Higher Levels of Vitamin B12 Linked to Healthier Brain Aging

by Anthony Thomas, Ph.D.

Vitamin B-12: Food for Thought!

            Recently published clinical research in The American Journal of Clinical Nutrition [1] showed lower vitamin B12 (B12) status within the normal range (i.e., not deficient) is associated with significantly poorer learning & memory performance, in part due to deterioration of key brain regions critical for memory, compared to higher B12 status in healthy adults with mild cognitive impairment (MCI).  These observations complement previous studies suggesting lower B12 status, even within the normal range, contributes to memory dysfunction [2, 3] and cognitive decline [4], and may indicate the current threshold for B12 supplementation (150 pmol/L)  [5] is inadequate. 


Study Summary

             One hundred adults (50 - 80 years old) with MCI, although with relatively preserved general cognition and no impairment in activities of daily living, were split into 2 groups based on blood B12 concentration (>150 and <300 pmol/L has generally been defined as being in the low-normal range): low-normal (n = 50; 153 - 303 pmol/L) or high-normal (n =50; 304 - 934 pmol/L).  The groups did not significantly differ with regard to age, sex, education, cardiovascular disease risk factors, or gene mutations commonly associated with impaired memory.  Learning & recognition performance (i.e., memory) was tested via the Rey Auditory Verbal Learning Test, and magnetic resonance imaging (MRI) was performed to assess volume & microstructural integrity of sub-regions within the hippocampus (brain regions critical for memory). 

            The low-normal B12 group had significantly different blood markers of B12 metabolism compared to the high-normal B12 group: reduced folate and holotranscobalamin & increased total homocysteine (tHcy) and methylmalonic acid (MMA).  Subjects in the low-normal B12 group showed significantly poorer memory performance, specifically in learning-ability and recognition scores, compared to the high-normal B12 group.  Furthermore, those in the low-normal B12 group had significantly worse microstructural integrity in regions of the hippocampus critical for memory performance.  The relationship between low-normal B12 status and poorer memory performance was determined to be mediated in part by worse integrity of these hippocampus sub-regions.  Statistical adjustment to account for potential confounding risk factors (e.g., age, sex, education, tHcy, folate) did not significantly alter these observations. 

            Due to the cross-sectional study design, definitive conclusions about causality cannot be made, although these results along with previous study results suggest lower B12 status, even in the absence of deficiency, may contribute to deterioration of hippocampus microstructure and function.  Thus, improving B12 status should likely be considered one nutritional strategy to discourage development and progression of cognitive decline with aging.    


To B-12 or Not to B-12

            Neural degeneration (e.g., brain atrophy, demyelination) and cognitive decline have been associated with B12 deficiency (<150 pmol/L) [5].  Low B12 status generally results in elevated tHcy (associated with brain atrophy & cognitive decline [6]) & MMA in the blood, but B12 concentrations in the low-normal range may cause neurologic symptoms including cognitive deficits even before abnormalities in blood markers of B12 metabolism manifest [7].  B12 blood levels >300 pmol/L (i.e., high-normal) may efficiently reduce blood levels of MMA, tHcy, and DNA disruptions [8-10]. 

            Intervention studies further support a causal relationship between B12 and cognitive function as supplementation with high-dose B12/folate/B6 was shown to improve memory performance even in people with high-normal baseline status (332 pmol/L) [11], pointing to benefits of higher B12 status already within the normal range, and slow the rate of atrophy in brain regions associated with cognitive decline including the hippocampus [12].  Given the high and increasing number of people with MCI, high prevalence of low-normal B12 status in the older population (up to 20% of those >60 years old) [13], and results from this as well as previous studies, the threshold for B12 supplementation (150 pmol/L) in older adults is unlikely adequate.  Thus, a higher cutoff for B12 deficiency (e.g., 300 pmol/L) and earlier supplementation in adults is advisable. 


B-Smart: Supplemental Considerations

            Aging people and vegetarians/vegans are at significant risk of B12 deficiency.  B-12 supplements are effective for preventing deficiencies.  Most dietary supplements contain cyanobalamin, a cheaper, synthetic form of vitamin B12 containing cyanide that requires multiple enzymatic transformations to become biologically active methylcobalamin (methyl-B12).  Methyl-B12, the form found in food, is better absorbed and retained by the body.  Furthermore, much of the general population has limitations in conversion due to high prevalence of genetic variation in the methylenetetrahydrofolate reductase (MTHFR) gene that reduces activity of the enzyme, the rate-limiting enzyme of the methylation cycle.  Therefore, methyl-B12 is considered to be the superior form.

            Stomach acid releases bound B12 in food, thus antacids and acid-neutralizing mediations, especially proton-pump inhibitors, may inhibit B12 absorption.  Decreased stomach acidity, common among older people, contributes to insufficient B12 absorption.  The necessity of stomach acid to liberate bound B12 is bypassed with supplementation of free B12.  B12 is absorbed by a complex intestinal mechanism, although a small fraction can be absorbed by passive diffusion, which is why modern high potency supplements effectively treat deficiency even when primary intestinal absorption mechanisms are impaired. 

            Methyl-B12 along with 5-methyltetrahydrofolate and pyridoxal-5-phosphate, the biologically active forms of folate and vitamin B6 (precursor forms require enzymatic conversion in the body), respectively, participate together in reactions that reduce levels of homocysteine in the body.  Common dietary diuretics such as caffeinated beverages (e.g., coffee) and alcohol can increase loss of nutrients such as B-vitamins thereby increasing the amount needed from dietary intake.  With various genetic and physiologic factors, including advancing age, influencing conversion of precursors to biologically active forms, direct combined supplementation with these bioactive forms is a good dietary safeguard to discourage accumulation of homocysteine in the body and promote proper integrated metabolic function.   



1.              Kobe T, Witte AV, Schnelle A, Grittner U, Tesky VA, Pantel J,     Schuchardt JP, Hahn A, Bohlken J, Rujescu D, Floel A: Vitamin B-12 concentration, memory performance, and hippocampal structure in patients with mild cognitive impairment. Am J Clin Nutr 2016, 103:1045-1054.

2.              Bryan J, Calvaresi E, Hughes D: Short-term folate, vitamin B-12 or vitamin B-6 supplementation slightly affects memory performance but not mood in women of various ages. J Nutr 2002, 132:1345-1356.

3.              Goodwin JS, Goodwin JM, Garry PJ: Association between nutritional status and cognitive functioning in a healthy elderly population. JAMA 1983, 249:2917-2921.

4.              Clarke R, Birks J, Nexo E, Ueland PM, Schneede J, Scott J, Molloy A, Evans JG: Low vitamin B-12 status and risk of cognitive decline in older adults. Am J Clin Nutr 2007, 86:1384-1391.

5.              Smith AD, Refsum H: Vitamin B-12 and cognition in the elderly. Am J Clin Nutr 2009, 89:707S-711S.

6.              de Jager CA: Critical levels of brain atrophy associated with homocysteine and cognitive decline. Neurobiol Aging 2014, 35 Suppl 2:S35-39.

7.              Lindenbaum J, Healton EB, Savage DG, Brust JC, Garrett TJ, Podell ER, Marcell PD, Stabler SP, Allen RH: Neuropsychiatric disorders caused by cobalamin deficiency in the absence of anemia or macrocytosis. N Engl J Med 1988, 318:1720-1728.

8.              Selhub J, Jacques PF, Dallal G, Choumenkovitch S, Rogers G: The use of blood concentrations of vitamins and their respective functional indicators to define folate and vitamin B12 status. Food Nutr Bull 2008, 29:S67-73.

9.              Eussen SJ, de Groot LC, Clarke R, Schneede J, Ueland PM, Hoefnagels WH, van Staveren WA: Oral cyanocobalamin supplementation in older people with vitamin B12 deficiency: a dose-finding trial. Arch Intern Med 2005, 165:1167-1172.

10.           Fenech M: Folate (vitamin B9) and vitamin B12 and their function in the maintenance of nuclear and mitochondrial genome integrity. Mutat Res 2012, 733:21-33.

11.           de Jager CA, Oulhaj A, Jacoby R, Refsum H, Smith AD: Cognitive and clinical outcomes of homocysteine-lowering B-vitamin treatment in mild cognitive impairment: a randomized controlled trial. Int J Geriatr Psychiatry 2012, 27:592-600.

12.           Douaud G, Refsum H, de Jager CA, Jacoby R, Nichols TE, Smith SM, Smith AD: Preventing Alzheimer's disease-related gray matter atrophy by B-vitamin treatment. Proc Natl Acad Sci U S A 2013, 110:9523-9528.

13.           Baik HW, Russell RM: Vitamin B12 deficiency in the elderly. Annu Rev Nutr 1999, 19:357-377.


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