The study followed 231 healthy older adults (median age 71.2), all with B12 levels that would generally be considered normal. It found, however, that those with lower levels of biologically active B12—specifically the form bound to transcobalamin (Holo-TC)—showed signs of neurological decline. These included slower visual processing, reduced cognitive speed and more white matter abnormalities on brain scans.
“Healthy older subjects exhibit neurological changes at both ends of the measurable ‘normal’ B12 spectrum,” the researchers reported. “These findings challenge our current understanding of optimal serum B12 levels and suggest revisiting how we establish appropriate nutritional recommendations.”
They made a key distinction between different forms of B12 in the blood. Holo-TC, which delivers B12 to cells, was linked to better brain function. In contrast, higher levels of holo-haptocorrin (Holo-HC)—a biologically inactive form of B12—were associated with increased Tau protein in the blood, a known marker of neurodegeneration.
While the study did not establish a direct cause-and-effect relationship, it raised questions about whether current B12 thresholds are too narrow—especially for older adults who may have subclinical deficiencies that don’t show up in traditional tests.
“Our findings support the idea that subtle neurological deficits manifest at higher levels than the current threshold defined for deficiency,” the researchers wrote.
They emphasized that while their study does not prove causation, the results “show a ‘precursor’ stage at which microstructural changes are present and already impairing neurological function.”
Time to reassess functional markers of B12 status?
Commenting independently on the findings, Shawn Wells, chief science officer and co-founder of NNB Nutrition, told NutraIngredients that the study reinforces concerns long held by clinicians and nutrition scientists about the limitations of serum-level diagnostics in assessing nutrient sufficiency.
“This study exposes a systemic blind spot in modern medicine: We’ve mistaken serum levels for functional status,” he said. “Just because a molecule is floating around in the blood doesn’t mean it’s doing its job in the cell.”
Drawing comparisons to other biomarkers, Wells noted that the medical field has previously seen similar disconnects.
“We’ve seen this story before—vitamin D levels look great on paper while VDR dysfunction blocks activity, T4 appears normal while patients drown in low T3 symptoms, insulin is sky-high but cells are starving. B12 is no different,” he said.
Wells argued that relying on serum B12 levels without assessing intracellular activity can lead to misdiagnosis or missed opportunities for early intervention.
“As a chief clinical dietitian who worked in practice for over a decade, I can tell you the numbers can lie,” he said. “What matters is what’s happening at the cellular level, and until we measure that, we’re practicing diagnostics with one eye closed.”
He pointed to the study’s use of Holo-TC and Holo-HC measurements, combined with neurological assessments, as a more meaningful approach.
“This is the direction we need to go—assessing bioactive forms and actual functional impact, not just total B12 in circulation,” Wells said.
As the industry continues to develop more precise tools and diagnostics, both researchers and product formulators may need to revisit how vitamin B12 sufficiency is defined and consider a shift toward personalized, functional biomarkers over population-based serum norms.
Source: Annals of Neurology. doi: 10.1002/ana.27200. “Vitamin B12 Levels Association with Functional and Structural Biomarkers of Central Nervous System Injury in Older Adults”. Authors: Beaudry-Richard, A. et al.
