Article Criticism (Brain Vitamin D Forms)

By Jens Allmer

December 7, 2024

The Curious Case of Vitamin D and Brain Health: A Study Worth Revisiting

Recently, the German journal FITBOOK ran an article discussing a study that examined the relationship between Vitamin D levels in brain tissue and cognitive function. The FITBOOK piece itself was riddled with oversimplifications and exaggerations (which I’ve dissected elsewhere), but now it’s time to look critically at the study that sparked the excitement.

At first glance, the study appears to offer intriguing insights into Vitamin D’s potential role in brain health. Upon closer inspection, however, it falls short in several ways. Here’s a breakdown of the study’s key limitations and why its findings need to be taken with a hefty pinch of salt.

1. Correlation Does Not Equal Causation

The study primarily reports associations between higher brain Vitamin D levels and better cognitive function. It does not establish causation. This is a classic pitfall in observational research, and the authors even acknowledge that dementia is multifactorial. Yet, the results have been presented (and reported) in a way that suggests a much stronger link than the evidence warrants.

Without understanding whether Vitamin D is a driver of improved brain function—or merely a marker of better overall health—it’s impossible to draw actionable conclusions.

2. Postmortem Design: A Static Snapshot

The study analyzed Vitamin D levels in postmortem brain tissue from 209 individuals. This design raises several issues:

Lack of Dynamics: It only provides a static snapshot of Vitamin D levels and their relationship to cognitive function at the end of life. We have no idea how these levels fluctuated over time or whether changes in Vitamin D influenced cognitive decline.
Sampling Bias: The participants were elderly individuals, likely already in advanced stages of cognitive impairment or other health conditions. This makes it harder to generalize the findings to broader populations or to earlier stages of disease progression.

3. The Role of Calcitriol: A Glaring Omission

Only the active form of Vitamin D, calcitriol (1,25-dihydroxyvitamin D), binds to Vitamin D receptors (VDRs) and triggers downstream biological effects. However:

Quantification Challenges: The study could not reliably measure calcitriol levels in the brain due to their low concentrations. Instead, it measured total Vitamin D and calcifediol (25-hydroxyvitamin D), which is the precursor of calcitriol.
Relevance of Findings: Without data on calcitriol or its interaction with VDRs, it’s unclear whether the observed Vitamin D levels had any functional significance. The study makes assumptions about Vitamin D’s activity in the brain that it cannot substantiate.

4. Brain’s Local Vitamin D Metabolism: Ignored

The brain expresses the enzyme CYP27B1, which converts calcifediol to calcitriol locally. This is a crucial point because:

Local Synthesis Matters: The brain’s ability to produce calcitriol could mean that systemic Vitamin D levels are less important than previously thought. Conversely, inadequate local production could limit brain health regardless of serum levels.
Study Oversight: The study does not explore this local conversion process or its implications, leaving a critical gap in understanding how Vitamin D operates in the brain.

5. Vitamin D Insufficiency in Participants

The participants in the study were likely Vitamin D insufficient, based on what we know about older populations. The study reports a mean plasma total 25(OH)D3 status of 35 +/- 16.4 ng/ml. It’s safe to assume that most participants were below the threshold for sufficiency. The authors of the study classified their participants as sufficient in Vitamin D according to the Institute of Medicine. Sufficient to prevent rickets, perhaps.

Baseline Deficiency: Studying an already deficient population limits the ability to evaluate the potential benefits of optimal or high Vitamin D levels.
Missed Stratification Opportunity: The study does not stratify participants by Vitamin D status, making it impossible to assess whether those with sufficient levels fared better than those who were deficient.

6. Cross-Sectional Design

The study is observational and cross-sectional, meaning it captures a single point in time rather than changes over time. This design has inherent limitations:

No Longitudinal Data: Without tracking participants over time, the study cannot determine whether higher Vitamin D levels prevented cognitive decline or were simply correlated with better brain health in healthier individuals.
Missed Intervention Insights: The study does not test whether increasing Vitamin D levels through supplementation improves brain function, leaving its practical relevance untested.

7. Misleading Statistics and Simplistic Conclusions

While the study’s data may be valid within its scope, its presentation creates opportunities for misinterpretation:

The 33% Reduction in Dementia Risk: This figure is based on associations and does not imply that supplementation or high Vitamin D levels will reduce dementia risk by one-third.
Overstating Significance: By failing to address key limitations, the study gives the impression of stronger findings than it can reasonably support.

8. The Inclusion of Calcifediol Alone is Limiting

The study’s exclusive focus on calcifediol levels in the brain is another limitation:

No Systemic Context: Calcifediol levels in brain tissue are not correlated with serum calcifediol or calcitriol levels, leaving a disconnect between systemic and local effects.
No Thresholds Defined: The study doesn’t establish what levels of Vitamin D in the brain are “sufficient” for cognitive function, making the findings difficult to translate into recommendations.

Final Thoughts

The study brings some interesting data to the table, particularly in its attempt to measure Vitamin D levels directly in brain tissue. However, its limitations overshadow its contributions:

Lack of Mechanistic Insight: Without data on calcitriol, VDR activity, or local brain metabolism, the study cannot explain how—or even if—Vitamin D influences brain health.
Overreliance on Correlation: The study stops short of causation, making its implications speculative at best.
Poor Generalizability: A postmortem, cross-sectional design with a likely deficient population limits the relevance of the findings for broader health recommendations.

While the study is not without merit, it doesn’t provide the groundbreaking insights its coverage implies. Until we have better-designed research with longitudinal data, clearer mechanistic insights, and actionable thresholds, sweeping claims about Vitamin D’s role in brain health should be approached cautiously.