Beyond Total Homocysteine: Context-Specific Biomarker Roles and Molecular Phenotypes Across Vascular and Neurological Disorders

Plasma total homocysteine (tHcy) is analytically mature, but its clinical meaning depends on the question the test is intended to answer. This narrative review interprets homocysteine as a context-specific biomarker using the FDA–NIH BEST (Biomarkers, EndpointS, and other Tools) framework, distinguishing susceptibility/risk, diagnostic, prognostic, monitoring, pharmacodynamic, and surrogate-endpoint uses, together with the pre-analytical, renal, nutritional, and pharmacological determinants of routine results. tHcy has established clinical utility as a diagnostic-pathway and monitoring marker in severe inherited homocysteine disorders. In vascular disease, stroke, and cognitive decline, it is a nonspecific susceptibility or prognostic marker, and in selected levodopa- or antiseizure-medication users, a candidate treatment-associated monitoring marker. It is not a diagnostic biomarker for Alzheimer’s or Parkinson’s disease, and reliable biochemical lowering by B vitamins has not translated consistently into clinical benefit, so it is not a qualified surrogate endpoint. We propose five molecular homocysteine phenotypes—remethylation-deficient, transsulfuration-deficient, renal-retention, treatment-related methylation, and protein-modification—as a hypothesis-generating conceptual framework that has not been empirically validated. Each phenotype is specified by routine measurements and exploratory analytes; S-adenosylmethionine, S-adenosylhomocysteine, homocysteine-thiolactone, and N-homocysteinylated proteins remain research tools. A tiered testing framework and a staged validation roadmap are proposed, both requiring prospective evaluation before clinical implementation.