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.


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.

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.

Zhuo et al.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.

In the previously reported study by Nillson et al.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.

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