More Evidence That Vitamin D Protects Against Alzheimer’s

by Jim Schnabel

August 27, 2014

Evidence is building that vitamin D, the “sunshine vitamin,” might help prevent or delay Alzheimer’s disease. Two recent observational studies, which tracked large groups of people over time, have found that those with low blood levels of vitamin D were significantly more likely—in one study more than twice as likely—to go on to develop the so far incurable brain disorder.

Such observational studies can’t establish conclusively that low vitamin D causes Alzheimer’s, and in any case it’s still unclear how, biologically, vitamin D would protect the brain from the disease. But there is an ongoing clinical trial-type study of vitamin D supplementation that should be more conclusive, and its results, due several years from now, will be eagerly awaited by Alzheimer’s researchers. Scientists also will now want to examine more closely vitamin D’s effects on the brain.

The Copenhagen study

The first of the two studies, published online in 2013, was conducted by researchers at the University of Copenhagen, and was based on blood samples and data from the Copenhagen City Heart Study, a long-term study of a large sample of the Danish population, begun in the 1970s.

Børge G. Nordestgaard and his colleagues gained access to blood samples taken from the Heart Study’s subjects in the early 1980s, and for each subject that was free of clinically diagnosed dementia—more than 10,000 people in all—measured levels of 1,25-dihydroxyvitamin D, the biologically active form of vitamin D.

Comparing subjects with levels on the low end of the distribution (0–24th percentiles) to subjects on the high end (>50th percentile) Nordestgaard and colleagues found that proportionately 29% more of the low-end group were diagnosed with Alzheimer’s dementia in the next three decades, according to Danish hospital records.

When the subjects were grouped according to absolute blood levels—less than 25 nmol/L vs. greater than or equal to 50 nmol/L—25% more of the low-level group were found to have been diagnosed with Alzheimer’s. Although that finding just missed the standard cutoff for statistical significance, the overall trend in the data suggested a link between lower vitamin D and higher Alzheimer’s risk.

The Exeter study

In a study published in early August of this year, a team led by researchers from the University of Exeter performed a similar analysis of serum samples and data from the Cardiovascular Health Study, a National Institutes of Health-sponsored project in the 1990s that looked for cardiovascular risk factors in a large sample of older people in the US.

In this analysis, based on data from 1,658 subjects, the researchers found that subjects with low vitamin D levels (<25 nmol/L) later developed signs of Alzheimer’s at a 2.2 times higher rate during the study period, compared to subjects with adequate levels (greater than or equal to 50 nmol/L). There were indications of a “dose response effect” too. Subjects with moderately low vitamin D levels (25-50 nmol/L) had a more moderately increased (69%) rate of Alzheimer’s diagnoses during followup compared to the adequate-level group.

The scientists concluded that the rate of Alzheimer’s among their subjects “markedly increased below a threshold of 50 nmol/L”—hinting that people with serum vitamin D levels below that threshold should consider boosting their levels. (Note that vitamin D can become toxic at very high levels.)

These studies aren’t the first to link vitamin D levels to Alzheimer’s. Earlier cross-sectional studies—effectively snapshots taken at certain points in time—had indicated that people who have Alzheimer’s also tend to have lower vitamin D levels, though it wasn’t clear which came first, the disease or the low vitamin D levels.

Recent genetics studies also have made at least tentative connections between Alzheimer’s risk and the gene for the vitamin D receptor—a receptor found on many cell types in the brain and body. A 2012 study from the University of Miami linked higher Alzheimer’s risk to a variant of the gene that apparently results in under-production of the receptor—hinting, as do the Copenhagen and Exeter studies, that the disease becomes more likely when vitamin D signaling is weaker.

Why did the Exeter study appear to find a much stronger Alzheimer’s/low-vitamin-D link than the Copenhagen study? One possibility is that it was statistically “noisier” and less accurate—in other words, it included fewer people and thus had less power to cancel out the random variations among them. Other differences are that it involved checking for Alzheimer’s a relatively short time after vitamin D sampling, and also focused on subjects who were older on average than those enrolled in the Danish study. “By looking at individuals at higher risk of Alzheimer’s, they might have got a clearer association,” says Nordestgaard, though he emphasizes that the difference between two studies might be only a matter of chance: “What I would focus on is that they showed the same [association] basically.”

How would vitamin D protect the brain?

Ever since the first epidemiological studies began to link low vitamin D to Alzheimer’s, scientists have wondered how the former might cause the latter. There are now data to suggest at least several different hypotheses.

One is that the lack of vitamin D disrupts the healthy working of the immune system in the brain. Alzheimer’s brains typically show signs of abnormal immune cell activation, which studies have implicated as a contributor to the disease process. Many if not all human immune cells have receptors for vitamin D, and the vitamin’s activation of those receptors is now thought to lead to an enhanced anti-bacterial effect, even in the brain, as well as a reduction in chronic, potentially harmful T cell activity. (The T-cell-mediated autoimmune disease multiple sclerosis is also associated with low vitamin D levels.)

Brain-resident immune cells called microglia appear to do worse at clearing away Alzheimer’s-linked aggregates of the protein amyloid beta when they are chronically activated. Some recent studies have found that low vitamin D appears to have a broadly similar effect on microglia as well as on their cousins outside the brain, called macrophages. In other words, the lack of vitamin D appears to weaken these cells’ ability to clear amyloid beta or other unwanted molecules—whereas added vitamin D boosts the clearance of amyloid beta, and at the same time seems to damp down signs of harmful immunological activation.

Liyong Wang, a researcher at the University of Miami who was lead author of the 2012 genetic study mentioned above, notes that vitamin D might have an even more direct impact on amyloid beta. In that study, she and her colleagues investigated potential mechanisms of vitamin D activity relevant to Alzheimer’s, and found evidence that it directly inhibits the transcription of the gene that codes for amyloid beta’s mother protein, APP.

“Our data showed that either exogenous vitamin D receptor expression and/or [vitamin D] treatment inhibits the APP promoter activity,” she says. “This finding suggests that individuals with either extrinsically low vitamin D level or intrinsically low vitamin D receptor level would have more APP transcribed and therefore increased risk for late-onset Alzheimer’s disease.”

Vitamin D also helps regulate the level of calcium throughout the body, including the levels of calcium ions—essential electrolytes—in neurons. It may thereby protect neurons from stresses that disrupt calcium levels, including stresses generally associated with neurodegenerative disease, and specific calcium-dysregulating stresses associated with Alzheimer’s.

Additionally, vitamin D appears to have a broad, brain-cell-nourishing, “neurotrophic” effect. “It has been shown that vitamin D in the brain regulates the expression of several important neurotrophic factors including nerve growth factor, neurotrophin 3, neurotrophin 4, and glial cell line-derived neurotrophic factor,” says Wang.

Possibly the benefits of vitamin D also include those from mechanisms that work throughout the body. As Nordestgaard points out, his group and others have found links between low vitamin D and other common ailments including metabolic syndrome, obesity and type 2 diabetes (all three are also risk factors for Alzheimer’s), tobacco-related cancers, venous blood clots, chronic obstructive pulmonary disease, stroke, heart attack—and even early death from any cause.

“Low vitamin D could be a marker of poor health generally,” says Nordestgaard.

A clinical trial

Further laboratory studies will help clarify the mechanisms through which vitamin D benefits the brain and body. But perhaps the most important study in this field that will be completed in the near future is a large clinical trial. Now being run by doctors at Brigham and Women’s Hospital in Boston, with funding from the National Institutes of Health, the trial is meant to run from 2010 to 2017. It has enrolled over 25,000 middle-aged men and women, who have been randomly assigned to take a vitamin D supplement and/or an omega-3-containing fish oil supplement, or just a placebo. The trial is meant to discover whether vitamin D or fish oil (or the two combined) prevents cancer or cardiovascular disease. But the researchers in the trial will be monitoring participants’ overall health status including any new medical diagnoses, so any large effect of vitamin D in preventing other common diseases should be evident.

“I’m sure that as a secondary endpoint they will look at Alzheimer’s disease,” Nordestgaard says.


vitamin D


9/2/2014 8:34:20 AM

If this would have been the case def. Of vitamin D, Alzemiers and MS are not to be seen in tropical countries where sun rays are plenty