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

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;97:1190-1204.

FIGURE 1

Flow chart of the participants' recruitment. The BrANCH cohort comprises 861 healthy elder recruited as controls, and 231 of them joined the Myelin and Aging subcohort to have their B12 blood levels measured. Holo‐TC was measured in the serum of 214 of them, and Holo‐HC values were calculated by subtracting Holo‐TC from total B12. mfVEP was performed on 155 of these participants, 231 underwent cognitive tests, 153 had biomarkers of neurodegeneration measured in their serum, and 183 had MRI scans performed. BrANCH = Brain Aging Network for Cognitive Health; Holo‐HC = holo‐haptocorrin; Holo‐TC = holo‐transcobalamin; mfVEP = multifocal visual evoked potential; MRI = magnetic resonance imaging.

FIGURE 2

Low available serum indicators of B12 status (total B12 and Holo‐TC) associate with mfVEP latency prolongation. (A) Mixed linear model of mfVEP latency with log B12 as the independent variable, correcting for age (years), sex at birth, education (years), BMI, CVRF, and APOEε4, as well as accounting for the eye as a random factor. The relationship between B12 and mfVEP latency was significant for people with log‐transformed B12 values under the mean of 2.61 (dashed line). Black = B12 values below the mean; gray = B12 values above the mean. (B) Mixed linear model of mfVEP latency with Holo‐TC as the independent variable, correcting for age (years), sex at birth, education (years), BMI, CVRF, HbA1C, and APOEε4, as well as accounting for the eye as a random factor for people with log‐transformed B12 values under the mean. APOEε4 = apolipoprotein E ε4 allele; BMI = body mass index; CVRF = cardiovascular risk factor; HbA1C = hemoglobin A1C; Holo‐HC = holo‐haptocorrin; Holo‐TC = holo‐transcobalamin; mfVEP = multifocal visual evoked potential.

FIGURE 3

The association of vitamin B12 blood levels and cognitive tests is age dependent. The association between processing speed (response latency z‐score) and Holo‐TC appears with higher age. Linear regression model evaluating the association between Holo‐TC and processing speed with an interaction term with age (p‐value = 0.006), correcting for age, BMI, CVRF, sex, education level, HbA1C, and APOEε4 status. On this graph, the predicted regression for processing speed is represented for each quartile by age (hinges: 67, 70, and 76 years old; light shade is youngest; dark shade is eldest). APOEε4 = apolipoprotein E ε4 allele; BMI = body mass index; CVRF = cardiovascular risk factor; HbA1C = hemoglobin A1C; Holo‐TC = holo‐transcobalamin.

FIGURE 4

High unavailable B12 associates with an elevation in biomarkers for neurodegeneration. (A) There is a significant positive association between the levels of total measured B12 and the levels of the protein T‐Tau (z‐score adjusted for age, sex, BMI, CVRF, education, HbA1C, APOEε4 status and creatinine). (B) No correlation was found between T‐Tau and Holo‐TC. (C) A significant positive association exists between T‐Tau and derived Holo‐HC. (D) Another biomarker of neuroaxonal injury, UCH‐L1, correlated positively with the levels of derived Holo‐HC. BMI = body mass index; CVRF = cardiovascular risk factor; HbA1C = hemoglobin A1C; Holo‐HC = holo‐haptocorrin; Holo‐TC = holo‐transcobalamin; UCH‐L1 = ubiquitin carboxy‐terminal hydrolase L1.

FIGURE 5

Low available B12 on Holo‐TC associates with a higher burden of WMH. (A) Linear regression model of log WMH with log B12 as the independent variable. The variables did not significantly associate after correcting for age, sex, BMI, education, total intracranial volume, HbA1C, APOEε4 and cardiovascular risk factors. (B) There is a significant negative association between log WMH and log Holo‐TC after correcting for the same covariates as in (A). (C) Graph representing the absolute volume of WMH and the absolute Holo‐TC values. APOEε4 = apolipoprotein E ε4 allele; BMI = body mass index; Holo‐TC = Holo‐transcobalamin; WMH = white matter hyperintensity.