Cobalamin Deficiency and Cognitive Decline: Mechanistic Insights and Clinical Evidence - Abstract
Vitamin B12 (cobalamin) has long been implicated in cognitive health. Observational associations between low B12, elevated Methylmalonic Acid (MMA)
or Homocysteine (Hcy), and cognitive decline have motivated trials of supplementation. The clinical picture is complex. Biochemistry links B12 to methylation,
myelin maintenance, and neurotransmitter synthesis. Observational cohorts show consistent associations between low B12 biomarkers and accelerated cognitive
decline or dementia risk. Randomized Controlled Trials (RCTs) of B12 or B-vitamin combinations show mixed results. Selected trials in high-risk subgroups or
trials that reduced brain atrophy reported positive effects. Large pragmatic trials in unselected older populations generally did not demonstrate clinically
meaningful cognitive benefit. Diagnostic testing is imperfect, and functional deficiency can exist despite “normal” serum B12. Treatment is safe and corrects
hematological and some metabolic abnormalities, but neurological recovery is variable and often partial if treatment is delayed. Recent mechanistic and
imaging data suggest that benefit is most likely when supplementation is applied early, in subjects with biochemical deficiency or elevated Hcy, and perhaps
Highlights
when co-factors (folate, B6, omega-3 fatty acids) are adequate. This review synthesizes biochemical, epidemiological, clinical, interventional, diagnostic, and
therapeutic evidence and outlines priorities for research and practice.
• Vitamin B12 deficiency is a frequent, underdiagnosed condition in older adults and a reversible cause of neurological impairment.
• The relationship between vitamin B12 status and cognitive decline remains controversial; recent evidence challenges the belief in a direct causal link.
• Elevated homocysteine and methylmalonic acid are stronger predictors of cognitive impairment than serum B12 concentration alone.
• Interventional trials show that B12 supplementation improves cognition only in truly deficient individuals, not in the general elderly population.
• Future research should focus on functional biomarkers and combined nutritional-neurovascular pathways rather than isolated vitamin supplementation.