Logo of demKargerHomeAlertsResources
Dement Geriatr Cogn Disord. Feb 2009; 27(1): 11–17.
Published online Dec 16, 2008. doi:  10.1159/000182421
PMCID: PMC2698462
NIHMSID: NIHMS105994

Plasma Homocysteine and Risk of Mild Cognitive Impairment

Abstract

Background and Objective

There are conflicting data relating homocysteine levels to the risk of Alzheimer's disease (AD). We sought to explore whether fasting plasma homocysteine is associated with the risk of mild cognitive impairment (MCI), an intermediate stage to dementia.

Methods

Fasting levels of plasma homocysteine were obtained from 678 elderly subjects chosen at random from a cohort of Medicare recipients. There were longitudinal data in 516 subjects without MCI or dementia at baseline who were followed for 2,705 person-years. The relation of plasma homocysteine with prevalent and incident all-cause MCI, amnestic MCI and non-amnestic MCI was assessed using logistic and Cox proportional hazards regression analyses.

Results

There were 162 cases of prevalent MCI and 132 cases of incident MCI in 5.2 years of follow-up. There was no association between plasma homocysteine and prevalence of MCI or amnestic or non-amnestic MCI in the cross-sectional analyses. There was no association between higher homocysteine levels and a lower risk of all-cause MCI. Consistent with the cross-sectional analyses, there was no specific association with the amnestic or non-amnestic subtype of MCI in crude or adjusted models.

Conclusion

Plasma homocysteine levels measured at baseline were not related to MCI or its subtypes in an elderly multiethnic cohort.

Key Words: Homocysteine, Dementia, Mild cognitive impairment

Introduction

The prevalence of Alzheimer's disease (AD) is expected to quadruple by the year 2047 [1]. Delaying the onset by a few years would decrease its prevalence and public health burden [1]. There are no known cures or preventive measures, but there is growing evidence that modifiable vascular risk factors may have an important role in its etiology [2]. A potentially important risk factor for heart disease and stroke is hyperhomocysteinemia [3,4,5,6]. Homocysteine is converted by folate, vitamin B12 and B6 to methionine and cysteine. Homocysteine levels in blood increase with age and with diminishing renal function, but are largely determined by dietary intake and levels of vitamins B12, B6, and folate [7], but increase with age and with diminishing renal function. Thus, homocysteine levels can be modified through dietary interventions.

Previous studies relating homocysteine levels with the risk of dementia were inconsistent [8,9,10,11,12,13]. While some longitudinal data show an association between hyperhomocysteinemia and a higher risk of AD, other studies reported inverse or no associations [8,9,10,11,12,13]. We previously explored the associations of homocysteine levels with risk of AD and amyloid beta (Aβ) protein and observed a relation between homocysteine levels and Aβ40 but not Aβ42 or AD [14, 15].

As a transitional stage between normal cognition and dementia and a target for early treatment and prevention, mild cognitive impairment (MCI) has attracted increasing interest over the past years. Studies using the criteria by Petersen et al. [16, 17] for diagnosing MCI in clinical and epidemiological settings report an incidence rate of 9.9/1,000 person-years for MCI among non-demented elderly [18], and an annual conversion rate of 10–12% to AD in subjects with MCI, particularly amnestic MCI, in contrast to a conversion rate of 1–2% in the normal elderly population [17]. Recent data suggest that non-amnestic MCI progresses to dementia at a markedly lower rate than amnestic MCI [19], and that non-amnestic MCI is probably more representative of vascular cognitive impairment than amnestic MCI [20].

The objective of the present study was to determine whether or not homocysteine is associated with the risk of MCI or its amnestic or non-amnestic subtypes. Clarification of the association between homocysteine levels and cognitive impairment can help understand the etiology of cognitive decline, can help identify persons at risk which could benefit from dietary intervention, and can help design strategies for prevention and treatment.

Methods

Subjects and Setting

Participants were enrolled in a longitudinal cohort study by a random sampling of Medicare recipients 65 years or older residing in northern Manhattan (Washington Heights, Hamilton Heights, Inwood). The sampling procedures have been described elsewhere [21]. Each participant underwent an in-person interview of general health and function at the time of study entry followed by a standard assessment, including medical history, physical and neurological examination as well as a neuropsychological battery [22]. Baseline data were collected from 1992 through 1994. Follow-up data were collected during evaluations at sequential intervals of approximately 18 months, performed from 1992 to 2006. This study was approved by the institutional review board of the Columbia-Presbyterian Medical Center.

Plasma homocysteine was measured in a subsample of the cohort chosen at random [15]. The sample for this study comprised those participants who were without MCI or dementia at baseline, who had measures of plasma homocysteine levels, and who had complete information to ascertain MCI following the Petersen criteria [16, 17]. Of the 1,772 participants in whom a full neuropsychological examination was attempted, 371 (20.9%) were excluded due to prevalent dementia, and 723 (40.8%) were not part of the homocysteine subsample. Thus, the final analytic sample included 678 individuals. Compared to the original 1,772 participants, the final sample was younger (77.3 vs. 78.1 years; p = 0.01), had similar proportions of women (70.3 vs. 69.2%; p = 0.64); non-Hispanic Whites (18.7 vs. 21.0%; p = 0.25), African-Americans (31.1 vs. 34.9%; p = 0.09), diabetes (16.7 vs. 16.7, p = 0.1), heart disease (14.9 vs. 17.9%, p = 0.1) and hypertension (51.3 vs. 50.5%, p = 0.7), and had a higher proportion of Hispanics (50.2 vs. 44.0%; p = 0.01).

Clinical Assessments

Data were available from medical, neurological, and neuropsychological evaluations [22]. All participants underwent a standardized neuropsychological test battery examining multiple domains at baseline and subsequent assessments using the Mini-Mental State Examination, the Boston Naming Test, the Controlled Word Association Test, category naming, the Complex Ideational Material and Phrase Repetition subtests from the Boston Diagnostic Aphasia Evaluation, the WAIS-R Similarities subtest, the Mattis Dementia Rating Scale, the Rosen Drawing Test, the Benton Visual Retention Test, the multiple choice version of the Benton Visual Retention Test and the Selective Reminding Test [22].

Diagnosis of Dementia and MCI

Dementia was diagnosed by consensus of neurologists, psychiatrists and neuropsychologists based on DSM-IV criteria [23]. Consistent with standard criteria [17] for all subtypes of MCI, those considered for MCI were required to have: (1) memory complaint; (2) objective impairment in at least one cognitive domain based on the average of the scores on the neuropsychological measures within that domain and a 1.5-SD cutoff using normative corrections for age, years of education, ethnicity, and sex; (3) essentially preserved activities of daily living, and (4) no dementia. Participants with MCI were stratified into those with: (1) isolated impairment in memory or impairment in memory and one or more other cognitive domains (‘amnestic MCI’) or (2) no impairment in memory but impairment in two or more other cognitive domains (‘non-amnestic MCI’), as described in detail previously [24].

Plasma Homocysteine Levels

Blood was drawn at baseline under fasting conditions. It was drawn into EDTA tubes, and centrifuged, separated into plasma aliquots, and stored at −70° C within 2 h of collection. Homocysteine levels were measured from plasma using high-performance liquid chromatography with fluorescence detection [25].

Other Covariates

APOE genotyping was determined using the method of Hixson and Vernier [26]. Participants were classified as positive for the APOE-[sm epsilon]4 allele genotype if they had one or two [sm epsilon]4 alleles. Plasma folate and vitamin B12 were determined by radioassay (Simultrac, ICN Pharmaceuticals, Costa Mesa, Calif., USA). Plasma pyridoxal-5′-phosphate, an indicator of vitamin B6 status, was determined by radioenzymatic assay (ALPCO, Wyndham, N.H., USA). Creatinine was measured by spectrophotometric assay (Sigma, St. Louis, Mo., USA). Stroke was defined according to the WHO criteria [27]. The presence of stroke was ascertained from an interview with participants and their informants. Persons with stroke were confirmed through their medical records, 85% of which included results of brain imaging. The remainderwas confirmed by direct examination.

Statistical Methods

First we evaluated the demographic and clinical characteristics of the study sample at baseline. The distributions of homocysteine, cysteine, vitamin B12 and folate were skewed and were transformed before further analyses using natural logarithm to achieve normal distributions. Then levels of homocysteine, folate and vitamin B12 were compared between persons with and without MCI at baseline using ANOVA. Logistic regression analyses were used to relate homocysteine levels to prevalent all-cause MCI, amnestic MCI and non-amnestic MCI. Each outcome was examined in a separate model. Cox proportional hazards regression was used to relate homocysteine levels to incident MCI and MCI subtypes, the time-to-event variable in these models was from age at baseline to age at onset of MCI. Among individuals who did not develop MCI, those who developed dementia were censored at the time of dementia diagnosis, and those who did not develop dementia, whodied, or who were lost to follow-up owing to relocation beforedevelopment of MCI were censored at the time of their lastevaluation. We first performed crude models, subsequently we adjusted all models for age, gender, ethnic group and APOE-[sm epsilon]4, and then in addition for creatinine. Homocysteine levels were explored as a continuous variable, in tertiles, and as a dichotomized variable using the acknowledged level of 14 μmol/l as the cutoff. Data analysis was performedusing SPSS version 15.0 software (SPSS Inc., Chicago, Ill., USA) and SAS 9.1 for Windows (Cary, N.C., USA).

Results

Characteristics of the study sample are shown in table table1.1. The mean age of the sample of 678 subjects was 77.4 ± 5.8 years, and 70.4% were women. There were 162 cases of prevalent MCI and 132 cases of incident MCI in ~5.2 years of follow-up. This corresponds to a follow-up time of 2,705 person-years. Out of the 132 persons who developed MCI during follow-up, 78 persons (59.1%) developed MCI at the first follow-up interval, 52 persons (39.4%) at the second follow-up interval, and 2 persons (1.5%) at the third follow-up interval. Of the 384 persons who remained free of MCI during follow-up, 81 (21.1%) were censored at the first follow-up, 101 (26.3%) at the second follow-up, 71 (18.5%) at the third follow-up, 24 (6.3%) at the fourth follow-up, 41 (10.7%) at the fifth follow-up and 66 at the sixth follow-up (17.2%). Levels of homocysteine, vitamin B12 or folate did not significantly differ between persons with and without MCI at baseline (table (table2).2). Homocysteine levels at baseline did also not differ between persons who remained free of MCI during follow-up (mean ± SD: 17.32 ± 9.1 μmol/l) or persons who developed MCI during the course of the study (mean ± SD: 16.03 ± 6.0 μmol/l).

Table 1
Characteristics of the study sample in cross-sectional analyses
Table 2
Comparison of transformeda homocysteine, vitamin B12 and folate levels across persons with normal cognition, all-cause MCI, amnestic MCI or non-amnestic MCI at baseline

The mean age at onset of MCI was 81.2 ± 5.9 years. There was no association between plasma homocysteine levels and prevalence of MCI or amnestic or non-amnestic subtype of MCI in the cross-sectional analyses (table (table3).3). In the longitudinal analyses, there was a trend towards an association between higher homocysteine levels and a lower risk of all-cause MCI in crude models, but this risk was appreciably attenuated with adjustment for ethnic group and APOE-[sm epsilon]4 genotype (table (table4).4). There was also no specific association with the amnestic or non-amnestic subtype of MCI in the longitudinal analyses. Additional adjustment for creatinine, or using time to event or last evaluation as the time variable did not change these relations.

Table 3
OR and 95% CI relating plasma homocysteine levels with all-cause MCI, amnestic MCI and non-amnestic MCI in cross-sectional analyses
Table 4
Hazard ratios (HR) and 95% CI relating plasma homocysteine levels and the risk of incident MCI

Discussion

In this multiethnic urban cohort, higher plasma levels of homocysteine measured at baseline were not associated with all-cause MCI, amnestic MCI or non-amnestic MCI in cross-sectional or longitudinal analyses.

The mechanisms through which homocysteine could affect cognitive function remain controversial. Higher homocysteine levels could lead to cognitive impairment through cerebrovascular disease [13, 28, 29] or increased cortical or hippocampal atrophy [30]. It is also possible that vitamins involved in homocysteine metabolism such as folic acid, vitamin B6 and vitamin B12[31], confound relations between homocysteine and cognition or vice versa [32] or that homocysteine itself has neurotoxic and excitotoxic properties. However, the evidence for neurotoxic effects comes largely from in vitro studies [33, 34], and several studies suggested that elevated homocysteine levels in persons with cognitive impairment or dementia are not a cause of but reflect concomitant vascular disease [35].

Previous studies relating homocysteine levels with the risk of dementia or MCI were inconsistent. Some cross-sectional or longitudinal studies reported associations between elevated homocysteine levels and an increased risk of cognitive impairment [13,36,37,38,39]. The Framingham Study reported a twofold increased risk of AD for individuals in the highest quartile of homocysteine levels after adjustment for age [13]. The Sacramento Area Latino Study on Aging reported an association between higher homocysteine levels and a combined outcome of cognitive impairment no dementia and dementia [10]. In other studies, elevated serum concentrations of homocysteine were associated with cognitive impairment in elderly persons but not with an increased rate of cognitive decline [11] indicating that high serum concentrations of homocysteine may be a consequence but not cause of the disease. Finally, in several studies, homocysteine levels were not associated with cognitive impairment [8, 9, 40].

MCI, an intermediate stage between normal cognition and dementia [41], is increasingly studied as a cognitive outcome in research and clinical practice. MCI has been characterized into subtypes [42, 43]. Amnestic MCI is thought to be more specific to AD, while non-amnestic MCI seems to be related to other causes such as cerebrovascular disease [42]. This notion is supported by recent work in our cohort that has shown that risk factors for AD are also risk factors for amnestic MCI, such as diabetes [44], while risk factors for vascular dementia, such as hypertension [20], and also diabetes [45] are also risk factors for non-amnestic MCI. We had previously found that homocysteine was not associated with AD in longitudinal analyses, and others reported an association with vascular disease but not AD pathology [46]. Thus, we would have expected an association with non-amnestic MCI, and no association with amnestic MCI. However, in neither cross-sectional nor longitudinal analyses adjusting for age, sex and other potential confounders were homocysteine levels associated with prevalence or risk of MCI. Results from trials assessing the impact of homocysteine-lowering treatment on cognition have been inconclusive [47,48,49]. The most definitive data to date on the relation between homocysteine and cognition comes from a 2-year, double-blind, placebo-controlled, randomized clinical trial of homocysteine-lowering treatment with B12, B6 and folate supplements in 276 elderly participant with high plasma homocysteine by McMahon et al. [47]. This trial demonstrated a lowering of plasma homocysteine in the treatment group. However, this was not accompanied by better cognitive performance. The results of our study are in agreement with those showing no association and with the results of McMahon et al.

The third tertile of homocysteine in our analyses was related to a lower risk of MCI which was not statistically significant. This could be interpreted as deviating markedly from previous literature and could be dismissed as caused by selection bias or variability in a small sample. However, there is increasing evidence that the interaction among the vitamins that determine homocysteine levels is complex and that higher intake of these vitamins could result in worse cognition. A cross-sectional analysis of the National Health and Nutrition Examination Survey data showed that in elderly people with low serum B12, high folate levels were related to cognitive impairment [50]. A longitudinal analysis in the Chicago Health and Aging Project showed that higher intake of folate was related to cognitive decline in the elderly [51]. An analysis from our cohort showed that higher folate intake was related to lower risk of AD that became apparent after controlling for B12 intake. Lastly, post-hoc analyses in the trial by McMahon et al. [47] suggested that persons in the vitamin supplementation group had worse cognitive performance despite a decrease in homocysteine levels. More studies are needed examining how the complex interactions among the vitamins that determine homocysteine levels affect cognition.

We must consider alternative explanations for our findings. It is possible that our sample was too homogeneous in homocysteine levels not permitting enough variability to detect a harmful association. The proportion of persons with high homocysteine levels and vascular disease in the population of Northern Manhattan is higher than in other populations in which associations between high homocysteine and a higher dementia risk have been reported [15, 52]. It is possible that most of our sample may have been at a high risk of dementia given relatively high homocysteine levels. However, we conducted secondary longitudinal analyses classifying homocysteine using the 14 μmol/l cutoff point and found no association (all-cause MCI: HR 0.8; 95% CI 0.54–1.10; amnestic MCI: 0.68, 95% CI 0.38–1.20; non-amnestic MCI: HR 0.84, 95% CI 0.54–1.32). Another possibility is that homocysteine levels are related to cognitive impairment in younger individuals but not the older sample in our study. Our sample was older than 65 years with a mean age of 77.5 years. It is possible that individuals with adverse outcomes related to homocysteine levels did not survive to inclusion in our study. It is also possible that in older age the brain is less vulnerable to the effects of homocysteine levels than in middle age, or that the follow-up period in this study was too short to detect a harmful effect in this elderly population. Another possibility is that we did not have enough power to find an association in a relatively small sample. At a 0.05 α level, we had 80% power to detect a relative risk of 2.0. However, the effects estimates in all tertiles in models adjusted for age and sex, particularly in the smaller longitudinal sample, were close to 1, suggesting that lack of power is not an explanation for the lack of significant results.

Limitations include that we used only one measurement of homocysteine levels, which could have led to measurement error and an underestimation of the association between homocysteine and cognitive impairment. Due to lack of repeat homocysteine measurement during follow-up we could not investigate how changes in homocysteine levels over time affect the risk to develop cognitive impairment. However, repeat measurements after 6–18 months in the elderly show good reproducibility of baseline levels with non-significant intraindividual variations of as little as 0.85–1.2 μmol/l, suggesting that such study likely would have yielded similar results [53, 54]. An important strength of our study is that it is a prospective cohort study especially designed for the diagnosis of cognitive impairment and dementia.

Acknowledgements

Support for this work was provided by grants from the National Institutes of Health AG15294, AG07232, AG07702, RR00645 from the Charles S. Robertson Memorial Gift for research on Alzheimer's disease, from the Blanchette Hooker Rockefeller Foundation.

References

1. Brookmeyer R, Gray S, Kawas C. Projections of Alzheimer's disease in the United States and the public health impact of delaying disease onset. Am J Public Health. 1998;88:1337–1342. [PMC free article] [PubMed]
2. Luchsinger JA, Mayeux R. Cardiovascular risk factors and Alzheimer's disease. Curr Atheroscler Rep. 2004;6:261–266. [PubMed]
3. Casas JP, Bautista LE, Smeeth L, Sharma P, Hingorani AD. Homocysteine and stroke: evidence on a causal link from mendelian randomisation. Lancet. 2005;365:224–232. [PubMed]
4. Hankey GJ. Is plasma homocysteine a modifiable risk factor for stroke? Nat Clin Pract. 2006;2:26–33. [PubMed]
5. Toole JF, Malinow MR, Chambless LE, Spence JD, Pettigrew LC, Howard VJ, Sides EG, Wang CH, Stampfer M. Lowering homocysteine in patients with ischemic stroke to prevent recurrent stroke, myocardial infarction, and death: the Vitamin Intervention for Stroke Prevention (VISP) randomized controlled trial. JAMA. 2004;291:565–575. [PubMed]
6. Zylberstein DE, Bengtsson C, Bjorkelund C, Landaas S, Sundh V, Thelle D, Lissner L. Serum homocysteine in relation to mortality and morbidity from coronary heart disease: a 24-year follow-up of the population study of women in Gothenburg. Circulation. 2004;109:601–606. [PubMed]
7. Selhub J, Jacques PF, Wilson PW, Rush D, Rosenberg IH. Vitamin status and intake as primary determinants of homocysteinemia in an elderly population. JAMA. 1993;270:2693–2698. [PubMed]
8. Ariogul S, Cankurtaran M, Dagli N, Khalil M, Yavuz B. Vitamin B12, folate, homocysteine and dementia: are they really related? Arch Gerontol Geriatr. 2005;40:139–146. [PubMed]
9. Gunstad J, Bausserman L, Paul RH, Tate DF, Hoth K, Poppas A, Jefferson AL, Cohen RA. C-reactive protein, but not homocysteine, is related to cognitive dysfunction in older adults with cardiovascular disease. J Clin Neurosci. 2006;13:540–546. [PMC free article] [PubMed]
10. Haan MN, Miller JW, Aiello AE, Whitmer RA, Jagust WJ, Mungas DM, Allen LH, Green R. Homocysteine, B vitamins, and the incidence of dementia and cognitive impairment: results from the Sacramento Area Latino Study on Aging. Am J Clin Nutr. 2007;85:511–517. [PMC free article] [PubMed]
11. Mooijaart SP, Gussekloo J, Frolich M, Jolles J, Stott DJ, Westendorp RG, de Craen AJ. Homocysteine, vitamin B12, and folic acid and the risk of cognitive decline in old age: the Leiden 85-Plus Study. Am J Clin Nutr. 2005;82:866–871. [PubMed]
12. Seshadri S. Elevated plasma homocysteine levels: risk factor or risk marker for the development of dementia and Alzheimer's disease? J Alzheimers Dis. 2006;9:393–398. [PubMed]
13. Seshadri S, Beiser A, Selhub J, Jacques PF, Rosenberg IH, D'Agostino RB, Wilson PW, Wolf PA. Plasma homocysteine as a risk factor for dementia and Alzheimer's disease. N Engl J Med. 2002;346:476–483. [PubMed]
14. Luchsinger JA, Tang MX, Miller J, Green R, Mehta PD, Mayeux R. Relation of plasma homocysteine to plasma amyloid β levels. Neurochem Res. 2007;32:775–781. [PubMed]
15. Luchsinger JA, Tang MX, Shea S, Miller J, Green R, Mayeux R. Plasma homocysteine levels and risk of Alzheimer disease. Neurology. 2004;62:1972–1976. [PubMed]
16. Petersen RC, Doody R, Kurz A, Mohs RC, Morris JC, Rabins PV, Ritchie K, Rossor M, Thal L, Winblad B. Current concepts in mild cognitive impairment. Arch Neurol. 2001;58:1985–1992. [PubMed]
17. Petersen RC, Smith GE, Waring SC, Ivnik RJ, Tangalos EG, Kokmen E. Mild cognitive impairment: clinical characterization and outcome. Arch Neurol. 1999;56:303–308. [PubMed]
18. Larrieu S, Letenneur L, Orgogozo JM, Fabrigoule C, Amieva H, Le Carret N, Barberger-Gateau P, Dartigues JF. Incidence and outcome of mild cognitive impairment in a population-based prospective cohort. Neurology. 2002;59:1594–1599. [PubMed]
19. Luis CA, Barker WW, Loewenstein DA, Crum TA, Rogaeva E, Kawarai T, St George-Hyslop P, Duara R. Conversion to dementia among two groups with cognitive impairment. A preliminary report. Dement Geriatr Cogn Disord. 2004;18:307–313. [PubMed]
20. Reitz C, Tang MX, Manly J, Mayeux R, Luchsinger JA. Hypertension and the risk of mild cognitive impairment. Arch Neurol. 2007;64:1734–1740. [PMC free article] [PubMed]
21. Tang MX, Stern Y, Marder K, Bell K, Gurland B, Lantigua R, Andrews H, Feng L, Tycko B, Mayeux R. The APOE-[sm epsilon]4 allele and the risk of Alzheimer disease among African-Americans, Whites, and Hispanics. JAMA. 1998;279:751–755. [PubMed]
22. Stern Y, Andrews H, Pittman J, Sano M, Tatemichi T, Lantigua R, Mayeux R. Diagnosis of dementia in a heterogeneous population. Development of a neuropsychological paradigm-based diagnosis of dementia and quantified correction for the effects of education. Arch Neurol. 1992;49:453–460. [PubMed]
23. Diagnostic and Statistical Manual of Mental Disorders, ed 4. Washington, DCAPA.
24. Manly JJ, Bell-McGinty S, Tang MX, Schupf N, Stern Y, Mayeux R. Implementing diagnostic criteria and estimating frequency of mild cognitive impairment in an urban community. Arch Neurol. 2005;62:1739–1746. [PubMed]
25. Gilfix BM, Blank DW, Rosenblatt DS. Novel reductant for determination of total plasma homocysteine. Clin Chem. 1997;43:687–688. [PubMed]
26. Hixson JE, Vernier DT. Restriction isotyping of human apolipoprotein E by gene amplification and cleavage with HhaI. J Lipid Res. 1990;31:545–548. [PubMed]
27. Hatano S. Experience from a multicentre stroke register: a preliminary report. Bull World Health Organ. 1976;54:541–553. [PMC free article] [PubMed]
28. Vermeer SE, Prins ND, den Heijer T, Hofman A, Koudstaal PJ, Breteler MM. Silent brain infarcts and the risk of dementia and cognitive decline. N Engl J Med. 2003;348:1215–1222. [PubMed]
29. Vermeer SE, van Dijk EJ, Koudstaal PJ, Oudkerk M, Hofman A, Clarke R, Breteler MM. Homocysteine, silent brain infarcts, and white matter lesions: The Rotterdam Scan Study. Ann Neurol. 2002;51:285–289. [PubMed]
30. Den Heijer T, Vermeer SE, Clarke R, Oudkerk M, Koudstaal PJ, Hofman A, Breteler MM. Homocysteine and brain atrophy on MRI of non-demented elderly. Brain. 2003;126:170–175. [PubMed]
31. Selhub J, Bagley LC, Miller J, Rosenberg ICH. B vitamins, homocysteine, and neurocognitive function in the elderly. Am J Clin Nutr. 2000;71:614S–620S. [PubMed]
32. Kado DM, Karlamangla AS, Huang MH, Troen A, Rowe JW, Selhub J, Seeman TE. Homocysteine versus the vitamins folate, B6, and B12 as predictors of cognitive function and decline in older high-functioning adults: MacArthur Studies of Successful Aging. Am J Med. 2005;118:161–167. [PubMed]
33. Kruman II, Culmsee C, Chan SL, Kruman Y, Guo Z, Penix L, Mattson MP. Homocysteine elicits a DNA damage response in neurons that promotes apoptosis and hypersensitivity to excitotoxicity. J Neurosci. 2000;20:6920–6926. [PubMed]
34. Parsons RB, Waring RH, Ramsden DB, Williams AC. In vitro effect of the cysteine metabolites homocysteic acid, homocysteine and cysteic acid upon human neuronal cell lines. Neurotoxicology. 1998;19:599–603. [PubMed]
35. Miller AL. The methionine-homocysteine cycle and its effects on cognitive diseases. Altern Med Rev. 2003;8:7–19. [PubMed]
36. Dufouil C, Alperovitch A, Ducros V, Tzourio C. Homocysteine, white matter hyperintensities, and cognition in healthy elderly people. Ann Neurol. 2003;53:214–221. [PubMed]
37. Tucker KL, Qiao N, Scott T, Rosenberg I, Spiro A., 3rd High homocysteine and low B vitamins predict cognitive decline in aging men: the Veterans Affairs Normative Aging Study. Am J Clin Nutr. 2005;82:627–635. [PubMed]
38. Ravaglia G, Forti P, Maioli F, Martelli M, Servadei L, Brunetti N, Porcellini E, Licastro F. Homocysteine and folate as risk factors for dementia and Alzheimer disease. Am J Clin Nutr. 2005;82:636–643. [PubMed]
39. Schafer JH, Glass TA, Bolla KI, Mintz M, Jedlicka AE, Schwartz BS. Homocysteine and cognitive function in a population-based study of older adults. J Am Geriatr Soc. 2005;53:381–388. [PubMed]
40. Kalmijn S, Launer LJ, Lindemans J, Bots ML, Hofman A, Breteler MM. Total homocysteine and cognitive decline in a community-based sample of elderly subjects: the Rotterdam Study. Am J Epidemiol. 1999;150:283–289. [PubMed]
41. Petersen RC, Doody R, Kurz A, Mohs RC, Morris JC, Rabins PV, Ritchie K, Rossor M, Thal L, Winblad B. Current concepts in mild cognitive impairment. Arch Neurol. 2001;58:1985–1992. [PubMed]
42. Luis CA, Loewenstein DA, Acevedo A, Barker WW, Duara R. Mild cognitive impairment: directions for future research. Neurology. 2003;61:438–444. [PubMed]
43. Manly J, Bell-McGinty S, Tang M-X, Schupf N, Stern Y, Mayeux R. Implementing diagnostic criteria and estimating frequency of mild cognitive impairment in an urban community. Arch Neurol. 2005;62:1739–1746. [PubMed]
44. Luchsinger JA, Reitz C, Patel B, Tang M-X, Manly JJ, Mayeux R. Relation of diabetes to mild cognitive impairment. Arch Neurol. 2007;64:570–575. [PubMed]
45. Luchsinger JA, Tang MX, Stern Y, Shea S, Mayeux R. Diabetes mellitus and risk of Alzheimer's disease and dementia with stroke in a multiethnic cohort. Am J Epidemiol. 2001;154:635–641. [PubMed]
46. Miller JW, Green R, Mungas DM, Reed BR, Jagust WJ. Homocysteine, vitamin B6, and vascular disease in AD patients. Neurology. 2002;58:1471–1475. [PubMed]
47. McMahon JA, Green TJ, Skeaff CM, Knight RG, Mann JI, Williams SM. A controlled trial of homocysteine lowering and cognitive performance. N Engl J Med. 2006;354:2764–2772. [PubMed]
48. Eussen SJ, de Groot LC, Joosten LW, Bloo RJ, Clarke R, Ueland PM, Schneede J, Blom HJ, Hoefnagels WH, van Staveren WA. Effect of oral vitamin B12 with or without folic acid on cognitive function in older people with mild vitamin B12 deficiency: a randomized, placebo-controlled trial. Am J Clin Nutr. 2006;84:361–370. [PubMed]
49. Durga J, van Boxtel MP, Schouten EG, Kok FJ, Jolles J, Katan MB, Verhoef P. Effect of 3-year folic acid supplementation on cognitive function in older adults in the FACIT trial: a randomised, double-blind, controlled trial. Lancet. 2007;369:208–216. [PubMed]
50. Morris MS, Jacques PF, Rosenberg IH, Selhub J. Folate and vitamin B12 status in relation to anemia, macrocytosis, and cognitive impairment in older Americans in the age of folic acid fortification. Am J Clin Nutr. 2007;85:193–200. [PMC free article] [PubMed]
51. Morris MC, Evans DA, Bienias JL, Tangney CC, Hebert LE, Scherr PA, Schneider JA. Dietary folate and vitamin B12 intake and cognitive decline among community-dwelling older persons. Arch Neurol. 2005;62:641–645. [PubMed]
52. Luchsinger JA. Folate, related vitamins and risk of Alzheimer's disease. Expert Rev Endocrinol Metab. 2007;2:559–561.
53. Clarke R, Woodhouse P, Ulvik A, Frost C, Sherliker P, Refsum H, Ueland PM, Khaw KT. Variability and determinants of total homocysteine concentrations in plasma in an elderly population. Clin Chem. 1998;44:102–107. [PubMed]
54. Garg UC, Zheng ZJ, Folsom AR, Moyer YS, Tsai MY, McGovern P, Eckfeldt JH. Short-term and long-term variability of plasma homocysteine measurement. Clin Chem. 1997;43:141–145. [PubMed]

Articles from Dementia and Geriatric Cognitive Disorders are provided here courtesy of Karger Publishers
PubReader format: click here to try

Formats:

Related citations in PubMed

See reviews...See all...

Links

  • Compound
    Compound
    PubChem Compound links
  • MedGen
    MedGen
    Related information in MedGen
  • PubMed
    PubMed
    PubMed citations for these articles
  • Substance
    Substance
    PubChem Substance links

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...