Homocysteine metabolism and cerebrospinal fluid markers for Alzheimer's disease.

Disturbed homocysteine metabolism is a risk factor for Alzheimer's disease (AD) and may contribute to the disease pathophysiology by increasing both amyloid-beta (Abeta) 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, Abeta(1-42) 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 epsilon4 allele, P-tau181 was associated with SAH (beta = 0.490; p < 0.001), 5-MTHF (beta = -0.273; p = 0.010) levels, and SAM/SAH ratio (beta = -0.319; p = 0.013) in controls, and with SAH (beta = 0.529; p = 0.001) in AD patients. The levels of Abeta(1-42) 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.