Title: Homocysteine and Alzheimer’s disease

 

Key words: Alzheimer’s, micronutrient, deficiency, genetic, macronutrient, vitamin C, vitamin E, homocysteine, atherosclerosis, hyperhomocysteinaemia, cardiovascular disease, CVD, temporal lobe, atrophy, memory loss, cognitive dysfunction, impairment, neurological damage, lesions, brain, homocysteic acid, carotid arteriopathy, neurotoxic, B12, folate, B6, zinc, trimethylglycine, riboflavin, polymorphisms, multivitamins, minerals, antioxidants, aging, ageing

 

Date: Sept 2006

 

Category:

 

Nutrimed Module:

 

Type: Article

 

Author: Morgan, G

 

Homocysteine and Alzheimer’s disease

 

Alzheimer’s disease is a disease of old age and has been linked to cardio-vascular disease, genetic factors and macronutrient deficiencies. Micronutrient deficiencies have also been shown to be important. Vitamin C and E nutritional status, in particular, have been shown to be important, though the results of trials looking at the effects of supplementation with these vitamins have been conflicting (Engelhart MJ 2002, Laurin 2002). This article will review the pivotal role played by homocysteine and associated micronutrient deficiencies in the pathogenesis of Alzheimer’s disease, arguing that modulation of these factors is central to a nutritional understanding of the disease and that supplementation may hold out the prospect of being able to prevent or control the disease. Research into the key role played by homocysteine in Alzheimer’s is probably the most significant finding of recent research in this area.

 

The inflammatory and degenerative pathophysiology of both atherosclerosis and Alzheimer’s disease is now well recognised (Ross 1999, Budge 2002). Common to these associations is hyperhomocystinaemia. Its link to cardiovascular disease has been widely documented (Stampfer 1992, Graham 1997). More recent associations with memory loss, cognitive dysfunction, vitamin deficiencies and Alzheimer’s disease have been described, which are both age and dose related (Riggs 1996, Clarke 1998, Kalmijn 1999, Lehman 1999, Morris 2001). Elevated homocysteine levels have been linked to progressive neurological damage leading to characteristic histological lesions in the brain such as temporal lobe atrophy (Clarke 1998, Williams 2002, Smith 2003). Research has shown that one of homocysteine’s metabolites, homocysteic acid, is directly toxic to neuronal cells (Kruman 2000). The close link with cardiovascular disease is illustrated by the fact that both carotid arteriopathy, vascular and non-vascular Alzheimer’s disease are closely correlated with elevated homocysteine levels (Bell 1992, Kritchevsky 1995, McCaddon 1998). This indicates that both vascular and neurotoxic mechanisms play a role in the aetiology of Alzheimer’s disease.

 

Homocysteine has been shown to act as an independent risk factor in cardiovascular disease (Graham 1997). Its role in Alzheimer’s disease has been demonstrated in an 8 year prospective study in an at risk age group, the incidence of Alzheimer’s doubling in those whose homocysteine level was in the upper quartile at baseline (Seshadri 2002). Correlations with key vitamin cofactors, principally vitamin B12, folate and vitamin B6, also indicate the important role played by homocysteine in Alzheimer’s disease (Lindenbaum 1988, Riggs 1996, Clarke 1998, Selhub2000). The question arises as to whether homocysteine is acting as an independent risk factor in Alzheimer’s or merely serving as a marker for underlying micronutrient deficiencies. B12, folate and B6, key cofactors in homocysteine metabolism, have all been linked independently with the cognitive changes characteristic of Alzheimer’s (Refsum 2003, Wang 2001, Bates 1999). In addition, brain atrophy associated with the disease has been linked to folate deficiency (Snowdon 2000). In general, however, supplementation with these individual vitamins has not produced marked reductions in homocysteine levels (Malinow 2001, Koyama 2002).

 

Multivariate analysis of the data shows that correlations between individual vitamins and cognitive markers become less once other cofactors are factored in as covariates (Bates 1999). Such analyses have shown homocysteine to be the single most important independent variable in determining the cognitive decline of Alzheimer’s disease. This is born out by the greater response to combinations of these vitamins and related cofactors, such as zinc, trimethylglycine and riboflavin, both in terms of correction of homocysteine levels and in terms of atherogenesis-related disease end points (Franken 1994, Clarke 1998, Koyama 2002). Recent work by Duthie (Duthie 2002) has shown that there is a strong association between cognitive indices at age 11 and the incidence of Alzheimer’s disease at age 78, homocysteine levels at age 78 contributing some 8% of the variance of the cognitive score.

 

The ApoE4 phenotype and methylenetetrahydrofolate reductase (MTHFR) deficiency are the two most prevalent genetic polymorphisms associated with atherosclerosis, elevated homocysteine levels, and Alzheimer’s disease (Hoffman 1997, Ashfield- Watt 2002). They affect 25% and 10% of the population respectively (Singh 1985, Ashfield-Watt 2002). Diet is known to modify the expression of these polymorphisms and, in the case of MTHFR deficiency to be reduced by folic acid and riboflavin supplementation (Ashfield-Watt 2002, McNulty 2002). Long-term use of multivitamins has already been linked to a halving of homocysteine levels in the general population (Kato 1998).

 

Controlled prospective trials, allowing for confounding factors, looking at the ability of combinations of homocysteine-lowering vitamins, minerals, and other antioxidants, to modify the evolution of Alzheimer’s disease would appear to be indicated in the light of this evidence. It may well be the case that by giving supplements from an early age it might be possible to prevent the development of Alzheimer’s disease in significantly more than 8% of the population, given our present understanding of cardiovascular and Alzheimer’s as being vitamin, mineral and antioxidant-dependent diseases. The case is more pressing given the declining level of nutrition and the increasing incidence of Alzheimer’s disease in an ageing population.

 

 

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