid-peptide–mediated toxic effects in neuronal cell cultures51 and induces apoptosis in hippocampal neurons in rats.52 
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