Homocysteine Metabolism and Cerebrospinal Fluid Markers for Alzheimer's Disease

Article type: Research Article

Authors: Popp, Julius^{a; *} | Lewczuk, Piotr^b | Linnebank, Michael^c | Cvetanovska, Gabriela^a | Smulders, Yvo^d | Kölsch, Heike^a | Frommann, Ingo^a | Kornhuber, Johannes^b | Maier, Wolfgang^a | Jessen, Frank^a

Affiliations: [a] Department of Psychiatry, University of Bonn, Bonn, Germany | [b] Department of Psychiatry, University of Erlangen, Erlangen, Germany | [c] Deptartment of Neurology, University of Zurich, Zürich, Switzerland | [d] VU University Medical Center Amsterdam, Dept. Internal Medicine and Metabolic Unit, Amsterdam, The Netherlands and Institute for Cardiovascular Research – ICaR-VU, Amsterdam, The Netherlands

Correspondence: [*] Address for correspondence: Julius Popp, MD, Department of Psychiatry, University of Bonn, Sigmund-Freud-Strasse 25, 53105 Bonn, Germany. Tel.: +49 228 287 16367; Fax: +49 228 287 19419; E-mail: Julius.Popp@ukb.uni-bonn.de.

Abstract: Disturbed homocysteine metabolism is a risk factor for Alzheimer's disease (AD) and may contribute to the disease pathophysiology by increasing both amyloid-β (Aβ) production and phosphorylated tau (P-tau) accumulation. Here, we evaluated the relationship between the cerebrospinal fluid (CSF) concentrations of homocysteine (Hcys), S-adenosylmethionine (SAM), S-adenosylhomocysteine (SAH), and 5-methyltetrahydrofolate (5-MTHF), and the markers for AD pathology, Aβ1-42 and P-tau181, in 98 cognitively healthy subjects aged 16-81 years and 54 AD patients. In multivariate regression tests including age, gender, creatinine, and presence of the apolipoprotein E ε4 allele, P-tau181 was associated with SAH (β = 0.490; p < 0.001), 5-MTHF (β = -0.273; p = 0.010) levels, and SAM/SAH ratio (β = -0.319; p = 0.013) in controls, and with SAH (β = 0.529; p = 0.001) in AD patients. The levels of Aβ1-42 were not associated with the CSF concentrations of Hcys, SAM, SAH, or 5-MTHF neither in the AD nor in the control group. The results suggest that alteration of the homocysteine metabolism is related to increased accumulation of phosphorylated tau and may contribute to the neurofibrillary pathology in normal aging and in AD.

Keywords: Alzheimer's disease, amyloid-β, cerebrospinal fluid, homocysteine, phosphorylated tau

DOI: 10.3233/JAD-2009-1187

Journal: Journal of Alzheimer's Disease, vol. 18, no. 4, pp. 819-828, 2009