Beyond Total Homocysteine: Context-Specific Biomarker Roles and Molecular Phenotypes Across Vascular and Neurological Disorders
Year: 2026
Type: article
Abstract: 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.
Source: Biomolecules
DOI: 10.3390/biom16111645
Authors: Ayşegül Sümer, Sera Şahin, Ahmet Menteşe
Language: English
Subfield: Nutrition and Dietetics
Field: Nursing
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,258
OpenAlex ID: W7225819102