Alzheimer's disease (AD) is a devastating and debilitating neurodegenerative condition, and the most common cause of dementia among the elderly. Despite considerable advances in the cellular and molecular biology of AD, however, little progress has been made in identifying the causes of the disease. Both the canonical plaques and tangles correlate poorly with the extent of cognitive decline, and it is unclear whether they themselves are the primary culprits or rather markers of a later stage in a disease process (Joseph et al., 2001). If the latter is true, then concomitant pathologies such as cerebrovascular disease may be significant contributors to the disease even if they are neither necessary nor sufficient for plaque and tangle formation. Indeed, AD and cerebrovascular disease frequently overlap (de la Torre, 2002; Kalaria and Ballard, 1999; Moody et al., 1997), and the presence of such pathology contributes synergistically to the severity of cognitive impairment, beyond what would be predicted on the basis of the AD pathology alone (Nagy et al., 1997). In this context, recent epidemiological evidence for an association of AD with elevated serum total homocysteine (tHcy) and low levels of B vitamins is of considerable interest (Clarke et al., 1998; Seshadri et al., 2002; Snowdon et al., 2000).
Elevated tHcy is a recognized risk factor for vascular disease (Boushey et al., 1995; Clarke et al., 1991), cerebrovascular disease (Brattstrom et al., 1984; Yoo et al., 1998), stroke (Bostom et al., 1999a) and all-cause morbidity (Bostom et al., 1999b). Homocysteine is a non-protein-forming, sulfur-containing amino acid, produced by the body as it metabolizes the essential amino acid methionine. Homocysteine is metabolized by two pathways: methylation, in which methionine is synthesized using folate and vitamins B12, B6 and B2, and transsulfuration, in which vitamin B6 is a cofactor in the degradation of homocysteine (see Figure, as well as Selhub  or Finkelstein  for review).
Homocysteine metabolism is regulated by the cell to maintain a balance between the methylation and transsulfuration pathways and to maintain low levels of this potentially cytotoxic amino acid (Brattstrom et al., 1994; Brattstrom et al., 1988; Finkelstein, 1990). Barring kidney malfunction, the occurrence of hyperhomocysteinemia indicates that homocysteine metabolism has been disrupted and that the export mechanism is disposing excess cellular homocysteine into the blood. This response prevents toxicity to the cell, but leaves vascular tissue exposed to the potentially harmful effects of excess homocysteine.
Hyperhomocysteinemia can occur as a result of a nutritional deficiency of one or more of the vitamins that participate in homocysteine metabolism. Excess dietary methionine, found primarily in meat and dairy products, can also raise plasma homocysteine levels.
In a longitudinal case-control study, Clarke et al. (1998) calculated a risk ratio of 4.5 for histologically confirmed AD associated with serum total homocysteine in the upper third of homocysteine values, after controlling for age, sex, social class, smoking and apolipoprotein E (APO E)/4 genotype. When also controlling for folate and B12, the risk ratio rose to 5.1, suggesting that homocysteine's effects were (at least partially) independent of vitamin status. Homocysteine values were found to be relatively stable during three annual follow-ups compared with values at enrollment, were not related to duration of illness or to the severity of dementia prior to enrollment, and predicted the extent of medial temporal lobe atrophy.
We have enlarged these observations in a prospective study of incident AD in 1,092 subjects from the Framingham cohort. In nondemented subjects, plasma tHcy levels of >14 µmol/L at baseline nearly doubled the risk of incident dementia eight years later (Seshadri et al., 2002). After adjusting for age, sex, APO E genotype, vascular risk factors other than homocysteine, and plasma levels of folate and vitamins B12 and B6, the relative risk for all-cause dementia was 1.4 per standard deviation increase in tHcy, either at baseline or eight years earlier. Corresponding relative risks for AD were 1.8 and 1.6, respectively. The risk of AD attributable to a plasma tHcy in the highest age-specific quartile of our population was 16%, which is comparable to the population-attributable risk of having at least one APO E4 allele (Brookmeyer et al., 1998).
Our findings supported a strong graded association between plasma tHcy levels and the risk of developing dementia and AD. These findings may have even broader significance in light of repeated observations associating hyperhomocysteinemia with mild cognitive impairment and poor performance on neuropsychological tests in dementia-free subjects (Duthie et al., 2002; Morris et al., 2001; Nilsson et al., 2001).
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