Vitamin B-12 concentration, memory performance, and hippocampal structure in patients with mild cognitive impairment

Am J Clin Nutr. 2016 Apr;103(4):1045-54. doi: 10.3945/ajcn.115.116970. Epub 2016 Feb 24.


Background: Low-normal concentrations of vitamin B-12 (VitB12) may be associated with worse cognition. However, previous evidence has been mixed, and the underlying mechanisms remain unclear.

Objective: We determined whether serum VitB12 concentrations within the normal range were linked to memory functions and related neuronal structures in patients with mild cognitive impairment (MCI).

Design: In a cross-sectional design, we assessed 100 amnestic MCI patients (52 women; age range: 50-80 y) with low- and high-normal VitB12 concentration (median split: 304 pmol/L) for memory functions with the use of the Auditory Verbal Learning Test. MRI was performed at 3 tesla (n= 86) for the estimation of the volume and microstructure of the hippocampus and its subfields as indicated by the mean diffusivity on diffusion-weighted images. With the use of a mediation analysis, we examined whether the relation between VitB12 and memory performance was partially explained by volume or microstructure.

Results: MCI patients with low-normal VitB12 showed a significantly poorer learning ability (P= 0.014) and recognition performance (P= 0.008) than did patients with high-normal VitB12. Also, the microstructure integrity of the hippocampus was lower in patients with low-normal VitB12, mainly in the cornu ammonis 4 and dentate gyrus region (P= 0.029), which partially mediated the effect of VitB12 on memory performance (32-48%). Adjustments for age, sex, education, apolipoprotein E e4 status, and total homocysteine, folate, and creatinine did not attenuate the effects.

Conclusions: Low VitB12 concentrations within the normal range are associated with poorer memory performance, which is an effect that is partially mediated by the reduced microstructural integrity of the hippocampus. Future interventional trials are needed to assess whether supplementation of VitB12 may improve cognition in MCI patients even in the absence of clinically manifested VitB12 deficiency. This trial was registered at as NCT01219244.

Keywords: MCI; episodic memory; hippocampus; mean diffusivity; vitamin B-12.

Publication types

  • Randomized Controlled Trial

MeSH terms

  • Aged
  • Aged, 80 and over
  • Apolipoprotein E4 / blood
  • Cognition / drug effects
  • Cognitive Dysfunction / blood*
  • Cognitive Dysfunction / drug therapy
  • Creatinine / blood
  • Cross-Sectional Studies
  • Female
  • Folic Acid / blood
  • Genotyping Techniques
  • Hippocampus / drug effects*
  • Hippocampus / metabolism
  • Homocysteine / blood
  • Humans
  • Magnetic Resonance Imaging
  • Male
  • Memory / drug effects*
  • Middle Aged
  • Polymorphism, Single Nucleotide
  • Verbal Learning / drug effects
  • Vitamin B 12 / administration & dosage
  • Vitamin B 12 / blood*


  • Apolipoprotein E4
  • Homocysteine
  • Folic Acid
  • Creatinine
  • Vitamin B 12

Associated data