Vitamin D in dementia prevention

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1 Ann. N.Y. Acad. Sci. ISSN ANNALS OF THE NEW YORK ACADEMY OF SCIENCES Issue: Nutrition in Prevention and Management of Dementia Vitamin D in dementia prevention Cédric Annweiler 1,2,3 1 Division of Geriatric Medicine, Department of Neuroscience, University Memory Center, Angers University Hospital, Angers, France. 2 UPRES EA 4638, University of Angers, L UNAM, Angers, France. 3 Robarts Research Institute, Department of Medical Biophysics, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada Address for correspondence: Cédric Annweiler, M.D., Ph.D., H.D.R., Division of Geriatric Medicine, Department of Neuroscience, University Memory Center, Angers University Hospital, 4 Rue Larrey Angers Pays de la Loire, F Angers, France. CeAnnweiler@chu-angers.fr Beyond effects on bone health, vitamin D exerts effects on a variety of target organs, including the brain. The discussion herein presents the state of the art in research on the neurological role of vitamin D and clinical implications among older adults, including implications for dementia onset and progression. Some of the neurosteroid actions of vitamin D include regulation of calcium homeostasis, clearance of amyloid- peptide, antioxidant and anti-inflammatory effects, and possible protection against the neurodegenerative mechanisms associated with Alzheimer s disease (AD). The correction of age-related hypovitaminosis D and cognitive decline has been reported by various cross-sectional and longitudinal studies reporting associations of lower vitamin D concentrations with brain changes and poorer cognition, specifically with respect to executive dysfunction. Epidemiological studies have consistently shown an association between inadequate dietary intake of vitamin D and cognitive disorders, including greater AD risk. Although there have not been any randomized placebo-controlled trials conducted to examine the effectiveness of vitamin D supplementation to prevent AD, several nonrandomized controlled studies have found that older adults experienced cognitive improvements after 1 15 months of vitamin D supplementation. Therefore, it appears crucial to maintain vitamin D concentrations at sufficiently high levels in order to slow, prevent, or improve neurocognitive decline. Keywords: vitamin D; neuroendocrinology; Alzheimer s disease; cognition; dementia; older adults Introduction Dementia is characterized by a progressive decline in cognition and social activities. Alzheimer s disease (AD), the main cause of dementia in older adults, 1 is a significant worldwide concern because of its high prevalence and incidence, adverse consequences, and lack of curative medications. 1 Interestingly, AD onset may be modifiable, as reflected by a reported decrease in its prevalence over the past two decades in England. 2 Thus, even if some unavoidable factors (such as increased life expectancy beyond 80 years) augment the global prevalence of dementia, other factors may instead reduce its prevalence. In this view, vitamin D could be an important biological component that is able to influence the natural history of dementia. Vitamin D is a steroid hormone with classical roles in calcium metabolism and bone health regulation. 3 Over the past decade, accumulating evidence has underlined that adverse effects of hypovitaminosis D are not limited to the bone but, depending on the serum level of 25-hydroxyvitamin D (25OHD), also affect other nonclassical targets, 3,4 including the brain. Evidence on the role of vitamin D in the central nervous system (CNS) has increasingly been described. 5,6 It appears that hypovitaminosis D, which affects at least one billion people worldwide, 3 is closely associated with neurological dysfunction and cognitive decline in older adults. 7,8 This paper presents the state of the art in research on the neurological role of vitamin D and the clinical implications among older adults, doi: /nyas

2 Vitamin D and dementia Annweiler including the consequences on dementia onset and progression. VitaminDandtheCNS The effects of vitamin D are mediated by its nuclear hormone receptor, the vitamin D receptor (VDR). 3,4 The finding of VDRs in the CNS supports the possibility of a neurosteroid action of vitamin D. 5,6 Vitamin D metabolism and brain Serum vitamin D is able to reach the cerebrospinal fluid (CSF) and the brain by crossing the blood brain barrier (BBB) by passive diffusion. 9,10 Specific carriers have also been described in the cerebral capillaries and plexus choroideus. 9,10 Importantly, another source of vitamin D in the brain is of an intracrine nature. The enzymes required for the hydroxylation of provitamin D into active 1,25(OH) 2 D (i.e., the 25-hydroxylase and 1 -hydroxylase) have been identified in the brain, 11 with the main consequence being that the CNS is able to synthesize its own vitamin D and have auto- or paracrine neurosteroid actions locally in the brain. 11 Vitamin D exerts its actions through VDRs, 12 which are present in neurons and glial cells, 5 particularly in the temporal, cingulate, and orbital cortices and in the thalamus, nucleus accumbens, stria terminalis, and amygdala, 5 which are all areas essential for cognition. Effects on neurophysiology and neuroprotection have also been described, as further discussed below. Neurophysiology Vitamin D regulates the synthesis of neurotrophic agents, such as nerve growth factor, glial cell line derived neurotrophic factor, and neurotrophin 3, 13,14 thereby controlling neuronal differentiation and maturation. Neuronal growth has consistently been shown to be accelerated in rat hippocampus cell cultures enriched with vitamin D. 13 Moreover, vitamin D regulates the genetic expression of various neurotransmitters, including acetylcholine, dopamine, serotonin, and aminobutyric acid. 6 For instance, vitamin D repletion of rats deficient in vitamin D resulted in increased activity of choline acetyltransferase in the hypothalamus. 6 Neuroprotection Vitamin D may promote the neural mechanisms of protection against AD. For instance, it was found that vitamin D reverses age-related inflammatory changes in the hippocampus 15 and attenuates the accumulation of amyloid- (A ) 42 through phagocytosis 16 and clearance at the BBB. 17 The result was a decreased number of amyloid plaques in one study. 18 Additionally, vitamin D regulates voltage-gated calcium channels, 19 notably those targeted by the A peptide, 20 suggesting that vitamin D could fix neuronal calcium homeostasis altered by the A peptide. Finally, vitamin D may protect against glutamate neurotoxicity by upregulating VDR expression 21 and exerting antioxidant effects. 22 These findings support a role of vitamin D in CNS health and function. Serum vitamin D concentrations decrease with aging. Maintaining concentrations of vitamin D at sufficiently high levels throughout life may thus represent an attractive solution to prevent age-related neurological disorders. Vitamin D and brain structure Hypovitaminosis D is accompanied by a number of brain changes, including in volumetry, vasculature, and metabolism. For example, with respect to volumetry, rats born to vitamin D deficient mothers were reported to exhibit profound changes at birth, specifically thinner cortices and larger cerebral lateral ventricles. 23 In humans, although one study found no whole-brain volume difference depending on serum vitamin D concentration, 24 a meta-analysis showed that individuals with hypovitaminosis D exhibit 1.01 standard deviation larger cerebral lateral ventricles (a proxy for brain atrophy) than those without hypovitaminosis D. 7 Analysis of brain subvolumes indicates that the brain atrophy that accompanies hypovitaminosis D could be explained by a loss of gray matter, 25 mostly at the cranial vertex 26 rather than in the temporal lobe. 24 Regarding brain vascular changes, experiments in rats showed that vitamin D attenuates cortical ischemia after cerebral arterial ligation. 27 In humans, a meta-analysis reported that those with hypovitaminosis D have more strokes than other groups, 28 and a similar association was recently highlighted with cerebral small vessel disease. 29,30 Among older adults, hypovitaminosis D was associated with an increased volume of white matter 58

3 Annweiler Vitamin D and dementia damage (WMD), 29 specifically periventricular WMD, but not deep WMD. 30 With respect to brain metabolism, only one study has investigated metabolic changes according to vitamin D status in older adults. Using magnetic resonance spectroscopy in the motor cortex, the authors found that hypovitaminosis D was associated with reduced neuronal function in the cortex, even after adjustment for cortical thickness and WMD grade. 31 It is highly likely that these brain changes related to hypovitaminosis D explain part of the development of high-level disorders, including cognitive disorders, in the elderly. Vitamin D and cognition Observational studies Neuroepidemiological studies have repeatedly reported an association between hypovitaminosis D and cognitive disorders. 8,32 35 Thereisrobustevidence for a positive linear relationship between serum 25OHD and global cognitive performance in older adults. 8,32,33,35 A meta-analysis reported a 2.4-times greater risk of cognitive impairment in the case of hypovitaminosis D compared to those with adequate vitamin D status. 32 Interestingly, three other papers also reported a curvilinear relationship (i.e., people with both lower and higher 25OHD concentrations perform worse on cognitive tasks), but these results could be attributed to chance or to the recent supplementation of those with chronic hypovitaminosis D. The domain-specific cognitive functions altered in hypovitaminosis D include executive functions, particularly information processing speed, mental shifting, and working memory; 34 there may also be an effect on episodic memory, but the relationship is smaller in magnitude. 34 All of these cognitive functions are necessary for the cognitive control of behavior and the execution of cognitive programs in real time, and are involved in high-level motor control. 39 These findings support the clinical impact of hypovitaminosis D and may explain, at least in part, the increased propensity of individuals with hypovitaminosis D to fall. 40 Dysexecutive and amnestic syndromes are encountered in AD. Consistently, it has been reported that AD patients exhibit lower serum 25OHD concentrations than do control individuals without AD, 41 with the difference considered clinically relevant. Moreover, the association is found not only for severe stages of AD 42 but also for the prodromal stage (also known as mild cognitive impairment), 43 which corresponds to an isolated minor neurocognitive disorder with no effect on functional autonomy in activities of daily living. Interestingly, hypovitaminosis D is associated with subjective cognitive complaint, a sign that occurs earlier than the first objective signs of AD and predicts future cognitive decline and dementia. 44 Both of these latter findings highlight that hypovitaminosis D accompanies the onset of the first AD symptoms and therefore may contribute to the initiation of dementia. Other studies have confirmed the existence of a relation between vitamin D and AD; in particular, AD patients have increased levels of vitamin D binding protein, 45 as well as lower levels of 25OHD in the CSF. 46 A central question relates to whether one can infer causality: that is, does hypovitaminosis D precipitate cognitive disorders or vice versa? Longitudinal prospective studies have provided possible answers by showing that older ethnically diverse groups of individuals with hypovitaminosis D have a significantly increased risk of cognitive decline, 34,47 51 AD, 52 and all-cause dementia, 53,54 compared to those with higher vitamin D concentrations. Recent studies even suggest that the VDR may be a new factor of genetic susceptibility to AD. Certain human VDR variants may be less responsive to vitamin D and thus confer increased risk of cognitive decline. For example, AD patients exhibit decreased expression and levels of mrna encoding VDRs. 55 Also, the ApaI polymorphism of the VDR gene has been associated with AD onset, 56 and the same single-nucleotide polymorphism (ApaI, rs ) was reported to be significantly associated with word recall and digit-symbol coding performance. 50 Overall, published observational studies support the conclusion that age-related decreased concentrations of vitamin D, or its inefficient utilization, could undermine certain processes in the CNS, thus resulting in cognitive decline and dementia. Interventional studies Since hypovitaminosis D is associated with cognitive decline and increased risk of dementia in older adults, it appears advisable to maintain high levels of vitamin D. Consistently, higher dietary vitamin D intake is associated with better cognitive performance in older adults. 57 In one 59

4 Vitamin D and dementia Annweiler Table 1. Evidence that hypovitaminosis D is causally linked to the risk of dementia, according to Hill s criteria for causality in a biological system Criterion Evidence Temporality Hypovitaminosis D precedes the onset of cognitive decline in cohort studies. Strength of association Hypovitaminosis D is associated with cognitive disorders with an odds ratio of 2.4, according to a meta-analysis, meaning that the risk of cognitive disorders is more than twice as high in the case of hypovitaminosis D. Dose response relationship In most previous studies, increased 25OHD concentration was associated with better cognitive performance and decreased incidence of dementia. Consistency of findings Observational evidence available from cross-sectional and longitudinal studies. Interventional evidence still limited. Plausibility (e.g., mechanisms) Vitamin D involved in neurophysiology and neuroprotection against dementiogenic stress. Alternate explanations Reverse causation (i.e., dementia precipitates hypovitaminosis D) made unlikely by cohort studies; and second, a role for potential confounders: association between hypovitaminosis D and dementia still significant after adjustment for all potential confounders. Experiment Cognitive improvements after vitamin D supplementation in the general older population and in Alzheimer s disease patients. Specificity Although particularly severe among Alzheimer s disease patients, the prevalence of hypovitaminosis D is too high in the general older population to be considered specific to dementia. Consistency with known facts Robust evidence was gathered in this review that serum vitamin D status is a biological determinant associated with brain structure and cognitive function in older adults. study, consuming approximately 800 IU/day of vitamin D divided AD risk by five after 7 years. 58 This cognitive effect was confirmed by before after and nonrandomized clinical trials that reported cognitive improvements in the general older population 59,60 and in AD patients. 60,61 Some cognitive benefits were observed after 4 weeks of supplementation, 59 with a particularly marked improvement in executive functions and information processing speed. 34 Supraphysiological doses, such as 7000 IU/day, seem to provide no additional benefit, 61 while common supplementation dosages around IU/day appear to be sufficient and desirable. 62 Nevertheless, it is noticeable that, although cognition favorably evolves in patients receiving vitamin D supplementation (as shown by before-and-after approaches), between-group comparisons of cognitive scores at the end of follow-up (comparative approach) does not show better cognitive scores in the supplementation arm compared to the comparative arm. 34 It should also be mentioned that most trials, and a fortiori the inconclusive ones, have included participants with relatively high serum 25OHD concentrations, possibly above the cerebral needs for vitamin D (if any), which could mask the cognitive effect of vitamin D supplementation. 63 Moreover, the comparative arm of several trials continued to receive vitamin D supplements, either as part of the study 61 or as part of routine care. 59 It will therefore be important to conduct well-designed, randomized, placebo-controlled clinical trials testing the effectiveness of vitamin D supplementation in populations exhibiting hypovitaminosis D at baseline. The definition of hypovitaminosis D remains controversial because it is not based on a population-based reference value (i.e., normality is the reference range of 95% of the population) but rather on health-based reference values (i.e., normality is the 25OHD concentration range that prevents adverse health effects). 4 Apreviousreview aimed to determine which of the three common 25OHD thresholds (i.e., 10, 20, or 30 ng/ml) is suitable as a brain-based reference value. 64 The findings showed that the 25OHD threshold associated with cognition is likely around 10 ng/ml; people with 25OHD concentrations lower than 10 ng/ml have greater risks of cognitive disorders 60

5 Annweiler Vitamin D and dementia than those with 25OHD concentrations higher than 10 ng/ml, and even greater risk compared to those with 25OHD concentrations higher than 30 ng/ml. 64 Thus, future trials should recruit preferentially older participants with 25OHD less than 10 ng/ml, because inclusion of individuals with higher concentrations might mask the cognitive effects of supplementation (if any). Furthermore, it seems desirable to propose a supplement plan designed to achieve a final 25OHD concentration of more than 30 ng/ml to prevent cognitive decline in AD patients or AD onset in a healthy population. Hill s criteria for causality Hill s criteria for causality in a biological system 65 can be used to evaluate whether hypovitaminosis D can be considered causally linked to the risk of dementia. Not all criteria need to be satisfied to claim causality, but the more criteria that are satisfied, the stronger the claim. Table 1 lists the applicable criteria. In this case, all criteria were satisfied with the exception of specificity, which is a minor criterion generally not used for vitamin D. Conclusions The correction of hypovitaminosis D in older adults is justified from a cognitive perspective in preclinical studies and by a number of cross-sectional and longitudinal observational studies reporting direct associations between decreased 25OHD concentrations and cognitive disorders. 63 Although no randomized placebo-controlled trials have tested the effects of vitamin D supplements on cognitive decline in AD patients or on AD onset in healthy participants, several nonrandomized trials have reported cognitive improvements among older adults supplemented with vitamin D. There is much hope for the development and use of multitarget drugs based on vitamin D In conjunction with these innovative therapeutic strategies, the considerations discussed above may encourage clinicians to correct hypovitaminosis D in elderly patients. Conflicts of interest The author declares no conflicts of interest. References 1. Anand, R., K.D. Gill & A.A. Mahdi Therapeutics of Alzheimer s disease: past, present and future. Neuropharmacology 76: Matthews, F.E., A. Arthur, L.E. Barnes, et al A twodecade comparison of prevalence of dementia in individuals aged 65 years and older from three geographical areas of England: results of the Cognitive Function and Ageing Study I and II. Lancet 382: Hossein-Nezhad, A. & M.F. Holick Vitamin D for health: a global perspective. Mayo Clin. Proc. 88: Annweiler, C., J.C. Souberbielle, A.M. Schott, et al Vitamin D in the elderly: 5 points to remember. Geriatr. Psychol. Neuropsychiatr. Vieil. 9: Kalueff, A.V. & P. Tuohimaa Neurosteroid hormone vitamin D and its utility in clinical nutrition. Curr. Opin. Clin. Nutr. Metab. Care 10: Annweiler, C., A.M. Schott, G. Berrut, et al Vitamin D and ageing: neurological issues. Neuropsychobiology 62: Annweiler, C., T. Annweiler, M. Montero-Odasso, et al Vitamin D and brain volumetric changes: systematic review and meta-analysis. Maturitas 78: Annweiler, C., G. Allali, P. Allain, et al Vitamin D and cognitive performance in adults: a systematic review. Eur. J. Neurol. 16: Holmøy, T., S.T. Moen, T.A. Gundersen, et al Hydroxyvitamin D in cerebrospinal fluid during relapse and remission of multiple sclerosis. Mult. Scler. 15: Balabanova, S., H.P. Richter, G. Antoniadis, et al Hydroxyvitamin D, 24, 25-dihydroxyvitamin D and 1,25- dihydroxyvitamin D in human cerebrospinal fluid. Klin. Wochenschr. 62: Garcion, E., N. Wion-Barbot, C.N. Montero-Menei, et al New clues about vitamin D functions in the nervous system. Trends Endocrinol. Metab. 13: Bouillon, R., G. Carmeliet, L. Verlinden, et al Vitamin D and human health: lessons from vitamin D receptor null mice. Endocr. Rev. 29: Brown, J., J.I. Bianco, J.J. McGrath, et al ,25- Dihydroxyvitamin D 3 induces nerve growth factor, promotes neurite outgrowth and inhibits mitosis in embryonic rat hippocampal neurons. Neurosci. Lett. 343: Naveilhan, P., I. Neveu, D. Wion, et al ,25- Dihydroxyvitamin D3, an inducer of glial cell line-derived neurotrophic factor. Neuroreport 7: Nissou, M.F., A. Guttin, C. Zenga, et al Additional clues for a protective role of vitamin D in neurodegenerative diseases: 1,25-dihydroxyvitamin D3 triggers an antiinflammatory response in brain pericyte. J. Alzheimers Dis. 42: Masoumi,A.,B.Goldenson,S.Ghirmai,et al ,25- Dihydroxyvitamin D 3 interacts with curcuminoids to stimulate amyloid- clearance by macrophages of Alzheimer s disease patients. J. Alzheimers Dis. 17: Ito, S., S. Ohtsuki, Y. Nezu, et al ,25- Dihydroxyvitamin D 3 enhances cerebral clearance of human amyloid- peptide(1 40) from mouse brain across the blood brain barrier. Fluids Barriers CNS 8: Yu, J., M. Gattoni-Celli, H. Zhu, et al Vitamin D 3 - enriched diet correlates with a decrease of amyloid plaques in the brain of A PP transgenic mice. J. Alzheimers Dis. 25:

6 Vitamin D and dementia Annweiler 19. Brewer, L.D., V. Thibault, K.C. Chen, et al Vitamin D hormone confers neuroprotection in parallel with downregulation of L-type calcium channel expression in hippocampal neurons. J. Neurosci. 21: Dursun, E., D. Gezen-Ak & S. Yilmaze A novel perspective for Alzheimer s disease: vitamin D receptor suppression by amyloid- induced alterations by vitamin D in cortical neurons. J. Alzheimers Dis. 23: Taniura, H., M. Ito, N. Sanada, et al Chronic vitamin D 3 treatment protects against neurotoxicity by glutamate in association with upregulation of vitamin D receptor mrna expression in cultured rat cortical neurons. J. Neurosci. Res. 83: Ibi, M., H. Sawada, M. Nakanishi, et al Protective effects of 1,25-(OH) 2 D 3 against the neurotoxicity of glutamate and reactive oxygen species in mesencephalic culture. Neuropharmacology 40: Eyles,D.,J.Brown,A.Mackay-Sim,et al Vitamin D 3 and brain development. Neuroscience 118: Buell, J.S., B. Dawson-Hughes, T.M. Scott, et al Hydroxyvitamin D, dementia, and cerebrovascular pathology in elders receiving home services. Neurology 74: Brouwer-Brolsma, E.M., N.L. van der Zwaluw, J.P. van Wijngaarden, et al Higher serum 25-hydroxyvitamin D and lower plasma glucose are associated with larger gray matter volume but not with white matter or total brain volume in Dutch community-dwelling older adults. J. Nutr. 145: Annweiler, C., M. Montero-Odasso, V. Hachinski, et al Vitamin D concentration and lateral cerebral ventricle volume in older adults. Mol. Nutr. Food Res. 57: Wang, Y., Y.H. Chiang, T.P. Su, et al Vitamin D 3 attenuates cortical infarction induced by middle cerebral arterial ligation in rats. Neuropharmacology 39: Brøndum-Jacobsen, P., B.G. Nordestgaard, P. Schnohr, et al Hydroxyvitamin D and symptomatic ischemic stroke: an original study and meta-analysis. Ann. Neurol. 73: Annweiler, C., R. Bartha, S.N. Karras, et al Vitamin D and white matter abnormalities in older adults: a quantitative volumetric analysis of brain MRI. Exp. Gerontol. 63: Annweiler, C., T. Annweiler, R. Bartha, et al Vitamin D and white matter abnormalities in older adults: a crosssectional neuroimaging study. Eur. J. Neurol. 21: 1436 e Annweiler, C., O. Beauchet, R. Bartha, et al Vitamin D and caudal primary motor cortex: a magnetic resonance spectroscopy study. PLoS One 9: e Etgen, T., D. Sander, H. Bickel, et al Vitamin D deficiency, cognitive impairment and dementia: a systematic review and meta-analysis. Dement. Geriatr. Cogn. Disord. 33: Balion, C., L.E. Griffith, L. Strifler, et al Vitamin D, cognition, and dementia: a systematic review and metaanalysis. Neurology 79: Annweiler, C., M. Montero-Odasso, D.J. Llewellyn, et al Meta-analysis of memory and executive dysfunctions in relation to vitamin D. J. Alzheimers Dis. 37: Oudshoorn, C., F.U. Mattace-Raso, N. van der Velde, et al Higher serum vitamin D 3 levels are associated with better cognitive test performance in patients with Alzheimer s disease. Dement. Geriatr. Cogn. Disord. 25: McGrath, J., R. Scragg, D. Chant, et al No association between serum 25-hydroxyvitamin D 3 level and performance on psychometric tests in NHANES III. Neuroepidemiology 29: Maddock,J.,M.C.Geoffroy,C.Power,et al Hydroxyvitamin D and cognitive performance in mid-life. Br.J.Nutr.111: Granic, A., T.R. Hill, T.B. Kirkwood, et al Serum 25- hydroxyvitamin D and cognitive decline in the very old: the Newcastle 85+ study. Eur. J. Neurol. 22: , e6 e Beauchet, O., C. Annweiler, M. Montero-Odasso, et al Gait control: a specific subdomain of executive function? J. Neuroeng. Rehabil. 9: Annweiler, C. & O. Beauchet Questioning vitamin D status of elderly fallers and nonfallers: a meta-analysis to address a forgotten step. J. Intern. Med. 277: Annweiler, C., D.J. Llewellyn & O. Beauchet Low serum vitamin D concentrations in Alzheimer s disease: a systematic review and meta-analysis. J. Alzheimers Dis. 33: Annweiler, C., B. Fantino, Le Gall D, et al Severe vitamin D deficiency is associated with advanced-stage dementia in geriatric inpatients. J.Am.Geriatr.Soc.59: Annweiler, C., B. Fantino, A.M. Schott, et al Vitamin D insufficiency and mild cognitive impairment: cross-sectional association. Eur. J. Neurol. 19: Tot Babberich Ede, N., C. Gourdeau, S. Pointel, et al Biology of subjective cognitive complaint amongst geriatric patients: vitamin D involvement. Curr. Alzheimer Res. 12: Moon,M.,H.Song,H.J.Hong,et al Vitamin D- binding protein interacts with A and suppresses A mediated pathology. Cell Death Differ. 20: Johansson, P., E.G. Almqvist, J.O. Johansson, et al Cerebrospinal fluid (CSF) 25-hydroxyvitamin D concentration and CSF acetylcholinesterase activity are reduced in patients with Alzheimer s disease. PLoS One 8: e Slinin, Y., M.L. Paudel, B.C. Taylor, et al Hydroxyvitamin D levels and cognitive performance and decline in elderly men. Neurology 74: Llewellyn, D.J., I.A. Lang, K.M. Langa, et al Vitamin D and risk of cognitive decline in elderly persons. Arch. Intern. Med. 170: Slinin, Y., M. Paudel, B.C. Taylor, et al Association between serum 25(OH) vitamin D and the risk of cognitive decline in older women. J. Gerontol. A Biol. Sci. Med. Sci. 67: Jorde,R.,E.B.Mathiesen,S.Rogne,et al Vitamin D and cognitive function: the Tromsø Study. J. Neurol. Sci. 355: Miller, J.W., D.J. Harvey, L.A. Beckett, et al Vitamin D status and rates of cognitive decline in a multiethnic cohort of older adults. JAMA Neurol. 72: Afzal, S., S.E. Bojesen & B.G. Nordestgaard Reduced 25-hydroxyvitamin D and risk of Alzheimer s disease and vascular dementia. Alzheimers Dement. 10:

7 Annweiler Vitamin D and dementia 53. Annweiler, C., Y. Rolland, A.M. Schott, et al Serum vitamin D deficiency as a predictor of incident non- Alzheimer dementias: a 7-year longitudinal study. Dement. Geriatr. Cogn. Disord. 32: Littlejohns, T.J., W.E. Henley, I.A. Lang, et al Vitamin D and the risk of dementia and Alzheimer disease. Neurology 83: Sutherland, M.K., M.J. Somerville, L.K. Yoong, et al Reduction of vitamin D hormone receptor mrna levels in Alzheimer as compared to Huntington hippocampus: correlation with calbindin-28k mrna levels. Brain Res. Mol. Brain. Res. 13: Gezen-Ak, D., E. Dursun, T. Ertan, et al Association between vitamin D receptor gene polymorphism and Alzheimer s disease. Tohoku J. Exp. Med. 212: Annweiler, C., A.M. Schott, Y. Rolland, et al Dietary intake of vitamin D and cognition in older women: a large population-based study. Neurology 75: Annweiler, C., Y. Rolland, A.M. Schott, et al Higher vitamin D dietary intake is associated with lower risk of Alzheimer s disease: a 7-year follow-up. J. Gerontol. A Biol. Sci. Med. Sci. 67: Przybelski, R., S. Agrawal, D. Krueger, et al Rapid correction of low vitamin D status in nursing home residents. Osteoporos. Int. 19: Annweiler, C., B. Fantino, J. Gautier, et al Cognitive effects of vitamin D supplementation in older outpatients visiting a memory clinic: a pre post study. J. Am. Geriatr. Soc. 60: Stein, M.S., S.C. Scherer, K.S. Ladd, et al A randomized controlled trial of high-dose vitamin D2 followed by intranasal insulin in Alzheimer s disease. J. Alzheimers Dis. 26: Annweiler, C. & O. Beauchet Vitamin D and cognition: recommendations for future trials. J. Am. Geriatr. Soc. 61: Annweiler, C., E. Dursun, F. Féron, et al Vitamin D and cognition in older adults : updated international recommendations. J. Intern. Med. 277: Annweiler, C. & O. Beauchet Vitamin D in older adults: the need to specify standard values with respect to cognition. Front. Aging Neurosci. 6: Hill, A.B The environment and disease: association or causation? Proc. R. Soc. Med. 58: Annweiler, C., F.R. Herrmann, B. Fantino,et al Effectiveness of the combination of memantine plus vitamin D on cognition in patients with Alzheimer disease: a pre post pilot study. Cogn. Behav. Neurol. 25: Annweiler, C., B. Brugg, J.M. Peyrin, et al Combination of memantine and vitamin D prevents axon degeneration induced by amyloid-beta and glutamate. Neurobiol. Aging 35: Charier, D., O. Beauchet, M. Bell, et al Memantine plus vitamin D prevents axonal degeneration caused by lysed blood. ACS Chem. Neurosci. 6: