Hyperhomocysteinemia and Its Role in Cognitive Impairment and Alzheimer's Disease

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.

HHcy may be caused by several factors including age, renal failure, genetic polymorphisms, dietary habits and lifestyle conditions. It has been demonstrated that high levels of Hcy might be able to cause neuronal damage through different mechanisms: induction of oxidative stress, impaired synthesis of NO in the endothelium with structural and functional changes in cerebral microcirculum, homocysteinilation, excitation of NMDA receptors, upregulation of the γ-secretase pathway with enhanced production of Aβ and selective activation of the cyclin-dependent kinase 5 with consequent hyperphosphorylation of tau, reduction of Aβ clearance and transport within the brain by down-regulation of IDE, induction of ER stress and epigenetics modifications.

Some authors have also hypothesized a direct toxic action of Hcy on neuronal and glial cells.

Several studies investigated the association between HHcy and the risk of cognitive decline and AD. Most of retrospective and cross-sectional studies showed an evidence of increased risk of cognitive decline in patients with high levels of Hcy when compared to matched controls, but this kind of investigations are not able to determine whether HHcy can act as a causative factor of cognitive decline/dementia or if it is a result of the disease. Most of prospective studies, performed in different populations, also showed that high levels of Hcy were associated with a higher risk of cognitive decline. On the other hand, intervention trials with Hcy lowering treatments such as supplementation of vitamin B12, B6, folic acid and antioxidants showed inconsistent results in terms of cognitive outcomes. It seems that the threshold level of Hcy could play an important role. Indeed, more positive responses have been observed in trials with higher baseline levels of Hcy [45,46]. Moreover, the timing of intervention would play an important role as a greater effect may be obtained with early stage supplementation that can act before neuronal death has already happened. On the other side, vitamin supplementation could be an “add on” therapeutic strategy in dementia patients, as the pharmacological approach to manifest disease should be multifactorial.

With population aging, cognitive decline and dementia have become important issues for health and socio-economic systems. As a disease modifying therapy is still not available for clinicians, further investigations in the field of preventive strategies could be of great importance.

Dosing vitamin B12, folate and Hcy should routinely be performed in middle aged/elderly people and in subjects with early signs of cognitive impairment. Subjects with HHcy should receive dietary and lifestyle indications in order to try to lower Hcy levels. The clinicians will then evaluate the opportunity of prescribing a supplementation therapy, especially for moderate/severe HHcy, after having examined the risk/benefit balance for each patient.

In conclusion, further and better designed clinical trials and good animal models of HHcy would be useful in order to establish a conclusive opinion on the link between HHcy and the decline of cognitive functions.

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