A UCSF led study found that healthy older people with lower vitamin B12 levels, even when those levels still fell within the accepted normal range, showed signs of subtle neurological and cognitive problems. The findings raise a provocative possibility: some people may be told their B12 status is fine while their brains are already showing early signs of strain.

"Normal" B12 May Not Always Mean Optimal

The study, published in Annals of Neurology, looked at older adults who did not have dementia or mild cognitive impairment. Even in this relatively healthy group, lower levels of active B12 were linked to slower thinking, slower visual processing, and more visible injury in the brain's white matter. White matter is made up of the nerve fibers that allow different parts of the brain to communicate.

The work was led by senior author Ari J. Green, MD, of the UCSF Departments of Neurology and Ophthalmology and the Weill Institute for Neurosciences. Green and his colleagues said the results call attention to a possible weakness in current B12 guidelines. The minimum threshold used to define deficiency may not capture early functional changes in the nervous system.

"Previous studies that defined healthy amounts of B12 may have missed subtle functional manifestations of high or low levels that can affect people without causing overt symptoms," said Green, noting that clear deficiencies of the vitamin are commonly associated with a type of anemia. "Revisiting the definition of B12 deficiency to incorporate functional biomarkers could lead to earlier intervention and prevention of cognitive decline."

Brain Scans Revealed a Troubling Pattern

Researchers enrolled 231 healthy participants through the Brain Aging Network for Cognitive Health (BrANCH) study at UCSF. The participants had an average age of 71, and none had dementia or mild cognitive impairment.

Their average blood B12 level was 414.8 pmol/L, far above the U.S. minimum cutoff of 148 pmol/L. Instead of relying only on total B12, the researchers focused on the biologically active form of the vitamin, which may better reflect how much B12 the body can actually use.

After adjusting for age, sex, education, and cardiovascular risk factors, the team found that participants with lower active B12 had slower processing speed on cognitive tests. The effect was stronger with older age. They also had delayed responses to visual stimuli, pointing to slower visual processing and reduced brain signaling efficiency.

MRI scans added another warning sign. Participants with lower active B12 had a higher volume of white matter lesions, which are areas of brain injury that have been linked to cognitive decline, dementia, and stroke risk.

Why Older Adults May Be More Vulnerable

The study focused on older adults, a group that may be especially sensitive to lower B12 because absorption can become less efficient with age. Some medications, digestive conditions, and diets low in animal based foods can also increase the risk of low B12.

Co-first author Alexandra Beaudry-Richard, MSc, said the findings suggest that low but technically normal B12 could have broader effects than previously recognized. These levels could "impact cognition to a greater extent than what we previously thought, and may affect a much larger proportion of the population than we realize." Beaudry-Richard is currently completing her doctorate in research and medicine at the UCSF Department of Neurology and the Department of Microbiology and Immunology at the University of Ottawa.

"In addition to redefining B12 deficiency, clinicians should consider supplementation in older patients with neurological symptoms even if their levels are within normal limits," she said. "Ultimately, we need to invest in more research about the underlying biology of B12 insufficiency, since it may be a preventable cause of cognitive decline."

Newer Evidence Adds Important Context

Research published after and around the UCSF study has added nuance rather than a simple answer. A 2025 comprehensive review concluded that B12 deficiency remains a modifiable risk factor for neurological and cognitive problems, especially in high risk groups such as older adults and vegetarians. The review also highlighted the growing importance of better biomarkers and brain imaging for detecting problems earlier.

A 2025 systematic review and meta analysis of randomized trials found that supplementation with B vitamins, including B6, B9, or B12, produced a very small benefit in global cognitive function among older adults. The authors rated the cleaned analysis as high certainty, but the effect was small, suggesting that supplementation is not a dramatic brain boost for everyone.

Another 2025 study using Mendelian randomization found no clear evidence that genetically higher total serum B12 levels protect the general population from psychiatric disorders or cognitive impairment. However, the authors noted an important limitation: their analysis used total serum B12, not the bioactive form measured in the UCSF work.

Together, the newer evidence supports a more careful message. B12 is clearly essential for the nervous system, and deficiency should not be ignored. But simply raising B12 for everyone may not be the answer. The more urgent question is whether current testing misses people whose brains are already affected despite "normal" results.

A Preventable Risk Worth Taking Seriously

The UCSF findings do not prove that lower active B12 directly causes cognitive decline, and they do not mean every older adult should begin taking supplements without medical guidance. They do, however, suggest that the current definition of B12 deficiency may be too blunt for brain health.

For clinicians, the study points to the possible value of looking beyond total B12, especially when older patients have neurological symptoms. For patients, it highlights a practical message: a "normal" lab result may not always tell the full story, particularly when subtle changes in memory, thinking speed, or vision are already appearing.

Authors: Co first author is Ahmed Abdelhak, MD, PhD, of the UCSF Department of Neurology and the Weill Institute for Neurosciences.

Funding and Disclosures: Westridge Foundation and the Canadian Institutes of Health and Research. There are no conflicts of interest to report.