Google+Linking To And Excerpting From "Vitamin B12 Levels Association with Functional and Structural Biomarkers of Central Nervous System Injury in Older Adults" - Tom Wade MD
Linking To And Excerpting From “Vitamin B12 Levels Association with Functional and Structural Biomarkers of Central Nervous System Injury in Older Adults”
Today, I review, link to, and excerpt from Vitamin B12 Levels Association with Functional and Structural Biomarkers of Central Nervous System Injury in Older Adults [PubMed Abstract] [Full-Text HTML] [Full-Text PDF]. Ann Neurol. 2025 Feb 10. doi: 10.1002/ana.27200. Online ahead of print.
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.
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.14–16In 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.
Discussion
Our results suggest that in a cohort of healthy elderly individuals, lower B12 associates with a delay in VEP latency, and that it is specific to the biologically available fraction of serum B12 bound to transcobalamin (Holo-TC). Low levels of Holo-TC also associate with slowed spatial processing speed in an age-dependent manner. On MRI, participants with lower Holo-TC have a higher burden of T2 WMH. Remarkably, we find that high levels of Holo-HC, the biologically unavailable fraction of B12, associate with an increase in the levels of T-Tau proteins in the serum, a biomarker for neurodegeneration. These findings suggest that current parameters for defining adequate B12 levels may be inappropriate when considering neurophysiological, neuropsychological, serological, and neuroradiological outcomes.
Our findings are of critical importance for rethinking the “biologically sufficient” B12 levels. The population-based studies that defined healthy micronutrient levels may have missed the subclinical manifestations of low or high B12 at the extremes of the population distribution that can affect people without causing overt symptoms. While the clinical features of unambiguous B12 deficiency are well defined as predominantly hematological (most conspicuously macrocytic anemia) and neurological, the condition can manifest with either hematological or neurological syndromes in isolation.27 Without sensitive tools to detect subtle neurological deficits, the heterogeneous nature of the symptoms remained unexplained. Notably, during and following B12 repletion therapy, patients often request higher dosing of B12 to treat their neurological symptoms, even after their hematological symptoms have resolved.62 Our findings support the idea that subtle neurological deficits manifest at higher levels than the current threshold defined for deficiency, and most importantly, it could provide an explanation for the often-reported discrepancy between hematological and neurological symptoms.63, 64 When B12 intake or absorption is impaired, the levels of Holo-TC initially decrease in the blood, which can be first compensated by releasing the B12 in storage.65, 66 This slow progression toward deficiency could be better described by a sliding scale of insufficiency, wherein the tissue levels decline until Holo-TC falls below what is necessary to supply critical cells for biochemical reactions in the nervous system, and then the bone marrow. Revisiting the definition for healthy B12 levels could promote earlier intervention and prevention of cognitive decline, especially in the elderly carrying increased risk for B12 malabsorption and insufficiency.67, 68 A study on an aging population previously argued for a broadening of the reference range for B12 levels in elder people, and our results further support such a shift to account for age.69 The elderly population may be particularly vulnerable to the effects of declining B12 availability and may benefit from a change in guidelines for what is currently defined as healthy levels of vitamin B12.
