Holly Murphy

The Role of Vitamin D in Dementia and Alzheimers Disease

Introduction
The importance of Vitamin D or 1,25-dihydroxyvitamin D in bone and skeletal health is long
established [1]. More recently, researchers have taken aim at elucidating Vitamin Ds potential role in the
slowing and prevention of diseases related to cognitive decline such as dementia and Alzheimers disease
(AD). Low serum 25-hydroxyvitamin D [25(OH)D] levels - the precursor to the bioactive 1,25dihydroxyvitamin D [1,25(OH)D] form of the provitamin - have been correlated with declining cognitive
function and conditions such as dementia and AD, but a causative link in humans has not been confirmed
[2]. Possible mechanisms of Vitamin Ds preventative action against cognitive decline have been
suggested, including the provitamins antioxidant capacity and the presence and expression of both
vitamin D receptors (VDRs) and the enzyme 1-alpha-hydroxylase throughout the brain [2,3].
According to global estimates, around 1 billion people are considered Vitamin D insufficient (serum
25(OH]D levels <30ng/mL) or deficient (serum 25(OH)D levels <20 ng/mL) [4]. The elderly are particularly
susceptible, as this population generally spends less time outdoors, intestinal absorption diminishes with
age, and increased body fat stores sequester the provitamin, making it less bioavailable [2, 4]. As the
worlds population continues to grow and age, determining whether vitamin D supplementation is effective
in slowing and/or preventing the onset of cognitive decline, and whether improved vitamin D status
throughout life may prevent such decline altogether is imperative [2].
Literature Review
Scientists have utilized various research methods, each with their own strengths and weaknesses,
in an attempt to uncover the relationship between Vitamin D status and cognitive decline and AD risk.
Methodologies ranging from small, cross-sectional techniques to cohort studies tracking serum status
against dementia and AD for close to two decades have been used to shed light on the possible
connection. Additionally, animal intervention studies have taken aim at uncovering the provitamins
possible mechanism of action.

In investigating prior prospective studies on vitamin Ds relation to diseases of cognitive decline,

Thomas Littlejohn and colleagues found much of the findings to be conflicting [3]. They set out to design
and conduct one of the first large-scale population based studies in the field in order to eliminate statistical
error and correct design flaws that may have been responsible for such discrepant results [3]. One
thousand six hundred fifty-eight elderly participants with no prior diagnosis of stroke or cognitive decline
were assessed for vitamin D status and then followed up with after about 5.6 years [3]. To eliminate the
possibility for reverse causation, participants diagnosed with AD or dementia within the first year of the
study were not included in analyses [3]. The results were quite convincing that a strong association exists
between vitamin D deficiency and a significantly increased risk of cognitive decline [3]. In fact, participants
who were deficient at baseline were 51% more likely to develop dementia and for those severely deficient,
risk was increased by122%.
With its large and diverse sample, this study stands robust, but the researchers recognize certain
limitations including the inability to investigate a possible association between vitamin D status and
vascular dementia, as the number of reported cases was quite small (n=15) likely due to the exclusion of
participants who had previously been diagnosed chronic disease [3]. Analysis with such a small number of
reported cases would lack statistical significance. Its noted that the strong association between vitamin D
status and dementia/AD diagnosis requires further investigation among populations expressing vascular
dysfunction [3].
Buell and colleagues work investigating vitamin D status, dementia and cerebrovascular pathology
helps to bridge the gap left by the limitations of work done by Littlejohns et al. [5]. Working with a much
smaller group of participants, Buell et al. explored vitamin Ds possible mechanism of action in the brain
by comparing vitamin D status, MRI indicators of vascular brain pathology, and changes in the brain
structures of 318 elderly nursing home residents against diagnoses of stroke, dementia and AD [5].
Results indicated that participants with insufficient or deficient serum 25(OH)D levels expressed increased
diagnoses of stroke as well as more than two times the diagnoses of AD and dementia [5]. An inverse
relationship was found between serum 25(OH)D and white matter hyperintensitie (WMH) volume and
concentration or severity, an MRI indicator of vascular brain pathology often seen in brain scans of

patients with neurological disorders [5]. The researchers concluded that their findings suggest that
vitamin Ds role in the brain may be vasculoprotective in the prevention of diseases of cognitive decline
[5]. These findings are consistent with therapeutic intervention studies done with rats exhibiting reduction
in inflammation, improved cognition, and increased excitability of hippocampal neurons with vitamin D
supplementation [2,6].
The researchers of one such study investigated a potential mechanism of action in diseased rats
leading to cognitive decline [6]. Initially, the development of insulin resistance and metabolic syndrome
creates chronic central and peripheral nervous system inflammation [6]. This initiates neurotoxic free
radical production in the brain [6]. These free radicals have the potential to cause neurological damage,
which may result in cognitive decline [6]. In order to mimic this chain of events, two groups of rats were
fed 35% fructose solution over the course of 8 weeks in order to induce hepatosteatosis, or fatty liver
disease, a serious physical manifestation of metabolic syndrome [6]. After the initial 8 weeks, both groups
were supplemented with oral vitamin D for 2 weeks [6]. Just one of these groups continued to consume
the 35% fructose solution in addition to oral vitamin D supplementation [6]. A third group never consumed
the fructose solution but was supplemented with vitamin D [6]. The control was neither fed fructose
solution nor vitamin D, just standard rat chow [6]. After the treatment period, the rats were evaluated
using passive avoidance tests, intended to gauge memory latency, and then euthanized [6]. Each rats
plasma, liver and brain were analyzed [6]. The researchers found that while vitamin D supplementation
without hepatosteatosis did not have a significant effect on memory, rats with induced hepatosteatosis
expressed a significant reduction in memory [6]. However, when supplemented with vitamin D, the
diseased rats showed marked improvement in this measure [6]. Brain and plasma analysis revealed that
rats expressing metabolic syndrome also had elevated indicators of inflammation and oxidative stress as
measured by tumor necrosis factor alpha (TNF- alpha) levels and plasma maladialdehyde (MDA).
However, these biomarkers were significantly mitigated by vitamin D supplementation [6]. These findings
expand on the possible preventative and vasculoprotective effects of Vitamin D put forth by Buell et al. by
suggesting that emergency or defensive action may be taken within the brain by up-regulation or
activation of vitamin D receptors given life-threatening conditions like chronic inflammation [5,6].

In another animal intervention study, Latimer et al. fed middle-aged rats low, medium or highvitamin D diets for 6 months in order to mimic human 25(OH)D deficient, insufficient and sufficient serum
levels [2]. Each rats vitamin D status was measured before they underwent testing of hippocampaldependent learning and memory [2]. The rats on the high vitamin D diet consistently and outperformed
rats on the low and medium vitamin D diets in various measures of learning and memory retention [2]. In
order to connect serum 25(OH)D levels with possible mechanisms of cognitive function, the researchers
examined the expression of 10,071 genes within the hippocampus of rats from each treatment group [2].
Expression of 128 of these genes differed significantly in the hippocampus of the high-vitamin D diet
treatment rats versus low and medium treatment. Further, many of these 128 genes are known to be
involved in neuronal functioning, including synaptic transmission and cell communication [2]. The loss of
such functions is often observed as an early sign of aging [2]. Latimer and colleagues work suggests
vitamin Ds action in gene regulation through adequate serum status throughout life may serve as a
preventative mechanism for cognitive decline [2].
In contrast to several prospective analyses on Vitamin D status and cognitive decline, Schneider
and colleagues recently published their work finding no significant association between serum 25(OH)D
and dementia risk or cognitive function - either at baseline or over the course of around 16.6 years [4].
The authors expressed concern around methodologies used in past research, specifically selecting
participants too late in life. The effects of age and cognitive decline may already be altering daily behavior
like time spent outdoors, thus opening the possibility for reverse causation [4]. Its possible that low serum
25(OH)D may simply be an indicator of poor health or other compounding factors of aging, rather than a
causative link to cognitive decline [4]. To correct for this source of error, the researchers selected a
younger population of individuals than typically studied, ages 45 to 65, measured serum 25(OH)D levels,
and tracked cognitive functioning through various verbal and reasoning tests and MRIs for close to two
decades [4].

Limitations
While an association appears to exist between vitamin D status and cognitive decline, current
research is not conclusive and is at times conflicting [3,4]. The prospective, cohort nature of much of the
current research investigating a possible connection is limited in its generalizability across differing
populations and ethnic backgrounds and in providing the ability for researchers to draw causative
conclusions. Further, reverse correlation or the possibility that vitamin D status may be a result of other
compounding factors of age or early signs of cognitive decline prior to diagnosis must be considered and
associations made cautiously [3,4,5]. Associations made between animal models and human cognitive
function must also be made cautiously [2,6]. Last, as vitamin D status may fluctuate throughout ones life,
a single measure of serum 25(OH)D tracked against cognitive decline may not be fully representative or
even significant.
Future Directions
Randomized supplementation studies conducted with human participants will be necessary in
order generalize causative relationships demonstrated in animal models [2]. Additionally, future
longitudinal studies tracking vitamin D status and markers of cognitive function at multiple points from
youth through middle age and older would be useful in reducing error due to reverse causation, survivor
bias and varying serum vitamin D status throughout life.
Conclusions
As the worlds population continues to grow and age in greater numbers, determining whether
vitamin D supplementation is effective in slowing or preventing the onset of cognitive decline is more
critical than ever before [2]. A greater understanding into the connection between vitamin D status and
degenerative diseases of the mind will aid the medical community in the treatment of individuals already
suffering from diseases like dementia and AD, as well provide younger populations with lifelong protective
measures for successful cognitive aging.

References:
1. Ross AC, Caballero B, Cousins RJ, Tucker KL, Ziegler TR. Vitamin D. In: Modern Nutrition in
Health and Disease. 11th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2014: 278-292.
2. Latimer CS, Brewer LD, Searcy JL, et al. Vitamin D prevents cognitive decline and enhances
hippocampal synaptic function in aging rats. Proceedings of the National Academy of Sciences.
2014; 111(41): E4359-E4366.
3. Littlejohns TJ, Henley WE, Lang IA, et al. Vitamin D and the risk of dementia and Alzheimer
disease. American Academy of Neurology. 2014; 83(10): 920-8.
4. Schneider ALC, Lutsey PL, Alonso A, et al. Vitamin D and cognitive function and dementia risk in a
biracial cohort: the ARIC Brain MRI Study. European Journal of Neurology. 2014; 21: 1211-18.
5. Buell JS, Dawson-Hughes B, Scott TM, et al. 25-Hydroxyvitamin D, dementia, and cerebrovascular
pathology in elders receiving home services. Neurology. 2010; 74(1): 18-26.
6. Erbas O, Solmaz V, Aksoy D, Yavasoglu A, Mustafa S, Taskiran D. Cholecalciferol (vitamin D 3)
improves cognitive dysfunction and reduces inflammation in a rat fatty liver model of metabolic
syndrome. Life Sciences. 2014; 103: 68-72.