Uncovering Hyperhomocysteinemia: Global Risk Patterns and Molecular Disruption in Brain and Vascular Health

Hyperhomocysteinemia (HHcy), a condition characterized by elevated plasma levels of the sulfur-containing amino acid homocysteine, has emerged as a multifactorial and systemic risk factor with profound effects on neural and vascular integrity. This review integrates recent findings from epidemiological studies, clinical data, and mechanistic research to provide a comprehensive overview of HHcy's contribution to neurovascular dysfunction. We examine how nutritional deficits, aging, genetic polymorphisms-such as in the methylenetetrahydrofolate reductase (MTHFR) and cystathionine beta-synthase (CBS) genes-pharmacological agents, and comorbid conditions shape homocysteine homeostasis and susceptibility to pathology. Emphasis is placed on molecular pathways, including oxidative and nitrative stress, inflammasome activation, autophagy, and epigenetic modulation, which link HHcy to cognitive decline, memory impairment, endothelial dysfunction, and increased disease burden in neurodegenerative disorders. By consolidating multidisciplinary evidence, we position HHcy as a pivotal but under-recognized target for intervention in neurochemical and vascular health.