Homocysteine (Hcy), an intermediate product of methionine (Met) metabolism, is a sulfur-containing non-proteinogenic amino acid. Plasma level is determined by dietary intake of proteins, dysregulation of the Met-Hcy one C-unit metabolism and low vitamin B status. Our study is based on metabolomic, histomorphological and biochemical analysis of blood plasma and brain parenchyma alterations developed in the hHCy conditions induced either by Hcy intraperitoneal injections or by high Met diet. Induction of hHcy alters plasma and hippocampal and cortical metabolome, behavioural and histo-morphological patterns in rats. Changes are likely due to the alterations in “methylation index”, which eventually aggravates the noxious effect of hHcy and high methionine intake. In addition, study provides basic clues into the molecular mechanisms of how hHcy itself, or with combination with ischemic/reperfusion injury (IRI) could endorse development of concurrent neurodegeneration processes. Results also suggest an active role of hHcy in the neuropathological changes, such as amyloid deposition, the occurrence of hyperphosphorylation of tau protein. These patterns are exacerbated if hHCy is combined with global ischemia-reperfusion injury.Prevention of risk factors such as hHcy, ischemic stroke, appear to have important implications for development of neurodegeneration and deserves investigation. Supported by VEGA 274/23 and APVV 15/107