Homocysteine And Dementia

The utility of standard laboratory tests in the work-up of dementia and the true prevalence of potentially reversible etiologies has been examined by several authors. Recent evidence suggests an association between several specific nutrient excesses and deficiencies and AD, including alcohol abuse, vitamin B12 and folate deficiency and elevated total homocysteine levels. The exact nature and significance of this association remains uncertain. Three possible explanations exist for this association:

(1) 'Low-intake' hypothesis—cobalamin deficiency develops secondarily to impaired nutritional intake due to dementia.

(2) The 'common pathophysiology' hypothesis— there is a related mechanism for development of both AD and cobalamin deficiency.

(3) The 'etiological' hypothesis—the cobalamin deficiency itself contributes to the dementia.

Homocysteine metabolism is absolutely dependent on five B-complex vitamins: Bj, B2, B6, B12 and folate. Total homocysteine is a useful indicator of a subtle and early cobalamin-deficient state, as tissues cannot utilize this amino acid in the usual manner. Homocysteine has been shown to be associated with cardiovascular disease,88 such as heart attack and stroke. It is also an important emerging risk factor for AD and cognitive dysfunction in the elderly.89 Several associations also have been observed for cognitive impairment in the elderly.90 Whether vitamin B12 deficiency can alter the clinical presentation of DAT or contribute to its pathology is not clear.91 Vitamin B12 levels reflect multiple environmental causes, such as diet and reduced access to preventive medicine. In Wadi Ara, high levels of total homocysteine in both the control and demented cases and low levels of folic acid and vitamin B12 that were observed also in our study had no associations with DAT. It is well known that high total homocys-teine is a risk factor for vascular damage88,92 and possibly for dementia.89,93,94 The fact that such a relationship has not been observed by us is of interest. High levels are not considered to be causative for AD by themselves, but rather to be important factors in the pathogenesis of this multi-factorial disorder. The high prevalence of elevated total homocysteine levels in the general population of Wadi Ara thus may set the stage for other factors to set in and cause dementia.

The available information on risk factors for DAT (aging, genetic predisposition, lack of education, female gender, head injury and vascular risk factors), and microscopic pathology of DAT (amyloid plaques, NFTs) suggest that DAT is a clinical syndrome which can arise from a variety of causes. The relationship between genes and environmental risk factors in complex disorders (e.g. stroke,

Parkinson's disease and DAT) is a subject of great interest to investigators and is responsible for the growth in the discipline of genetic epidemiology. Thus, both genes and environment are important in AD susceptibility.

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