The Role of B Vitamins, Homocysteine in AD and Vascular Dementia

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 [1999] or Finkelstein [1990] 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.

Epidemiological Observations

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).

Possible Causative Risk

These epidemiological observations are consistent with the view that vascular dementia and AD share some common pathological mechanisms. The role of hyperhomocysteinemia is particularly interesting in this context, because plasma homocysteine can be safely lowered by relatively inexpensive nutritional intervention and vitamin supplements, which could conceivably reduce the associated risk (Homocysteine Lowering Trialists' Collaboration, 1998; Selhub et al., 2000b). However, association does not prove causality. Alternative explanations include the possibilities that these associations are secondary to disease-related metabolic disturbances, or the trivial explanation that they reflect a reduction in dietary intake with increasing severity of cognitive decline and dementia (Riviere et al., 1999). Even the early rise in homocysteine levels, which seems to increase the likelihood of subsequent dementia, could be secondary to other disease-related processes (Brattstrom and Wilcken, 2000). Nevertheless, elevated plasma homocysteine apparently reflects an early involvement of impaired one-carbon metabolism in AD (Figure).

In order to validate homocysteine as a causative risk factor for AD, two conditions must be satisfied: the epidemiological association must be shown to be causal, and the pathological mechanism underlying this association must be elucidated. Satisfying both conditions requires the application of complementary epidemiological and biochemical approaches to the problem.

Demonstrating causality can only be done in an experimental study by reducing the exposure of a treatment population to homocysteine while holding all other factors constant. Currently, several trials are planned or underway to test the benefit of B vitamin supplementation in lowering homocysteine and, in turn, preventing dementia or slowing its progression. Successful outcomes will support a causal role for homocysteine in AD and point to a considerable public health benefit of homocysteine-lowering. If, however, the trials successfully lower homocysteine without preventing cognitive decline, the relation of homocysteine to AD will remain uncertain.

A variety of theoretical mechanisms have been invoked to account for the association of homocysteine with AD and cognitive decline (see Selhub et al. [2000a] for a review). Homocysteine might contribute to thromboembolism of large vessels through damage to the endothelial cells that line the vessels, or by harming the brain capillaries (composed of a single layer of endothelial cells) that make up the blood-brain barrier. Homocysteine might also poison groups of neurons that have N-methyl-D-aspartate receptors (e.g., hippocampal pyramidal cells that are particularly vulnerable to AD pathology) (Lipton et al., 1997). There is considerable experimental evidence (largely in vitro) supporting such cytotoxic effects of homocysteine, but their relevance in vivo is uncertain, particularly in the brain where they have never been tested.

Alternatively, elevated plasma homocysteine might reflect the accumulation in the cells of its precursor, S-adenosylhomocysteine (SAH), a potent inhibitor of methylation reactions. Several important neurological processes require methylation, which, if disrupted significantly, could have a profound impact on neurological function. Furthermore, impaired one-carbon metabolism has also been linked to DNA damage (Duan et al. 2002; Kruman et al., 2002; Kruman et al., 2000) and altered metabolism of biogenic amines (e.g., dopamine, norepinephrine, serotonin) (Gospe et al., 1995; Hamon et al., 1986). Folate and vitamin B12 are necessary cofactors for normal brain metabolism, and severe deficiencies of either one will directly impair neurological function. This necessity, together with their intimate metabolic relationship to homocysteine, makes it difficult to dissociate the putative toxicity of homocysteine from the potentially harmful effects of inadequate folate or vitamin B12 status.

These and other questions will need to be addressed in order to fully understand the observed epidemiological relation of impaired one-carbon metabolism (elevated homocysteine and deficient B vitamins) to AD, and to justify widespread screening for tHcy and population-based vitamin intervention.

References:

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