Functional vitamin B12 deficiency and Alzheimer disease

Moderately elevated total serum homocysteine is associated with an increased risk of atherothrombotic vascular events. Accordingly, serum homocysteine is increased in patients with vascular dementia but is also increased in clinically diagnosed and histologically confirmed AD. It is generally considered that homocysteine potentiates endothelial and neuronal oxidative injury in these diseases. A complementary model of oxidative stress-induced hyperhomocystinemia is proposed by the authors. The hypothesis accounts for several unusual features relating to single-carbon metabolism and AD, including the absence of macrocytic anemia in these patients. It is suggested that cerebral oxidative stress augments the oxidation of an intermediate form of vitamin B-12 (cob[I]alamin) generated in the methionine synthase reaction, thereby impairing the metabolism of homocysteine. Oxidative stress also compromises the intraneuronal reduction of the vitamin to its metabolically active state. Currently available pharmaceutic forms of vitamin B-12 are unlikely to be utilized by neurons under these conditions. Glutathionylcobalamin might be preferential for the treatment of such patients.