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.
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
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.
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.
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.
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.
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.)
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.
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.
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
How would vitamin D protect the brain?
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.
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.)
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.
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.”
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.
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.
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
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.
vitamin D could be a marker of poor health generally,” says Nordestgaard.
A clinical trial
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
sure that as a secondary endpoint they will look at Alzheimer’s disease,”