Impact of Alterations in Homocysteine, Asymmetric Dimethylarginine and Vitamins-Related Pathways in Some Neurodegenerative Diseases: A Narrative Review

Abstract

Hyperhomocysteinemia (HHcy) influences the development and progression of neurodegenerative disorders in different ways. Homocysteine (Hcy) metabolism is related to that of asymmetric dimethylarginine (ADMA) and group B vitamins. The breakdown of the pathway involving nitric oxide (NO) and ADMA can be considered one of the causes of endothelial alteration that represents a crucial step in the development of several neurodegenerative disorders. Deficiencies of vitamins other than group B ones, such as D and A, have also been associated with central nervous system disorders. The aim of this narrative review is to describe the link between HHcy, ADMA, and vitamins in Parkinson's disease (PD), Alzheimer's disease (AD), and multiple sclerosis (MS) in terms of dysfunctional pathways and neuropathological processes, performing a literature search from 2015 to 2025 on PubMed. This review also provides an overview of the effects of vitamin supplementation on neurodegenerative diseases. The alteration of pathways involving NO production can lead to HHcy and elevated ADMA concentrations, causing neurodegeneration through various mechanisms, while vitamin supplementation has been shown to reduce Hcy levels, although with conflicting results about the improvement in clinical symptoms. Further studies are needed to develop optimal combined therapeutic strategies.

Keywords: Alzheimer’s diseases; Parkinson’s disease; asymmetric dimethylarginine; hyperhomocysteinemia; multiple sclerosis; vitamins.

Figure 1

Relationships between methionine–homocysteine metabolism and ADMA and NO synthesis pathways. THF, tetrahydrofolate; CH₂THF, 5,10-methylenetetrahydrofolate; CH₃THF, 5-methyltetrahydrofolate; MTHFR, methylenetetrahydrofolate reductase; MeSe, methionine synthase; BHMT, betaine-homocysteine methyltransferase; DMG, dimethylglycine; SAM, S-adenosyl methionine; SAH, S-adenosyl homocysteine; ADMA, asymmetric dimethylarginine; DDAH, dimethylarginine dimethylaminohydodrolase; NOS, nitric oxide synthase; NO, nitric oxide.

Figure 2

Effects of physiological and supraphysiological concentrations of ADMA on biological systems. ADMA, asymmetric dimethylarginine; BBB, blood–brain barrier; HHcy, hyperhomocysteinemia; NO, nitric oxide; ONOO−∙, peroxynitrite.

Figure 3

Flow chart describing the process used to identify and select relevant publications.