Homocysteine and cognition--a historical perspective.

The discovery of a relationship between homocysteine and cognition stems from clinical observations of an association between vitamin B12 and folate deficiency and cognitive dysfunction. This retrospective details the history of vitamin B12 and folic acid and the conceptual evolution of their association with dementia. The hematological and neuropsychiatric manifestations of these deficiencies are discussed, together with the nature of their relationship with dementia, generalized cognitive decline and discrete neuropsychological function. An evaluation of the potential of reversing "homocysteine-associated" and/or "vitamin-associated" cognitive decline raises questions as to whether current interventions can unequivocally determine if homocysteine independently impacts on cognitive function. Alternative approaches specifically designed to address this issue are discussed.