Vitamin B12 Levels Association with Functional and Structural Biomarkers of Central Nervous System Injury in Older Adults

 Ask your competent? doctor about this conclusion:

but new research published in the Annals of Neurology suggests that even people with "normal" levels of B12 may not be getting enough to prevent cognitive decline. The study found that older adults with B12 levels in the lower range of normal had signs of central nervous system injury, including reduced brain volume and impaired neurological function.
B12 plays a crucial role in myelin production, the protective sheath around nerves that supports cognitive function. Deficiency has been linked to memory loss, brain fog, and even early dementia. The best way to increase B12 is to eat red meat, fish, poultry, and eggs; fortified foods, nutritional yeast, and tempeh if you’re a vegetarian; and keep your digestive system healthy with fiber and fermented foods.
Boost your B12 intake with foods like clams, sardines, eggs, and nutritional yeast. For a delicious and brain-boosting meal, try Stanley Tucci’s clam recipe (linked below).

Vitamin B12 Levels Association with Functional and Structural Biomarkers of Central Nervous System Injury in Older Adults

Alexandra Beaudry-Richard MSc, Ahmed Abdelhak MD, PhD, Rowan Saloner PhD, Simone Sacco MD, Shivany C. Montes MPH, Frederike C. Oertel MD, PhD, Christian Cordano MD, PhD … See all authors

First published: 10 February 2025

https://doi.org/10.1002/ana.27200

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Abstract

Objective

Vitamin B12 (B12) plays a critical role in fatty- and amino-acid metabolism and nucleotide synthesis. While the association between B12 deficiency and neurological dysfunction is well-known, the exact threshold for adequacy remains undefined in terms of functional impairment and evidence of injury. The objective was to assess whether B12 levels within the current normal range in a cohort of healthy older adults may be associated with measurable evidence of neurological injury or dysfunction.

Methods

We enrolled 231 healthy elderly volunteers (median age 71.2 years old) with a median B12 blood concentration of 414.8 pmol/L (as measured by automated chemiluminescence assay). We performed multifocal visual evoked potential testing, processing speed testing, and magnetic resonance imaging to assess neurological status. Moreover, we measured serum biomarkers of neuroaxonal injury, astrocyte involvement, and amyloid pathology.

Results

Low (log-transformed) B12, especially decreased holo-transcobalamin, was associated with visual evoked potential latency delay (estimate = −0.04; p = 0.023), processing speed impairment (in an age-dependent manner; standardized β = −2.39; p = 0.006), and larger volumes of white matter hyperintensities on MRI (β = −0.21; p = 0.039). Remarkably, high levels of holo-haptocorrin (biologically inactive fraction of B12) correlated with serum levels of Tau, a biomarker of neurodegeneration (β = 0.22, p = 0.015).

Interpretation

Healthy older subjects exhibit neurological changes at both ends of the measurable “normal” B12 spectrum. These findings challenge our current understanding of optimal serum B12 levels and suggest revisiting how we establish appropriate nutritional recommendations. ANN NEUROL 2025

Graphical Abstract

At low levels of B12, specifically when bound to transcobalamin for cellular uptake, evidence of slower conductivity in the brain could point toward impaired myelin. At high levels of B12, specifically when bound to the biologically inert transport protein haptocorrin, biomarkers of neurodegeneration appear in the serum, indicating neuroaxonal injury. The biological basis for this phenomenon has yet to be explored. Holo-HC = holo-haptocorrin; Holo-TC = holo-transcobalamin; VEP = visual evoked potentials.

Cobalamin, or vitamin B12 (B12), is an essential vitamin normally acquired through absorption in the enteric system in mammals. Deficiency in humans can be caused by a lack of intake (eg, vegan diet) or by any disease or procedure of the digestive tract impairing the absorption of B12.¹ After depletion of B12 stores, signs of deficiency such as hematological and neurological symptoms may develop, including megaloblastic anemia and subacute combined degeneration of the spinal cord.² The latter presents as a spinal syndrome (sensory ataxia, paresthesia, weakness, etc.) involving multiple tracts, principally the posterior columns.^{2, 3} Qualitative pathological analyses of the tissue revealed a degeneration with vacuolization of the tracts included in the white matter (WM),^4-7 suggesting that vitamin B12 might be important for maintenance of intact myelination. However, the exact cellular substrate that is impacted by B12 deficiency or insufficiency has not yet been elucidated. In addition to affecting general cognition and memory, vitamin B12 deficiency may even lead to dementia and psychosis, suggesting a broader dependence of the brain on B12.^8-11 Nonetheless, the VITACOG study established that B vitamin supplementation including B12 in older adults with mild cognitive impairment (MCI) leads to both functional and structural benefits.^{12, 13} According to their foundational work, B12 supplementation slows the progression of brain atrophy in MCI and of clinical decline in multiple areas of cognitive testing. Moreover, B12 deficiency is associated with a higher burden of WM hyperintensities (WMH) in the brain, which could indicate microstructural changes (ie, ependymal disruption or chronic ischemic changes) reflecting overall brain health.^14-16

In the United States, the cutoff value for B12 “deficiency” state is currently defined as below 148 pmol/L.¹ This value was simply calculated as 3 standard deviations below the U.S. population average, independent of clinical observations.¹⁷ The American Society for Nutrition criticized this approach in 2010, arguing that more than 5% of patients who have a syndrome consistent with B12 deficiency and who respond to B12 supplementation have blood levels above that threshold.¹⁸ Other studies demonstrated that B-vitamins supplementation was beneficial in people with clinical features of cobalamin deficiency, regardless of the measured levels in the blood.^{13, 19} Selecting a cutoff value based on clinical observations would better reduce disparities in B12 deficiency diagnosis and management.

Cases of biochemical B12 deficiency wherein suboptimal B12 levels have been reported without overt clinical manifestation have been reported as subclinical cobalamin deficiency (SCCD).²⁰ SCCD is most prevalent in the elderly and is associated with greater WMH burden and cognitive decline over time.^{21, 22} In this context of B12 insufficiency, age might act as a vulnerability factor, accentuating the deleterious effects of low B12. While defining a threshold for optimal B12 levels based on clinical findings is crucial to prevent SCCD, sensitive tools to detect subtle neurological changes have not yet been used. The recording of visual evoked potentials (VEP) is a validated and non-invasive tool to assess myelin function in the visual pathway,^{23, 24} but at the commencement of our study it had not yet been applied to a cohort of participants to study the effects of low B12.

Distribution of the fractions of B12 measured in the blood adds another layer of complexity to understanding the neurological manifestation of B12 deficiency. Once cobalamin is absorbed, the transport proteins haptocorrin (HC) and transcobalamin (TC) bind it with great affinity and act as transporters in circulation.^{25, 26} Since only TC has a specific receptor (CD320) for cellular uptake, Holo-TC1 is usually considered to be biologically available for cells (“active”). On the other hand, Holo-HC hypothetically represents the fraction of B12 that is not immediately available to tissues (“inactive”); it can only bind non-specific asialoglycoprotein receptors on liver cells for reuptake, degradation and excretion in the bile.²⁷

In this work, we hypothesized that lower total B12 levels within the specified normal range may still be associated with subtle functional and structural neurological deficits if the active fraction of plasma B12 (Holo-TC) is too low to sustain adequate cellular B12 needs. To that end, we evaluated the association of B12 concentrations with markers of myelin integrity (multifocal VEP; mfVEP), cognitive performance, blood biomarkers of neuronal and glial integrity, as well as quantitative brain MRI analyses across a spectrum of measurable B12 levels as well as the active fraction of the plasma B12.

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