Baku, April 9, AZERTAC

A long-term study suggests that vitamin D levels in your 30s and 40s could influence early brain changes linked to Alzheimer’s, years before symptoms appear.

According to the Medical News, Dementia affects 57 million people worldwide. Existing research suggests that lower vitamin D levels in later life are linked to an increased risk of cognitive impairment and clinical dementia, but strong evidence is limited.

A recent study in Neurology reports that higher circulating vitamin D levels in early midlife were associated with lower tau-PET burden in the brain, a potential preclinical dementia marker, in adults without dementia.

Midlife vitamin D and early dementia risk

Research into dementia risk has increasingly focused on modifiable factors that may influence brain health over time. Vitamin D has attracted particular interest because of its role in immune regulation, inflammation, and neuronal function, with observational studies in older adults linking lower levels to poorer cognitive outcomes.

However, most of this work has examined vitamin D later in life, when neurodegenerative processes may already be underway. It remains unclear whether vitamin D status earlier in adulthood is associated with the earliest, preclinical brain changes linked to Alzheimer’s disease, before symptoms emerge.

What the study looked at

The authors conducted a prospective cohort study drawing on 793 dementia-free participants from the Framingham Heart Study Generation 3 cohort, including 369 with tau-PET data and 424 with amyloid-PET data.

Participants had their vitamin D levels measured at a mean age of 39 years, with an average level of 38 ng/mL. While 34 % of participants had levels below the study-defined threshold (<30 ng/mL), 5 % were on vitamin D supplementation.

Participants later underwent brain positron emission tomography (PET) scanning between 2015 and 2023 to pick up amyloid and tau deposition. The mean gap between the blood test and the PET was 16 years.

Higher vitamin D linked to lower tau deposition

The results showed that higher serum vitamin D levels in early midlife were associated with a lower global and composite tau deposition on PET. Composite tau refers to deposition in the areas first affected in AD dementia.

No associations were found at the study threshold of vitamin D <30 ng/mL (used for analysis rather than a universal definition of deficiency), perhaps because of the small subgroup size. There was no change in amyloid deposition in relation to vitamin D levels at any threshold.

The results remained consistent after adjusting for confounders, including demographic, seasonal, vascular, and depressive symptoms. The findings were not altered when participants on vitamin D supplements were excluded.

The APOE ε4 genotype is a risk factor for amyloid and tau deposition. However, no interaction between this and vitamin D levels was observed for tau or amyloid deposition.

Putative dose-response relationship

Preliminary analyses showed that the highest quintile of vitamin D concentration was associated with a suggested reduction in tau deposition in early-affected brain regions compared with the lower four quintiles. When deciles were used, the top decile was associated with lower global and composite tau burden than the lower nine, although these were exploratory post hoc findings and should be interpreted with caution.

These findings align with preclinical studies suggesting a potential role for vitamin D in modulating tau burden in the brain, both under normal conditions and following traumatic brain injury. Notably, prior research among older participants with pre-existing memory deficits failed to show a benefit of vitamin D supplementation on plasma tau levels.

Multiple prospective observational studies have shown similar correlations with cognitive outcomes, although a previous Framingham Heart Study (Generation 2) found associations with cognitive performance and brain structure rather than dementia risk.

How vitamin D affects the brain

Vitamin D receptors and the enzyme that converts it to its active form are widely distributed in the hippocampus and other areas of the brain, as well as in immune cells.

Vitamin D exerts multifaceted activity on neuronal cell metabolism, improves immune cell responses, and reduces the production of inflammatory cytokines. It is critical to the expression of primary antioxidant enzymes, such as superoxide dismutase and glutathione peroxidase, thereby increasing systemic anti-inflammatory capacity.

Vitamin D deficiency exacerbates neuroinflammation and reduces antioxidant defenses. The resulting increase in kinase enzyme activity enhances tau phosphorylation at key sites.

Vitamin D in the form of calcitriol restores neurotrophic factor signaling and normalizes tau phosphorylation activity. It restores protein phosphatase 2A (PP2A) activity, preventing tau accumulation in cells exposed to okadaic acid, a PP2A-inhibitor and neurotoxin.

Similar findings have been reported in some previous human studies. Other trials have produced conflicting results regarding reductions in amyloid-related biomarkers with vitamin D supplementation.

The authors suggest that the observed association with tau, but not amyloid, may reflect the earlier accumulation of tau pathology in preclinical Alzheimer’s disease, which might explain why, in this younger sample without clinical dementia, an association was seen with tau but not with amyloid burden.

Strengths and limitations

This was among the larger studies in this field and used longitudinal data, including gold standard neuroimaging markers of preclinical dementia. The relatively young baseline age allowed the researchers to investigate a potentially useful predictive relationship between vitamin D and preclinical dementia. Multiple confounders were considered in the analysis to select a dementia-free sample.

Some limitations remain, however. Most participants were Caucasian. Repeat vitamin D levels were unavailable over time, and other factors, including changes in lifestyle and diet, could have affected vitamin D status during the long follow-up period.

What this means for dementia prevention

This is among the first studies to examine the relationship between serum vitamin D and neuroimaging markers of preclinical dementia. Early midlife measurement of vitamin D occurs during a period when there is an opportunity to modify dementia risk.

Low vitamin D in midlife may represent a potentially modifiable target to mitigate the risk of neuroimaging signs of preclinical dementia.

However, as this was an observational study, it does not establish causation, and further longitudinal studies and randomized controlled trials are needed to confirm whether vitamin D plays a preventive role.