Beauty and the beast

Pernicious anemia was described 100 years before formulation of liver extracts to correct the fatal disorder. Later, the elucidation of the crystalline structure of vitamin B₁₂ (cobalamin) and recognition of its beautiful ruby color resulted in its description as “nature's most beautiful co-factor.”¹ These discoveries led to 2 Nobel prizes, for Minot, Murphy, and Whipple in 1934 (Physiology or Medicine), and for Hodgkins in 1964 (Chemistry), only the third woman to win a Nobel in Chemistry.

Although low B₁₂ levels had long been known to cause neurologic disease, Lindenbaum and colleagues² uncovered B₁₂-responsive neuropsychiatric conditions in persons without macrocytic anemia, some with normal circulating B₁₂ levels (>200 pg/mL or >150 pmol/L). Vitamin B₁₂ is an essential cofactor for the activation of methionine into S-adenosyl methionine (SAM), the primary methyl donor for most neuronal methylation reactions, including synthesis of catecholamine neurotransmitters, proteins, nucleic acids, phospholipids, and myelin. Homocysteine is an essential intermediary metabolite in this pathway and elevated plasma total homocysteine (tHcy) invariably accompanies low B₁₂ levels. Beginning in the 1990s, a series of observational case-control and cohort studies associated elevated tHcy with an increased risk of stroke, cognitive decline, and dementia, including Alzheimer disease (AD). These associations were generally more robust than those …