<jats:title>Abstract</jats:title><jats:p>Background: Increased plasma total homocysteine (tHcy) is a risk factor for neurological diseases, but the underlying pathophysiology has not been adequately explained.<jats:p>Methods: We evaluated concentrations of tHcy, S-adenosyl homocysteine (SAH), S-adenosyl methionine (SAM), folate, and vitamin B12 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 β-amyloid(1–42) in the CSF.<jats:p>Results: 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 &lt;0.001). The association between SAH and higher P-tau was observed in 3 age groups (&lt;41, 41–60, and &gt;60 years). CSF tHcy was predicted by concentrations of CSF cystathionine (β = 0.478), folate (β = −0.403), albumin (β = 0.349), and age (β = 0.298).<jats:p>Conclusions: 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.