Get Newsletter
AlzRisk Risk Factor Literature Search Strategy and Results
Back

Risk Factor: Homocysteine
Risk Factor Type: Metabolic
Current Understanding:
The evidence from observational epidemiologic studies suggests that higher levels of plasma total homocysteine (tHcy) may be associated with an increased risk of incident Alzheimer's disease (AD). This body of findings is consistent with findings from related studies of cognitive decline, of brain imaging, and of genetic polymorphisms predisposing individuals to hyperhomocysteinemia. Recent trials of the tHcy-lowering vitamins—B6, B12, and folate, however, have had mixed, predominantly null results. Further research will be required to know whether supplementation with B vitamins starting in midlife, when it could prevent chronic elevation of homocysteine over a longer span, would provide greater benefit. For a review of the putative mechanisms by which homocysteine may influence AD risk and detailed commentary on interpreting the findings below in a broader context, please view the Discussion.
Last Search Completed: 15 November 2013 - Last content update released on 20 Nov 2013.

Risk Factor Overview


Summary

We searched Pubmed for peer-reviewed articles reporting on the association between plasma homocysteine levels and Alzheimer’s disease (AD) incidence in cohort or nested case-control studies. The search returned 314 unique citations that, after title and abstract review against our inclusion criteria, were narrowed down to 54 citations for full-text review (all published in English). Of these, eight fully met criteria for inclusion in our summary tables. Among the excluded were two additional articles that otherwise met our inclusion criteria but duplicated analyses from a cohort that contributed data to other included articles. We review such duplicate articles on a case-by-case basis, and select the most informative article(s) based on sample size, follow-up time, exposure assessment or modeling, and appropriateness of analytic methods. Please see our methods section for more detail on our general systematic review methods.

Search & Review Flowchart
Search Strategy
Selection of Papers Reporting on Data from the Same Cohort



Search Strategy Flowchart


Search Strategy

Using our systematic review methods, we developed a search strategy (table below) for Pubmed.


Search Strategy Table


Selection of Papers Reporting on Data from the Same Cohort

Some cohort studies produced multiple articles reporting on the association between plasma homocysteine levels and risk for Alzheimer’s disease. To avoid presenting duplicate results, we reviewed such articles on a case-by-case basis and selected the most informative article(s) based on sample size, follow-up time, exposure assessment or modeling, and appropriateness of analytic methods.

For each cohort listed below, we cite the duplicative articles we reviewed and give our rationale for their inclusion or exclusion. The full citation for each article is provided in the reference section.

Conselice Study of Brain Ageing (CSBA)

We included Ravaglia 2005 but excluded Ravaglia 2007. The analytic cohorts and statistical modeling decisions were very similar, but the results from Ravaglia 2005 were reported in much more detail. Ravaglia 2007 presented a single adjusted estimate for hyperhomocysteinemia, whereas Ravaglia 2005 presented analogous estimates that were adjusted for various sets of covariates, as well as plots from a quartile-based analysis.

Kungsholmen Project

We included Kivipelto 2009 but excluded Annerbo 2009. While the analytic cohorts and covariate adjustments were identical, Kivipelto 2009 reported a detailed quartile-based analysis (comparing each to the lowest) while the Annerbo 2009 results only compared the highest and lowest tertiles of plasma homocysteine. In terms of statistical modeling, Kivipelto 2009 explicitly accounted for censoring through cox-proportional hazards regression; in contrast, Annerbo 2009 study did not specify how censoring was incorporated into the logistic regression analysis.

References

Annerbo S, Kivipelto M, Lökk J. A prospective study on the development of Alzheimer's disease with regard to thyroid-stimulating hormone and homocysteine. Dement Geriatr Cogn Disord. 2009;28(3):275-80.

Kivipelto M, Annerbo S, Hultdin J, Bäckman L, Viitanen M, Fratiglioni L, Lökk J. Homocysteine and holo-transcobalamin and the risk of dementia and Alzheimers disease: a prospective study. Eur J Neurol. 2009 Jul;16(7):808-13.

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 Sep;82(3):636-43.

Ravaglia G, Forti P, Maioli F, Chiappelli M, Montesi F, Tumini E, Mariani E, Licastro F, Patterson C. Blood inflammatory markers and risk of dementia: The Conselice Study of Brain Aging. Neurobiol Aging. 2007 Dec;28(12):1810-20.