Vitamin D deficiency accelerates cognitive decline only in women without Alzheimer’s risk gene

A Korean study led by a neuropsychiatrist at Seoul National University Bundang Hospital (SNUBH) has found that the widely held belief linking vitamin D deficiency to cognitive decline does not apply universally -- but is instead only significant in women without a specific genetic risk factor for Alzheimer’s disease.

The research team, led by Professor Kim Ki-woong of the Department of Neuropsychiatry at SNUBH, said vitamin D deficiency accelerates cognitive decline exclusively in women who lack apolipoprotein E (APOE) ε4, a well-known genetic marker associated with increased Alzheimer’s disease risk.

Vitamin D plays a key role in calcium and phosphorus absorption and is essential for bone health, muscle function, and immune responses. In recent years, mounting evidence has highlighted its additional neuroprotective properties, including inflammation regulation and support for neuronal function, leading to its popular moniker as the “brain vitamin.”

Several observational studies from the U.S., Europe, and Asia have reported that lower levels of vitamin D are associated with greater risk of cognitive impairment, reinforcing the nutrient’s reputation as a potential protector against cognitive decline.

However, researchers have long debated the consistency of this association. While some studies support the link, others report no correlation, raising concerns about overgeneralization.

To better define the scope of vitamin D’s cognitive impact, Kim’s team conducted a large-scale, long-term prospective cohort study involving 1,547 elderly individuals with normal cognitive function. Over 10 years, the participants underwent regular Mini-Mental State Examination (MMSE) assessments and blood tests to monitor vitamin D levels.

The analysis revealed a clear divergence in cognitive outcomes depending on sex and genetic background. Among male participants, low vitamin D levels did not significantly influence the rate of cognitive decline.

Likewise, female participants carrying the APOE ε4 gene, about 15 percent of all women, also did not show significant changes in cognitive performance due to vitamin D levels.

This means that more than half of the population may not be vulnerable to cognitive decline from vitamin D deficiency, the researchers noted.

In contrast, women without the APOE ε4 gene experienced significantly faster cognitive deterioration when vitamin D levels were low. In this group, cognitive scores declined by an average of 0.14 points per year more rapidly than those with sufficient vitamin D -- on a 30-point scale -- suggesting a meaningful and measurable acceleration of cognitive aging.

According to the research team, while APOE ε4 is a major genetic risk factor for Alzheimer’s disease, the team’s findings suggest that vitamin D deficiency becomes an important modifiable risk factor only in women non-APOE ε4 carriers.

According to Kim, the study is the first of its kind to simultaneously account for sex and APOE genotype in a prospective design, following over 1,000 participants for an average of more than eight years. The findings offer important insight into which populations are genuinely vulnerable to cognitive effects from low vitamin D.

“Not everyone needs to take vitamin D supplements out of fear of cognitive decline,” Professor Kim said. “But in non-APOE ε4 gene carrier women, early intervention to address vitamin D deficiency could play a key role in dementia prevention.”

The study was recently published in the international journal Clinical Nutrition.