Background
Vitamin D is a fat-soluble steroid hormone that seems crucial for brain health in humans [
1‐
5]. Low vitamin D status is common amongst the elderly and is considered a major health problem [
6‐
8]. Studies have shown that vitamin D insufficiency is associated with a higher risk of Alzheimer’s disease (AD) [
9‐
16] and accelerated cognitive decline [
12,
17,
18], although some conflicting results are reported [
19‐
21]. Randomized controlled trials (RCTs) investigating the effects of vitamin D supplementation (alone or in combination with other drugs) on cognitive decline and AD onset are limited [
22‐
25] and have largely proven unsuccessful to date [
22,
23,
25].
Despite the controversy surrounding the role of vitamin D in cognitive function and AD, animal studies suggest that vitamin D hypovitaminosis results in increased brain beta-amyloid (Aβ) [
26] and vitamin D promotes a reduction in Aβ brain burden [
27,
28]. In human studies, vitamin D has been shown to increase plasma Aβ, particularly in older adults, suggestive of decreased brain Aβ [
29]. Furthermore, vitamin D status assessed through a dietary questionnaire has been associated with less Aβ in AD-vulnerable brain regions in subjects at risk of AD [
30,
31]. However, to the best of our knowledge, studies have not addressed the relationship between circulating vitamin D (measured biochemically) and cerebral Aβ. Thus, we examined the cross-sectional associations between 25-hydroxyvitamin D (25(OH)D), the major circulating form of vitamin D, and cerebral Aβ in older adults at risk of dementia. We hypothesized that 25(OH)D would be inversely associated with Aβ.
Discussion
We have shown that vitamin D measured as 25(OH)D was not associated with cerebral Aβ independently or as a function of ApoE ε4 status. To the best of our knowledge, this is the first study to explore the associations between circulating plasma vitamin D (measured biochemically) and cerebral Aβ.
Our findings were against our original hypothesis based on animal experiments [
27,
28] and human studies using nutritional questionnaires to assess the associations between vitamin D status and cerebral Aβ [
30,
31]. However, the participants of these human studies were younger and cognitively normal. It might also be that dietary questionnaires do not best capture vitamin D status especially in those with memory complaints. Moreover, sun exposure is the major source of vitamin D.
Our findings are in line with those showing that vitamin D concentrations are not associated with cognitive decline or AD [
19‐
21], although a number of reports to the contrary are published [
9‐
18]. Considering that RCTs investigating the effects of vitamin D supplementation on brain health are negative to date [
22,
23,
25], it could be hypothesized that observational studies reporting a significant association between vitamin D status and cognitive decline or AD risk might be prone to reverse causality bias. Alternatively, the failure of vitamin D trials might be attributed to the short duration of therapy or the sub-optimal timing of vitamin D supplementation. Timing has recently been highlighted as an important criterion in the relationship between vitamin D and cognition [
18,
41]. Indeed, vitamin D status mid-life has been associated with cognition 10 years later [
42]. Thus, the duration and time window of vitamin D hypovitaminosis might dictate pathological changes associated with AD in older age. In the same vein, the assessment of cerebral Aβ in later life does not provide information on the slow pathophysiological accrual of Aβ [
43] and the role of vitamin D. Perhaps as with cognition, mid-life vitamin D deficiency might contribute more to Aβ deposition than vitamin D deficiency in later life. Thus, in this study we might have failed to detect an association between vitamin D status and cerebral Aβ load due to the inappropriate timing of measurements; however, plasma samples in mid-life were not available in the MAPT to test further hypotheses.
It is also feasible that vitamin D hypovitaminosis is linked to cognitive decline via Aβ-independent processes. Indeed, 25(OH)D insufficiency is associated with an increase in white matter abnormalities indicative of cerebrovascular disease [
44,
45] and decreasing 25(OH)D plasma levels are associated with an increased risk of ischaemic stroke [
46]. Thus, it is plausible that vitamin D might be associated with dementia of a more vascular nature. Vitamin D has also been shown to regulate the synthesis of neurotrophins [
47,
48] and therefore vitamin D hypovitaminosis could potentially promote neuronal death and cognitive decline. Moreover, vitamin D regulates the expression of a number of neurotransmitters including acetylcholine [
49] and dopamine [
50] and the expression of the enzyme involved in the rate-limiting step of catecholamine synthesis [
51], which in turn might impact cognition. In addition, vitamin D inhibits the synthesis of inducible nitric oxide synthase [
52], downregulates reactive oxygen species [
53], upregulates the antioxidant glutathione [
54] and inhibits the expression of pro-inflammatory cytokines [
55]. Thus, vitamin D hypovitaminosis might potentiate inflammation and oxidative damage to neurons, hence promoting cognitive deterioration.
Exploratory analysis showed that there was no interaction between 25(OH)D and ApoE ε4 genotype to modify cortical Aβ. It has been shown previously that ApoE ε4 carriers have a better vitamin D status [
56], which could potentially serve to reduce cerebral Aβ burden according to data from animal studies [
27,
28]. Moreover, a significant interaction between ApoE ε4 and 25(OH)D concentrations has been reported in relation to human memory function [
57]. Therefore, the links between 25(OH)D and ApoE ε4 to govern Aβ pathology is worthy of further research.
The strengths of the current study are the relatively large sample size and the availability of PET [18F]-florbetapir imaging data and plasma 25(OH)D measurements, providing a more accurate value for vitamin D levels, as opposed to vitamin status assessed through dietary questionnaires. In addition, we considered several cofounders, including a possible interaction between vitamin D and ApoE ε4 status. The limitations of our study included the cross-sectional design, which precluded the examination of the relationship between plasma 25(OH)D and change in cerebral Aβ load over time. PET scans were also performed throughout the 3-year period of the MAPT; therefore the study design was not truly cross-sectional. The inclusion of the time interval between baseline 25(OH)D measurements and the PET scan as a confounder in the linear regression models probably served to mitigate this bias. Furthermore, we only had data availability for vitamin D status in later life which might perhaps not be the optimal time window for studying the associations between vitamin D and cerebral Aβ.
Acknowledgements
The MAPT/DSA Group refers to the following.
MAPT Study Group
Principal investigator: Bruno Vellas (Toulouse); Coordination: Sophie Guyonnet; Project leader: Isabelle Carrié; CRA: Lauréane Brigitte; Investigators: Catherine Faisant, Françoise Lala, Julien Delrieu, Hélène Villars; Psychologists: Emeline Combrouze, Carole Badufle, Audrey Zueras; Methodology, statistical analysis and data management: Sandrine Andrieu, Christelle Cantet, Christophe Morin; Multidomain group: Gabor Abellan Van Kan, Charlotte Dupuy, Yves Rolland (physical and nutritional components), Céline Caillaud, Pierre-Jean Ousset (cognitive component), Françoise Lala (preventive consultation), Bertrand Fougère (Toulouse). The cognitive component was designed in collaboration with Sherry Willis from the University of Seattle, and Sylvie Belleville, Brigitte Gilbert and Francine Fontaine from the University of Montreal.
Co-investigators in associated centres: Jean-François Dartigues, Isabelle Marcet, Fleur Delva, Alexandra Foubert, Sandrine Cerda (Bordeaux); Marie-Noëlle-Cuffi, Corinne Costes (Castres); Olivier Rouaud, Patrick Manckoundia, Valérie Quipourt, Sophie Marilier, Evelyne Franon (Dijon); Lawrence Bories, Marie-Laure Pader, Marie-France Basset, Bruno Lapoujade, Valérie Faure, Michael Li Yung Tong, Christine Malick-Loiseau, Evelyne Cazaban-Campistron (Foix); Françoise Desclaux, Colette Blatge (Lavaur); Thierry Dantoine, Cécile Laubarie-Mouret, Isabelle Saulnier, Jean-Pierre Clément, Marie-Agnès Picat, Laurence Bernard-Bourzeix, Stéphanie Willebois, Iléana Désormais, Noëlle Cardinaud (Limoges); Marc Bonnefoy, Pierre Livet, Pascale Rebaudet, Claire Gédéon, Catherine Burdet, Flavien Terracol (Lyon), Alain Pesce, Stéphanie Roth, Sylvie Chaillou, Sandrine Louchart (Monaco); Kristelle Sudres, Nicolas Lebrun, Nadège Barro-Belaygues (Montauban); Jacques Touchon, Karim Bennys, Audrey Gabelle, Aurélia Romano, Lynda Touati, Cécilia Marelli, Cécile Pays (Montpellier); Philippe Robert, Franck Le Duff, Claire Gervais, Sébastien Gonfrier (Nice); Yannick Gasnier and Serge Bordes, Danièle Begorre, Christian Carpuat, Khaled Khales, Jean-François Lefebvre, Samira Misbah El Idrissi, Pierre Skolil, Jean-Pierre Salles (Tarbes).
MRI group: Carole Dufouil (Bordeaux), Stéphane Lehéricy, Marie Chupin, Jean-François Mangin, Ali Bouhayia (Paris); Michèle Allard (Bordeaux); Frédéric Ricolfi (Dijon); Dominique Dubois (Foix); Marie Paule Bonceour Martel (Limoges); François Cotton (Lyon); Alain Bonafé (Montpellier); Stéphane Chanalet (Nice); Françoise Hugon (Tarbes); Fabrice Bonneville, Christophe Cognard, François Chollet (Toulouse).
PET scan group: Pierre Payoux, Thierry Voisin, Julien Delrieu, Sophie Peiffer, Anne Hitzel, (Toulouse); Michèle Allard (Bordeaux); Michel Zanca (Montpellier); Jacques Monteil (Limoges); Jacques Darcourt (Nice).
Medico-economics group: Laurent Molinier, Hélène Derumeaux, Nadège Costa (Toulouse).
Biological sample collection: Christian Vincent, Bertrand Perret, Claire Vinel (Toulouse).
Safety management: Pascale Olivier-Abbal.
DSA Group
Sandrine Andrieu, Christelle Cantet, Nicola Coley.