"Normal" vitamin B12 levels may not prevent brain decline

By Dr. Liji Thomas, MDReviewed by Benedette Cuffari, M.Sc.Feb 24 2025

Study challenges accepted vitamin B12 levels, revealing hidden neurological risks even within 'normal' range.

Study: Vitamin B12 Levels Association with Functional and Structural Biomarkers of Central Nervous System Injury in Older Adults. Image Credit: Lightspring / Shutterstock.com

A recent study published in the Annals of Neurology uses a multimodal testing approach to identify associations between B12 levels currently accepted as normal and markers of neurological injury or impairment.  

Vitamin B12 deficiency

Vitamin B12, which is otherwise known as cobalamin, is an essential dietary vitamin that can be acquired from the consumption of animal products, certain dry fruits, nutritional yeast, and fortified foods. Vitamin B12 deficiency can lead to blood cell abnormalities like megaloblastic anemia and dysfunction of the neurological system, including subacute combined degeneration of the spinal cord (SACD).

Some symptoms associated with SACD include sensory ataxia, paresthesia, and weakness. Previous pathological analyses indicate that SACD arises due to degeneration of the myelin sheath, which ultimately leads to the destruction and vacuolization of the white matter (WM) of the spinal cord.

B12 deficiency is also associated with cognitive impairment, memory loss, dementia, and psychosis. However, vitamin B supplementation has been shown to reduce the rate of brain atrophy in older people with mild cognitive impairment (MCI).

In the United States, B12 deficiency is defined as a total blood level of less than 148 pmol/L, which is three standard deviations below the population average. Due to a lack of agreement on what blood levels constitute a B12 deficiency, clinical features are often considered a better indication for supplementation.

B12 absorbed from the gastrointestinal tract is bound to transport proteins in the blood, including haptocorrin (HC) and transcobalamin (TC). The B12-TC complex (Holo-TC) is the only bioactive form of this vitamin, as B12 bound to HC (Holo-HC) is unavailable for cell uptake and is considered inactive.

About the study

Visual evoked potentials (VEP) offer a more sensitive and non-invasive method to identify early alterations in myelin function in the visual pathway. The current study utilized multifocal VEP (mfVEP) to assess the impact of low B12 on neurologic health.

A total of 231 healthy individuals with a median age of 71 years who were part of the Brain Aging Network for Cognitive Health (BrANCH) at the University of California, San Francisco (UCSF) Memory and Aging Center were included in the study. In addition to B12 measurements, all study participants were tested annually for neurological function, cognitive performance, and magnetic resonance imaging (MRI) to detect signs of inflammation, axonal damage, or amyloid-related disease.

Study findings

The study cohort had a median blood B12 concentration of 415 pmol/L, with Holo-TC and Holo-HC median values of 93 and 298 pmol/L, respectively. Vitamin B12 levels were stratified into above and below the geometrical mean value of 408 pmol/L.

To this end, low levels of B12, especially Holo-TC, were associated with neurological dysfunction. At low B12 levels, mfVEP was 0.04 slower, thus indicating slower conduction of nerve impulses in the brain.

Lower Holo-TC was inversely correlated with latency, thus demonstrating that inadequate B12 bioavailability was responsible for greater nerve conduction latency. Low vitamin B12 levels were associated with decreased spatial processing speed, which demonstrates that brain dysfunction correlated with reduced total B12 and Holo-TC, but not Holo-HC.

This negative association was dependent on age, perhaps because older people are at a greater risk of low bioavailable B12 or suboptimal cognitive test performance at younger ages.

Increased Holo-HC correlated with serum tau protein and ubiquitin C-terminal hydrolase L1 (UCH-L1) levels. B12 prevents tau fibril formation, which precedes the formation of neurofibrillary tangles (NFT) in Alzheimer’s dementia (AD). Thus, high levels of non-bioavailable B12 were predictive of increased neurodegeneration markers.

Low B12 levels were associated with higher WMH volumes, despite all participants having levels within the currently accepted limits of normal. No correlation was observed with total B12; however, lower Holo-TC levels were associated with higher WMH burden.

Implications

With low B12 levels, especially bioavailable B12, white matter injury occurs in the spinal cord. The mechanism of injury remains unclear; however, it may be due to high homocysteine levels secondary to B12.

B12 supplementation for hematological symptoms often leads to their resolution; however, this therapeutic approach is typically not effective for reducing neurological symptoms associated with B12 deficiency. Thus, subtle neurologic dysfunction may persist, despite normal blood B12 levels.

Overall, the study findings emphasize the critical need to establish optimal B12 levels and calls for a broader reconsideration of nutritional guidelines.