Homocysteine (Hcy) is a sulfur-containing non-essential amino-acid produced as the result of the metabolism of the essential amino-acid methionine. Hcy levels are influenced by several factors, including age, renal function, genetic polymorphisms, dietary habits and lifestyle conditions. Increased plasma level of Hcy is defined as Hyperhomocysteinemia (HHcy). HHcy has been linked to several pathological conditions; among them cognitive decline and neurodegenerative diseases are receiving increasing attention by scientific investigations. The aim of this review was to discuss the pathological mechanisms, mostly investigated by basic research and animal models that HHcy is able to trigger in the brain and reporting the latest studies that examine the association between HHcy and cognitive decline/dementia. Moreover, we included a review of the recent clinical trials investigating the efficacy of Hcy lowering therapies on cognitive outcomes.
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