Increased plasma total homocysteine (tHcy) is a risk factor for neurological diseases, but the underlying pathophysiology has not been adequately explained. We evaluated concentrations of tHcy, S-adenosyl homocysteine (SAH), S-adenosyl methionine (SAM), folate, and vitamin B(12) in cerebrospinal fluid (CSF) and plasma or serum from 182 patients with different neurological disorders. We measured concentrations of phosphorylated tau protein (P-tau)((181P)) and beta-amyloid(1-42) in the CSF. Aging was associated with higher concentrations of tHcy and SAH in the CSF, in addition to lower concentrations of CSF folate and lower SAM:SAH ratio. Concentrations of CSF SAH and CSF folate correlated significantly with those of P-tau (r = 0.46 and r = -0.28, respectively). Moreover, P-tau correlated negatively with SAM:SAH ratio (r = -0.40, P <0.001). The association between SAH and higher P-tau was observed in 3 age groups (<41, 41-60, and >60 years). CSF tHcy was predicted by concentrations of CSF cystathionine (beta = 0.478), folate (beta = -0.403), albumin (beta = 0.349), and age (beta = 0.298). tHcy concentration in the brain is related to age, B vitamins, and CSF albumin. Increase of CSF SAH is related to increased CSF P-tau; decreased degradation of P-tau might be a plausible explanation. Disturbed methyl group metabolism may be the link between hyperhomocysteinemia and neurodegeneration. Lowering tHcy and SAH might protect the brain by preventing P-tau accumulation.