Hyperhomocysteinemia and Its Role in Cognitive Impairment and Alzheimer's Disease: Recent Updates from the Literature


Homocysteine (Hcy) is a sulfur-containing non-essential aminoacid produced as the result of the metabolism of the essential amino-acid methionine. Optimal methionine metabolism is vital to a great number of biochemical processes in the body. Hcy is normally metabolized via two biochemical pathways: remethylation, which converts Hcy back to methionine via the folate cycle, which is catalyzed by the enzyme methylenetetrahydrofolate reductase (MTHFR) and the essential cofactor vitamin B12, and trans-sulfuration, which converts Hcy to cysteine (Cys) via cystathionine beta synthase (CBS) and the essential cofactor vitamin B6. Therefore, these two metabolic pathways balance the level of methionine and Hcy.

A high level of plasma Hcy is defined as Hyperhomocysteinemia (HHcy). The normal range of Hcy plasma levels varies with age. In any case, the clinically acceptable concentration should be <12- 15 μmol/L. Several factors are able to influence the levels of Hcy. The dietary intakes of methionine, as well as folates and vitamin B12 levels are the principal determinants of the physiologic levels of Hcy .Lifestyle conditions such as excessive coffee or alcohol consumption, cigarette smoking and physical inactivity as well as overweight seem to be associated to higher levels of Hcy , even if some authors reported that modifications in plasma Hcy levels were not associated with changes in dietary habits, physical activity, smoking status, coffee, tea, total alcohol or wine consumption .Impaired renal and thyroid function can cause HHcy.

 Renal failure (which is often associated with diabetes mellitus) could also explain, at least in part, the wide range of Hcy levels reported in diabetic patients, even if the link between Hcy and diabetes needs further investigation. Moreover, genetic factors can influence Hcy concentrations. The MTHFR locus is mapped on chromosome 1 at the end of the short arm (1p36.6). This enzyme is crucial for the folate metabolism, as previously described. The common MTHFR C677T polymorphism, which results in the amino-acid product changing from alanine to valine, affects the activity of the enzyme and hence folate distribution.

Homozygous mutated subjects have higher Hcy levels while the heterozygous mutated subjects have mildly raised Hcy levels when compared with the normal non-mutated controls. Another MTHFR polymorphism has been described: the A1298C, which changes a glutamate into an alanine residue. This mutation results in decreased MTHFR activity, which is more pronounced in the homozygous than heterozygous state. Anyway, neither the homozygous nor the heterozygous state is associated with higher plasma Hcy or a lower plasma folate concentration, which is evident with homozygosity for the C677T mutation. However, it has been reported an interaction between these two common mutations.

Effects of HHCY in the brain

Several mechanisms have been proposed to explain the known Hcy neurotoxicity. Oxidative stress is generated during oxidation of free thiol group of Hcy. Several mechanisms have been hypothesized for Hcy-induced oxidative stress: auto-oxidation, inhibition of cellular antioxidant enzymes, nitric-oxide (NO)- synthase dependent generation of superoxide anion, disruption of extracellular superoxide dismutase from endothelial surfaces, activation of Nicotinamide-Adenine Dinucleotide Phosphate (NADPH)-oxidase.

 Hcy induced oxidative stress may result in the production of reactive oxygen species with consequent oxidation of proteins, lipids and nucleic acids, which may lead to endothelial dysfunction and damage to vessel wall with subsequent platelet activation and thrombus formation . It is also important to mention Hcy relation with glutathione (GSH) synthesis, which is one of the most important antioxidants in human cells. GSH biosynthesis is Cys dependent. It has been hypothesized that trans-sulfuration pathways could be less functional in the brain since a reduced expression of cystathionine γ-lyase in neurons leads to a higher susceptibility of the brain itself to oxidative damage. Impaired syntheses of NO in the endothelium as well as increased production of asymmetric dimethylarginine and activated oxygen species are involved in the impairment of vasodilator effects of NO; this could impair brain circulation with the consequence of triggering or enhancing neurodegenerative processes.

The conversion of Hcy to Homocysteine thiolactone (HcyTLN) followed by protein structure modifications (homocysteinilation) largely contributes to Hcy toxicity. HcyTLN, an intramolecular thioester of Hcy, is synthesized by methionyl-tRNA synthetase in an error-editing reaction that prevents translational incorporation of Hcy into proteins. HcyTLN reacts with proteins by a mechanism involving homocysteinylation of protein lysine residues; this mechanism seems to lead to several detrimental effects like immune activation, autoimmune inflammatory response, excitotoxicity and apoptosis of neuronal cells, amyloid-beta (A- β) deposition as well as predisposition of N-homocysteinylatyed proteins to aggregation and precipitation.

Hyperhomocysteinemia and cognitive functions

HHCY and mild cognitive impairment: Mild cognitive impairment (MCI) is an intermediate pathological condition between normal aging and definite dementia. It affects memory, language, thinking and judgment with greater symptoms when compared to normal age-related changes. Generally, these modifications are not severe enough to significantly interfere with basic activities of daily living. A minimal impairment in complex instrumental functions could be demonstrated. For the diagnosis of MCI, the patient must not meet the criteria for dementia. MCI is a heterogeneous entity, with possible evolutions including AD, other types of dementia, and even reversion to normal cognitive functioning. The transition from MCI to dementia is usually gradual. Several studies evidenced that HHcy is associated with this transition.

HHCY and alzheimer’s disease (AD): AD is a neurodegenerative disease, which results from the deposition of Aβ peptides and a form of tau protein. The primary cause of this multifactorial disease is the accumulation of Aβ, a peptide cleaved from the APP by the stepwise enzymatic action of the beta-secretase (BACE-1) and gamma-secretase. Regland et al. in 1990 first reported elevated Hcy levels in primary degenerative dementia patients.

 summarized the findings from observational and intervention trials with a minimal sample of 50 subjects published until 2011 on the association between HHcy and AD. Among retrospective studies, at least 12 reported higher Hcy levels in AD patients when compared to age-matched healthy controls. On the contrary, three studies reported no difference in plasma or cerebral spinal fluid Hcy levels between AD patients and controls. Among the 12 reported prospective studies, 10 found that HHcy was a risk factor for AD or cognitive decline, while only 2 did not report any association between HHcy and AD/cognitive decline.

 The authors reported that HHcy in AD patients was caused by cobalamin/folate deficiency or renal impairment, therefore they hypothesized that HHcy was not involved in the pathogenesis of AD.


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. 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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