Review

Click here to view the article Editorial Comment by M. F. Holick doi: 10.1111/joim.12279

‘Vitamin D and cognition in older adults’: updated

international recommendations
C. Annweiler1,2, E. Dursun3, F. F
eron4, D. Gezen-Ak3, A. V. Kalueff5, T. Littlejohns6, D. J. Llewellyn6, P. Millet4,
T. Scott7, K. L. Tucker8, S. Yilmazer3 & O. Beauchet1
From the 1Department of Neuroscience, Division of Geriatric Medicine and Memory Clinic, UPRES EA 4638, UNAM, Angers University
Hospital, Angers, France; 2Department of Medical Biophysics, Robarts Research Institute, Schulich School of Medicine and Dentistry, the
University of Western Ontario, London, ON, Canada; 3Department of Medical Biology, Cerrahpasa Faculty of Medicine, Istanbul University,
Istanbul, Turkey; 4CNRS, NICN UMR 7259, Aix Marseille Universit e, Marseille, France; 5ZENEREI Institute, Slidell, LA, USA; 6University of
Exeter Medical School, Exeter, UK; 7Jean Mayer USDA Human Nutrition Research Center on Aging, Tufts University, Boston, MA, USA; and
8
Department of Clinical Laboratory and Nutritional Sciences, University of Massachusetts, Lowell, MA, USA

Abstract. Annweiler C, Dursun E, F
eron F, Gezen-Ak Results. The experts reached an agreement that
D, Kalueff AV, Littlejohns T, Llewellyn DJ, Millet P, hypovitaminosis D increases the risk of cognitive
Scott T, Tucker KL, Yilmazer S, Beauchet O (Angers decline and dementia in older adults and may alter
University Hospital, Angers, France; University of the clinical presentation as a consequence of
Western Ontario, London, ON, Canada; Istanbul related comorbidities; however, at present, vitamin
University, Istanbul, Turkey; Aix Marseille D level should not be used as a diagnostic or
Universit
e, Marseille, France; ZENEREI Institute, prognostic biomarker of Alzheimer’s disease due to
Slidell, LA, USA; University of Exeter Medical lack of specificity and insufficient evidence. This
School, Exeter, UK; Tufts University, Boston, MA, population should be screened for hypovitaminosis
USA; University of Massachusetts, Lowell, MA, D because of its high prevalence and should receive
USA). ‘Vitamin D and cognition in older adults’: supplementation, if necessary; but this advice was
updated international recommendations (Review). not specific to cognition. During the debate, the
J Intern Med 2015; 277: 45–57. possibility of ‘critical periods’ during which vitamin
D may have its greatest impact on the brain was
Background. Hypovitaminosis D, a condition that is addressed; whether hypovitaminosis D influences
highly prevalent in older adults aged 65 years and cognition actively through deleterious effects and/
above, is associated with brain changes and or passively by loss of neuroprotection was also
dementia. Given the rapidly accumulating and considered.
complex contribution of the literature in the field
of vitamin D and cognition, clear guidance is Conclusions. The international task force agreed on
needed for researchers and clinicians. five overarching principles related to vitamin D and
cognition in older adults. Several areas of uncer-
Methods. International experts met at an invitational tainty remain, and it will be necessary to revise the
summit on ‘Vitamin D and Cognition in Older proposed recommendations as new findings
Adults’. Based on previous reports and expert become available.
opinion, the task force focused on key questions
relating to the role of vitamin D in Alzheimer’s Keywords: Alzheimer’s disease, brain, cognition, neu-
disease and related disorders. Each question was roendocrinology, older adults, vitamin D.
discussed and voted using a Delphi-like approach.

hormone vitamin D receptor (VDR) [2–7]. New

Introduction
target organs, such as the central nervous system
About 1 billion individuals worldwide are estimated (CNS), and evidence for a neurosteroid action of
to have hypovitaminosis D (i.e. inadequate levels of vitamin D have been reported [3–8]. The need to
serum 25-hydroxyvitamin D (25OHD) below explore the adverse impact of vitamin D depriva-
75 nmol L 1 or 30 ng mL 1) [1, 2]. In addition to tion on the ageing brain seems especially
regulating bone metabolism, vitamin D exerts important because nearly one in two older adults
multiple biological actions mediated by the nuclear (i.e. aged 65 years and above) [2] and 70–90% of

ª 2014 The Association for the Publication of the Journal of Internal Medicine 45
 13652796, 2015, 1, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/joim.12279 by Cochrane Philippines, Wiley Online Library on [16/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
C. Annweiler et al. Review: Vitamin D and cognition

adults with cognitive difficulties [9] have hypovita- participants. After discussion, the following pro-
minosis D. Together, this raises the possibility that gramme was approved by all: (i) neurosteroid
vitamin D plays a role in the natural history of properties of vitamin D (KLT and TS); (ii) contribu-
cognitive dysfunction, including Alzheimer’s dis- tion of transgenic animal models to understanding
ease (AD) and related disorders (ADRDs) [9–13]. the neurological effects of vitamin D (AVK); (iii)
vitamin D and ADRDs: lessons from animal models
Because of the rapidly accumulating and complex (FF); (iv) brain changes associated with hypovita-
contribution of both basic and clinical research in minosis D (CA); (v) polymorphisms of vitamin D
this field, an invitational summit of leading experts receptors: clinical implication for human variants
was convened in order to (i) identify areas clearly (ED and DGA); (vi) cognitive disorders and hypovi-
supported by the literature, (ii) nuance findings taminosis D: observational approach (DJL and TL);
that remain not proven, (iii) raise new research and (vii) vitamin D intake and cognition: interven-
questions and (iv) provide clear guidelines to the tional approach (OB).
medical and scientific communities.
In the third step, the task force met in person on 15
July 2013 at the invitational summit in Boston,
Methods
MA, USA. After presentations relating to each
Consensus finding at the invitational summit of aspect of the programme, group discussions were
experts consisted of a three-step process. In the held to attempt to identify consensus and disagree-
first step, in February 2013, the first author (CA) ments, in order to highlight knowledge gaps and to
invited leading international experts, including emphasize key messages for the scientific and
physicians and scientists from a wide range of medical communities. Finally, the discussion
disciplines identified on the basis of their relevant focused on five key questions regarding the impli-
publications and citations, to form an international cations of vitamin D as a risk factor for ADRDs, as
task force. All invited experts accepted the need for a diagnostic and/or prognostic biomarker of
a task force and agreed to meet at an invitational ADRDs, as an explanation of the variability of the
summit. clinical manifestations of ADRDs and the potential
benefits of vitamin supplementation D in the
In the second step, all experts communicated by management of ADRDs (Table 1). The 10 experts
email with the first author to better identify voted on each key questions: ‘yes’ (agreement) or
respective areas of expertise, discuss unmet needs ‘no’ (disagreement). It was agreed that questions
and potential learning objectives in the field and supported by ≥75% of ‘yes’ votes would be imme-
propose a holistic approach to the issue of ‘vitamin diately accepted whereas those with <25% would
D and cognition’ based on the expertise of all be rejected outright. Others would be subjected to

Table 1 Position of experts on key questions related to ‘Vitamin D and cognition in older adults’

Experts’ answers
(n = 10) Agreement
Questions Yes No percentage (%)
Can hypovitaminosis D be considered an aetiological/risk 10 0 100
factor for cognitive disorders/ADRDs?
Can serum vitamin D status be considered a useful biomarker 1 9 90
for the diagnosis of ADRDs?
Can serum vitamin D status be considered useful for determining 0 10 100
the prognosis of ADRDs?
Can serum vitamin D status explain part of the variability in 10 0 100
symptoms of ADRDs in older adults?
Should vitamin D supplementation be part of the care management 9 1 90
of older adults with cognitive disorders/ADRDs?

46 ª 2014 The Association for the Publication of the Journal of Internal Medicine
Journal of Internal Medicine, 2015, 277; 45–57
 13652796, 2015, 1, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/joim.12279 by Cochrane Philippines, Wiley Online Library on [16/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
C. Annweiler et al. Review: Vitamin D and cognition

further discussion and subsequent voting, where transport at the BBB [19], resulting in a decreased
≥67% support or, in an eventual third round, a number of amyloid plaques [20]. In addition, it
majority of ≥50% would be needed for acceptance. was reported that vitamin D regulates intraneu-
After the face-to-face meeting, the statements were ronal calcium homoeostasis via the regulation of
distributed to the committee members by email for voltage-gated calcium channels [21], including
final comments. Only suggestions for improve- those targeted by Ab [22], supporting the idea
ments for clarity of wording or to address redun- that vitamin D has the potential to rearrange
dancies were considered, whilst changes to the neuronal calcium homoeostasis altered by the Ab
meaning were not accepted. peptide. Finally, vitamin D was shown to exhibit
neuroprotective properties against glutamate tox-
Results icity [23, 24] through the upregulation of VDR
expression [23] and antioxidant effects [24].
Overview of the research topic
Indeed, it has been reported that vitamin D
At the beginning of the summit, the experts protects against free radicals generated by reactive
discussed the current status of the research topic. species of oxygen [24] and nitric oxide [25],
inhibits the synthesis of inducible nitric oxide
Neurosteroid properties of vitamin D: involvement in synthase [26] and regulates the activity of the c-
neurophysiology glutamyl transpeptidase [4], which is a key
Vitamin D enters the cerebrospinal fluid (CSF) and enzyme involved in the antioxidant metabolism of
brain by crossing the blood–brain barrier (BBB) via glutathione.
passive diffusion and via specific carriers in the
cerebral capillaries or the blood–CSF barrier in the Interestingly, these effects relate to mechanisms
plexus choroideus [14, 15]. The concentration of implicated in the pathogenesis of AD (Fig. 1),
25OHD (circulating form of vitamin D) in the CSF which suggests that the lack of vitamin D may
positively correlates with that in the serum under explain at least part of the natural history of this
physiological conditions [14]. In situ, vitamin D disease [27].
exerts most of its actions through its nuclear
hormone receptor the VDR, which is expressed in Hypovitaminosis D and/or inefficient utilization of
neuronal and glial cells in almost all regions of the vitamin D: which is most important?
CNS. In particular, the VDR is expressed in the Accumulating evidence suggests that hypovita-
hippocampus, hypothalamus, cortex and subcor- minosis D could be associated with the pathogen-
tex [5–7], the areas essential for cognition. The esis of AD. However, based on recent findings
active form of vitamin D, 1,25-dihydroxyvitamin D from in vitro studies that the vitamin D pathway is
(1,25OHD), has a trophic function of neuronal the target of Ab-induced toxicity in AD, this
differentiation and maturation via control of the question can be addressed in a different way.
synthesis of neurotrophic agents such as nerve Essentially, Ab renders neurons deficient in vita-
growth factor (NGF) and glial cell line-derived min D by increasing the degradation of active
neurotrophic factor (GDNF) [7, 16]. It also acceler- vitamin D and VDR [22, 28]. This may be referred
ates neuronal growth in rat hippocampal cell to as ‘inefficient utilization of vitamin D’. Ab may
cultures [16]. Moreover, 1,25OHD regulates the disrupt the utilization of vitamin D in the brain
genetic expression of numerous neurotransmitters even if the systemic concentration meets the
in the brain, including acetylcholine, dopamine, requirements of the brain. Any alteration in genes
serotonin and c-aminobutyric acid, notably in the related to the action of vitamin D, including its
hippocampus [4, 5]. receptors (VDR and 1,25-MARRS [membrane
associated, rapid response steroid-binding]),
Neurosteroid properties of vitamin D: neuroprotec- enzymes related to its metabolism or transporters,
tive action may also result in inefficient utilization of vitamin
Vitamin D appears to enhance neuronal defence. D, thus making neurons vulnerable to neurode-
Studies in mice have demonstrated that vitamin D generation [22, 28–32]. This possibility is sup-
may reverse age-related inflammatory changes in ported by the association between AD and
the hippocampus [17]. Vitamin D has also been polymorphisms of VDR and megalin [30, 31, 33]
shown to attenuate amyloid-b (Ab) 42 accumula- and the toxic effects of VDR and 1,25-MARRS
tion by stimulating phagocytosis of the Ab peptide suppression in neurons [29, 32, 34]. Although
[18], and enhance brain-to-blood Ab efflux hypovitaminosis D and inefficient utilization of

ª 2014 The Association for the Publication of the Journal of Internal Medicine 47
Journal of Internal Medicine, 2015, 277; 45–57
 13652796, 2015, 1, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/joim.12279 by Cochrane Philippines, Wiley Online Library on [16/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
C. Annweiler et al. Review: Vitamin D and cognition

Fig. 1 Potential targets and

neuroprotective roles of vitamin
D during the natural history of
Alzheimer’s disease.

vitamin D seem to be two different variables, Consequences of vitamin D deprivation on brain

crosstalk between the two should not be ignored structures
when considering the pathogenesis of AD. Few studies have investigated the effect of inade-
quate vitamin D status on brain structures. In
Consequences of the inefficient utilization of vitamin terms of brain volumetry, it was shown that rats
D on phenotype: the VDR knockout mouse model born to vitamin D-deficient mothers had profound
The VDR knockout (VDR-/-) mouse is a powerful alterations in the brain at birth compared to
model of disrupted vitamin D–VDR signalling and control animals, with a thinner cortex and
inefficient utilization of vitamin D in the CNS. Of enlargement of the lateral ventricles [41]. In
note, several robust phenotypes of the VDR-/- humans, no significant difference in whole-brain
mouse have been revealed. In particular, acceler- volume and sulcal grade according to serum
ated ageing was clearly observed in VDR-/- mice vitamin D levels was observed in one study [42],
[35], which may contribute to cognitive and whereas in another one, an association between
behavioural deficits in these mice. Consistently, vitamin D concentration and ventricular volume (a
mild cognitive deficits have been shown in VDR-/- proxy for brain atrophy) was found in older adults
mice [36]. Elevated anxiety and neophobia were [43]. This difference only applied to the main
also seen across multiple tests in these mice on ventricular bodies, and not to the temporal horns.
several different background strains [37]. Altered Consistently, no difference in hippocampal volume
instinctive and social behaviours, evidenced by was reported according to vitamin D levels
aberrant maternal behaviours, were also reported amongst older community dwellers in the former
[38]. In addition, progressive decline in sensory study [42].
abilities (especially hearing and balancing) of
VDR-/- mice [39] together with several motor Studies in rats to examine brain vascular changes
abnormalities [37, 40] have been demonstrated. showed that vitamin D attenuated cortical infarc-
These factors may also contribute nonspecifically tion induced by cerebral arterial ligation [44]. In
to overall cognitive decline and aberrant pheno- humans, a meta-analysis showed clearly, in both
types. cross-sectional and longitudinal studies, that the
risk of stroke was increased with hypovitaminosis
In general, findings from mouse models seem to D [45]. Of interest, this finding was also true for
parallel accumulating clinical evidence in various more subtle changes such as white matter damage
neurobehavioural domains. The specific issue of [42], which is thought to disrupt cortical–subcor-
changes in the brain (i.e. the organ that supports tical white matter tracts that connect important
high-level functions) related to vitamin D depriva- cognitive regions of the brain [46]. Thus, it is
tion should be considered. possible that cerebrovascular changes linked to

48 ª 2014 The Association for the Publication of the Journal of Internal Medicine
Journal of Internal Medicine, 2015, 277; 45–57
 13652796, 2015, 1, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/joim.12279 by Cochrane Philippines, Wiley Online Library on [16/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
C. Annweiler et al. Review: Vitamin D and cognition

hypovitaminosis D could explain some higher-level exert a cognitive effect [54], and consensual
disorders in older adults. supplementation, with the objective to raise the
concentration of 25OHD above 30 ng mL 1 (i.e.
Vitamin D deprivation and cognitive disorders: 75 nmol L 1), appears to be sufficient [56].
observational approach in older adults
Recent large and representative epidemiological
Consensus finding
population-based studies have been conducted to
examine the relationship between hypovitaminosis Following this overview of the different aspects of
D and cognitive disorders/ADRDs [9]. Subsequent ‘vitamin D and cognition in older adults’, the
meta-analyses confirmed that a low vitamin D experts expressed and discussed their position on
concentration in older adults is associated with the following five key questions (Table 1).
reduced cognitive performance [10, 12, 13], and is
more prevalent in those with AD [11, 12]. Never- Can hypovitaminosis D be considered an aetiolog-
theless, the possibility of reverse causality remains ical/risk factor for cognitive disorders/ADRDs?. In
a major concern; in other words, does hypovita- response to the first question (Table 1), all experts
minosis D contribute to cognitive decline or does agreed that hypovitaminosis D (and/or the ineffi-
cognitive decline lead to hypovitaminosis D? [27]. cient utilization of vitamin D) can be considered a
Importantly, further longitudinal prospective stud- aetiological/risk factor for cognitive decline and for
ies [47–49] have helped to establish the temporal dementia in general. This notion is supported in
sequence between hypovitaminosis D and cognitive part by experimental evidence showing an action of
disorders, showing that older individuals with vitamin D in the CNS [3–8], and primarily by
lower vitamin D concentrations had a significantly prospective longitudinal studies in humans, which
increased risk of global cognitive decline and have consistently demonstrated that vitamin D
executive dysfunction compared to those with concentration in older adults is associated with
higher concentrations [13]. Moreover, in addition subsequent cognitive change and, in particular,
to effects on cognitive decline, preliminary studies that hypovitaminosis D predicts incident occur-
confirmed that low vitamin D was associated with rence of cognitive decline and dementia [13, 48–51].
an increased risk of AD [50] and incident all-cause In addition, it is noteworthy that several preclinical
dementia [51]. Overall, there is evidence from studies have shown that the genetic polymorphism
observational studies indicating that low vitamin of VDR explains the existence of responders and
D concentrations contribute to the occurrence of nonresponders to vitamin D and modulates the
cognitive decline and dementia in older adults. neuroprotective efficiency of vitamin D, thus
explaining a higher rate of ADRDs in nonresponders
Vitamin D supplements and cognition: intervention- [30, 31]. For instance, a significant association was
al approach shown between the VDR gene APA1 polymorphism
Few intervention studies have been conducted spe- and the occurrence of AD, with the ‘Aa’ genotype
cifically to test the effect of vitamin D supplements increasing by 2.3-fold the risk of developing AD
on cognitive function. Of interest, observational compared to the ‘AA’ genotype [30]. Also in the same
studies have reported that a higher intake of vitamin study, the ‘AATT’ combined genotype was found to
D (whether from food, supplements or sun exposure) be less common in patients with AD than in healthy
is associated with better cognitive function in older control subjects [30].
individuals [27]. For instance, consuming more
than 800 IU of vitamin D per day resulted in a Can serum vitamin D status be considered a useful
fivefold reduction in the risk of AD after 7 years of biomarker for the diagnosis of ADRDs?. In
follow-up [52]. This neuroprotective effect has been response to the second question (Table 1), all
further confirmed by before–after studies and quasi- experts except one (CA) agreed that the concentra-
experimental studies reporting cognitive improve- tion of serum 25OHD cannot be used as a biomarker
ment after vitamin D supplementation in the general of ADRDs. The arguments in favour of its use as a
population of seniors [53] as well as in patients who biomarker were that 25OHD is the most effective
already have symptoms of ADRDs [54]. The cognitive indicator of vitamin D status and can be considered
benefits of supplementation appear from 4 weeks as a ‘biological indicator characterizing pathological
[55] and seem to be particularly strong for processes’ according to the definition of the World
executive function and processing speed [13]. Health Organization [57]. For example, in a previous
Supraphysiological doses may not be necessary to meta-analysis, it was shown that the probability

ª 2014 The Association for the Publication of the Journal of Internal Medicine 49
Journal of Internal Medicine, 2015, 277; 45–57
 13652796, 2015, 1, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/joim.12279 by Cochrane Philippines, Wiley Online Library on [16/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
C. Annweiler et al. Review: Vitamin D and cognition

that an individual without AD would have a higher the case in patients with ADRDs. It was stated
serum 25OHD concentration than an individual that studies addressing this specific issue are
with AD was 140% if both were selected randomly required.
from a population [11]. The arguments against the
use of serum 25OHD as a biomarker were that Can serum vitamin D status explain part of the
hypovitaminosis D is too common in older adults [1, variability in symptoms of ADRDs in older adults?. In
2] and that it is not sufficiently specific to be an response to the fourth question (Table 1), all experts
efficient biomarker of ADRDs, or to be useful for the agreed that vitamin D can explain, at least in part,
screening or diagnosis of ADRDs or for evaluating the diversity of symptoms in ADRDs. First, hypovi-
the response or tolerance to medical treatment. After taminosis D affects many organs other than the
discussion, the expert (CA) agreed that a systematic brain and has been associated with numerous
serum vitamin D determination is not justified as a diseases such as hypertension, type 2 diabetes,
biomarker for the diagnosis of ADRD, but added that vascular disease and osteoporosis, as well as the
the prevalence of hypovitaminosis D is sufficiently propensity to fall [1, 2] (Fig. 2). All these conditions
high in those with cognitive disorders/ADRDs that a may be found in patients with both ADRDs and
vitamin D assay is justified in this population to hypovitaminosis D, thus affecting patients’ func-
detect and supplement the probable hypovitamino- tional independence and the clinical presentation.
sis D. This addition was approved by all experts. Secondly, on the basis of animal experiments using
Finally, the group noted that the potential of other VDR-/- mice, it appears that genetic polymor-
vitamin D-related proteins such as the vitamin D- phisms of VDR may regulate the efficiency of vita-
binding protein (VDBP) should not be dismissed, min D use, resulting not only in cognitive but also in
and evaluation in larger studies is required [58, 59]. various noncognitive manifestations [35–40]. It was
thus concluded that alterations in the vitamin D/
Can serum vitamin D status be considered useful VDR axis might explain part of the variability in
for determining the prognosis of ADRDs?. In clinical characteristics observed in ADRDs.
response to the third question (Table 1), all
experts agreed that it is impossible at present to Should vitamin D supplementation be part of the
determine whether vitamin D status is a prog- care management of older adults with cognitive
nostic marker for ADRDs, as no studies have yet disorders/ADRDs?. In response to the final ques-
examined the risk of cognitive decline according tion (Table 1), all experts except one (TS) agreed
to vitamin D status in patients with ADRDs. that vitamin D supplements should be part of the
Specifically, it is unclear whether patients with care management of older adults with cognitive
hypovitaminosis D progress more quickly to a disorders/ADRDs (Table 1). The arguments
more severe stage of dementia than patients with against vitamin D supplementation in this popu-
higher vitamin D levels. Of note, such studies in lation were based on the small number of clinical
nondemented individuals have shown that hypo- trials in the field, and the lack of well-conducted
vitaminosis D predicted a faster and greater randomized clinical trials (RCTs) to test the effec-
cognitive decline compared to higher vitamin D tiveness of vitamin D supplements against pla-
levels [47–49], suggesting that this may also be cebo in patients with ADRDs [27]. Arguments in

Fig. 2 Relationship between

vitamin D and Alzheimer’s dis-
ease/vascular dementia: an
overview of the different condi-
tions, mechanisms and inter-
actions that may be involved.
Arrows represent the causal
direction of the influences.

50 ª 2014 The Association for the Publication of the Journal of Internal Medicine
Journal of Internal Medicine, 2015, 277; 45–57
 13652796, 2015, 1, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/joim.12279 by Cochrane Philippines, Wiley Online Library on [16/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
C. Annweiler et al. Review: Vitamin D and cognition

favour of this option were discussed. First, the inter-relationship between these disorders. On one
results of the few reported clinical trials were hand, dementia may alter the prognosis and
generally positive [53–56]. In particular, despite management of other chronic diseases. On the
their design limitations, before–after studies have other hand, chronic diseases can precipitate the
shown cognitive improvements, mainly of execu- evolution of dementia, changing the clinical pre-
tive functions, after vitamin D supplementation, sentation and accelerating the loss of indepen-
as highlighted by a meta-analysis [13]. Secondly, dence, which is the major determinant of patients’
whilst vitamin D repletion has positive effects on quality of life. Of note, the action of vitamin D is
the brain as well as on a number of other organs not confined to the brain; vitamin D also affects
[1, 2], with substantial benefits in terms of multiple other tissues and organs, and age-related
survival [60, 61], no adverse effects have been hypovitaminosis D has been associated with a
reported for consensual supplementation [62], number of conditions, including vascular disease,
which reduces the risk of this practice. After hearing loss, loss of visual acuity and osteoporosis
discussion, the expert (TS) agreed that patients [1, 2, 64]. This complicates the interpretation of
with both cognitive decline/ADRDs and hypovita- the impact of vitamin D on cognition. The different
minosis D should receive vitamin D supplemen- possible interactions between socio-demographic
tation, but added that this advice is not specific characteristics of older adults, their vitamin D
for cognitive decline/ADRDs and is justified by all status and the brain and nonbrain determinants
the expected bone and nonbone effects of vitamin of dementia are shown in Fig. 2. To better under-
D supplementation. This addition was approved stand the effect of vitamin D on these interactions,
by all experts. a model was proposed (Fig. 3) in which A, the
cognitive performance, is ‘balanced’ against B, the
performance/health/function of another organ/
Discussion
tissue of the body that is related to neurocogni-
The summit enabled international experts to adopt tion. Scenario 0 in Fig. 3 represents the ground
a common position on five issues of primary state, with basal functioning of cognition (A) and
importance for clinicians and researchers inter- of the other condition related to neurocognition
ested in the relationship between vitamin D and (B). Four other scenarios are shown in which the
cognition. It was concluded that hypovitaminosis A/B balance changes following vitamin D supple-
D and the inefficient utilization of vitamin D mentation. The first scenario corresponds to an
increase the risk of cognitive decline/ADRDs in overall improvement in both A and B (e.g.
older adults and may alter the clinical presentation improvement in hypertension and cognition fol-
of the disease, particularly as a consequence of lowing addition of vitamin D) [65]. The second
accompanying morbidities; however, current evi- scenario corresponds to an overall deterioration in
dence is insufficient to recommend hypovitamino- A and B (e.g. vascular calcification and deteriora-
sis D as a reliable diagnostic or prognostic tion in cerebrovascular health following addition
biomarker of cognitive decline/ADRDs. Moreover, of vitamin D) [66]. The third scenario corresponds
the experts recommended correcting hypovitamin- to an improvement in A, but a deterioration in B
osis D in individuals with cognitive decline/AD- (e.g. cognitive enhancement but transient
RDs. However, this advice was not specific for increased risk of falls following addition of a high
cognitive decline/ADRDs, and further well-con- dose of vitamin D) [67]. Finally, the fourth sce-
ducted RCTs are required to test more specifically nario corresponds to an improvement in B accom-
the causal relationship between hypovitaminosis D panied by a deterioration in A (e.g. increased
and cognitive decline/ADRDs. Finally, the follow- calcium absorption in the digestive tract following
ing new approaches and research questions were addition of vitamin D with a consequent amelio-
debated. rative effect on secondary osteoporosis, but a
deleterious effect on vascular calcification and
cerebrovascular health) [66]. Thus, due to the
The need to consider both brain and nonbrain effects of vitamin D
ubiquitous role of vitamin D, elucidating its cog-
when examining cognition
nitive effects is more complex than investigating
Ageing is accompanied by an increased incidence only the cerebral actions, and future basic and
of both dementia and chronic conditions, such as clinical studies should take into account all the
cardiovascular disease, neurosensorial deficits effects of vitamin D in the body, particularly with
and osteoporosis [63]. In fact, there is a close regard to morbidity burden.

ª 2014 The Association for the Publication of the Journal of Internal Medicine 51
Journal of Internal Medicine, 2015, 277; 45–57
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C. Annweiler et al. Review: Vitamin D and cognition

Fig. 3 Schematic diagram of

the possible influences of vita-
min D supplements on the bal-
ance between cognition (a) and
comorbidities (b). See text for
further details and examples.

period when vitamin D may have a beneficial effect

The ‘critical periods’ hypothesis
on neurological development (Fig. 4b); (ii) at youn-
The discussion of the action of vitamin D in the ger ages during which vitamin D would increase
CNS also raised the possibility of ‘critical periods of cognitive abilities and enhance cognitive reserve
life’ during which vitamin D may have the greatest (Fig. 4c); and (iii) at older ages during which
impact on the CNS and during which sufficient vitamin D would prevent neurocognitive loss
vitamin D would be essential. Previous studies (Fig. 4d).
have shown that variables related to the develop-
ment of ADRDs are present at particular times of These assumptions are consistent with previous
life, commonly long before the onset of disease [68]. experiments in animals. Specifically, it has been
A proposed representation of neurocognitive func- shown that rats born to vitamin D-deficient
tion is shown graphically in Fig. 4a. We have mothers had profound brain alterations at birth
identified a period of rapid neurobehavioural [41], consistent with altered signals for neuronal
development during the prenatal stage (especially differentiation [41]. The continuing brain changes
gain of brain volume, and also gain of brain after restoration of a normal vitamin D-containing
function) and younger ages (especially gain of diet [70], together with the observation of abnor-
function, and also gain of volume), a plateau phase mal adult behaviours [71], suggested that prena-
corresponding to adulthood and finally a phase of tal hypovitaminosis D disrupted not only brain
brain volume and function loss corresponding to development but also adult brain functioning.
older ages. In this model, the curve is similar to Additionally, in humans, although an association
that of the well-known lifetime changes in bone between cognitive disorders and hypovitaminosis
mass [69]. For prevention of osteoporosis in D has been reported during the foetal period [72,
women, it is important to (i) reach a peak in bone 73] and older ages [9–13], no studies conducted
mass as high as possible at the end of the growth amongst younger adults have found an associa-
period, and (ii) reduce the slope of decline as much tion between vitamin D and cognitive perfor-
as possible after the menopause [69]. With similar mance [74]. This suggests that vitamin D may
logic, based on the neurophysiological effects of play a crucial role in enhancing neurocognition
vitamin D, we suggest that there are three critical during foetal development, growth and senes-
periods in which cognitive impairment in the cence, but less of (or no) role during adulthood.
elderly can be prevented: (i) during the prenatal Such suggestions should be confirmed by further

52 ª 2014 The Association for the Publication of the Journal of Internal Medicine
Journal of Internal Medicine, 2015, 277; 45–57
 13652796, 2015, 1, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/joim.12279 by Cochrane Philippines, Wiley Online Library on [16/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
C. Annweiler et al. Review: Vitamin D and cognition

(a) (b)

(c) (d)

Fig. 4 Schematic diagram of the evolution of neurocognitive health throughout life (a), and the possible influence of vitamin
D at potential critical periods: prenatal (b), younger age (c) and older age (d).

studies, but could justify public health measures possibility should be considered that vitamin D is
to systematically provide supplements for preg- instead a neuroprotective agent, as suggested by
nant women, young children and elderly in order its antioxidant and anti-inflammatory effects [4–8],
to prevent cognitive and behavioural disorders. and its insufficiency could ‘passively’ lead to
increased CNS sensitivity with a reduced response
to ‘dementiogenic’ stress. Although this question of
Vitamin D: is there an ‘active’ or ‘passive’ influence on
whether the influence on neurocognition is ‘active’
neurocognition?
or ‘passive’ may appear trivial, the difference is in
The attempt to elucidate the mechanism of action fact crucial because it affects our future approach
of vitamin D on neurocognition raised the issue of to vitamin D repletion. Indeed, just enough sup-
whether lower levels/inefficient utilization of vita- plementation to correct hypovitaminosis D should
min D are causal factors that ‘actively’ trigger be sufficient if vitamin D is considered to be a
ADRDs or risk factors that ‘passively’ abolish CNS neuroprotectant, whereas much higher doses may
protection against ADRDs. The rationale for active be considered, with the aim of boosting mental
involvement of hypovitaminosis D in the genesis of faculties, if vitamin D ‘actively’ controls the CNS.
ADRDs is based on the involvement of vitamin D in Furthermore, determining whether hypovitamino-
neurophysiology (i.e. its neurotrophic role and the sis D is actively or passively involved in the history
regulation of neurotransmitters) [4–8], with the of ADRDs will help to define the objectives and
possibility that vitamin D insufficiency results in a outcomes of future RCTs. In other words, should
pathological dysfunction of the brain leading to vitamin D supplementation be tested for prevent-
ADRDs. An epidemiological argument against such ing the occurrence of ADRDs, or for reducing its
active involvement is based on the finding that 70– symptoms? And could hypovitaminosis D be
90% of older adults have hypovitaminosis D but involved in the resistance to standard antidementia
most do not suffer from ADRDs [2]. Thus, the treatments? If hypovitaminosis D explains in part

ª 2014 The Association for the Publication of the Journal of Internal Medicine 53
Journal of Internal Medicine, 2015, 277; 45–57
 13652796, 2015, 1, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/joim.12279 by Cochrane Philippines, Wiley Online Library on [16/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
C. Annweiler et al. Review: Vitamin D and cognition

the pathological process of ADRDs, it may also bridging, if possible) of the clinical and animal
enhance the effectiveness of standard antidemen- models using altered vitamin D systems available
tia treatments or account at least partially for the in the field (e.g. VDR-/-, developmental vitamin D
resistance to these treatments. Although specula- deficit, acute and chronic vitamin D treatment or
tive, this suggests that clinicians should restore depletion) should also be carried out in order to
vitamin D levels before starting antidementia treat- best interpret neurocognitive and behavioural
ments or use vitamin D as an adjunct to standard abnormalities associated with vitamin D depriva-
treatments. In line with this, a recent 6-month tion. Focusing on the threshold concentration of
controlled trial demonstrated that the combination 25OHD required to prevent these adverse events,
of memantine+vitamin D was superior to either and on the dose of supplementation required, will
memantine or vitamin D alone in preventing cog- also be important.
nitive decline amongst participants with AD [75]. In
fact, those taking both treatments had a clinically Finally, it will be necessary to revise the current
relevant and statistically significant gain of 4 document in due course, probably within the next
points on the Mini-Mental State Examination score 3–5 years, when significant evidence is available
of cognitive function. These results were consistent regarding the different aspects of the recommen-
with the finding of an in vitro study of less dations. It is hoped that there will be an expansion
degeneration of cortical axons after exposure to of high-quality research activities that either cor-
Ab peptide or glutamate in microfluidic neuronal roborate or lead to modification of these recom-
cultures enriched with memantine plus vitamin D mendations.
compared to control medium and cultures
enriched with either memantine or vitamin D alone
Conflict of interest statement
[76].
The authors have no conflicts of interest to declare.
Conclusions
Funding
In conclusion, this first task force on ‘Vitamin D
and Cognition in Older Adults’ enabled interna- The summit and this work were supported by the
tional experts to reach agreement that hypovita- Center for Research on Autonomy and Longevity
minosis D and the inefficient utilization of vitamin (CeRAL), University Hospital of Angers, France.
D increase the risk of cognitive decline/ADRDs in ED, DGA and SY are supported by the Research
older adults and may alter the clinical presentation Fund of Istanbul University (Project No: 460, 548,
of the disease, particularly as a consequence of 4426, ONAP-21712 and ONAP-28651) and by the
accompanying morbidities; however, at present, Scientific and Technological Research Council of
hypovitaminosis D should not be used as a diag- Turkey-TUBITAK (Project No. 107S041 and
nostic or a prognostic biomarker of cognitive 111S200). FF and PM are supported by the Health,
decline/ADRDs due to lack of specificity and Sport and Sustainable Development Foundation of
insufficient evidence. The experts also recom- Aix-Marseille University. DJL and TL: Additional
mended measurement of serum 25OHD because support was provided from the Alzheimer’s Associ-
of the high prevalence of hypovitaminosis D in this ation by NIRG-11-200737, the Mary Kinross
population and supplementation, if necessary. Charitable Trust, the James Tudor Foundation,
However, this advice was not specific for ADRDs the Halpin Trust, the Sir Halley Stewart Trust, the
in the absence of well-conducted RCTs. Age Related Diseases and Health Trust, and the
Norman Family Charitable Trust. DJL and TL are
Future studies should consider the effects of vita- also supported by the UK National Institute for
min D on comorbidities and explore the stimulat- Health Research (NIHR) Collaboration for Leader-
ing and/or protective effects of vitamin D on ship in Applied Health Research and Care (CLA-
neurocognition at different stages of life. A stronger HRC) for the South West Peninsula. The sponsors
focus on the role of vitamin D-related genetic had no role in the design and conduct of the study,
variance (e.g. in the genes encoding VDR, in the collection, management, analysis and inter-
a-hydroxylase or VDBP) in humans will also be pretation of the data, or in the preparation, review
important. In parallel, conditional and brain-spe- or approval of the manuscript. The views expressed
cific VDR mutations are eagerly expected to assess in this publication are those of the authors and not
their neurophenotypes. Critical evaluation (and necessarily those of the funding sources.

54 ª 2014 The Association for the Publication of the Journal of Internal Medicine
Journal of Internal Medicine, 2015, 277; 45–57
 13652796, 2015, 1, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/joim.12279 by Cochrane Philippines, Wiley Online Library on [16/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
C. Annweiler et al. Review: Vitamin D and cognition

D in human cerebrospinal fluid. Klin Wochenschr 1984; 62:

Authors’ contributions 1086–90.
16 Brown J, Bianco JI, McGrath JJ, Eyles DW. 1,25-
CA had full access to all data, takes responsibility
Dihydroxyvitamin D-3 induces nerve growth factor, promotes
for the data, the analyses and interpretation and neurite outgrowth and inhibits mitosis in embryonic rat
has the right to publish any and all data. All hippocampal neurons. Neurosci Lett 2003; 343: 139–43.
authors (i) contributed to the study conception and 17 Moore ME, Piazza A, McCartney Y, Lynch MA. Evidence that
design, or the analysis and interpretation of data; vitamin D3 reverses age-related inflammatory changes in the
(ii) contributed to drafting the article or revising it rat hippocampus. Biochem Soc Trans 2005; 33: 573–7.
18 Masoumi A, Goldenson B, Ghirmai S et al. 1Alpha,25-di-
critically for important intellectual content; and (iii)
hydroxyvitamin D3 interacts with curcuminoids to stimulate
approved the final version of the manuscript. amyloid-beta clearance by macrophages of Alzheimer’s dis-
ease patients. J Alzheimers Dis 2009; 17: 703–17.
19 Ito S, Ohtsuki S, Nezu Y et al. 1a,25-Dihydroxyvitamin D3
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