Eggersdorfer, Manfred

Gombart, Adrian F.

Michels, Alexander J.

Aging Cell

English

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There is no evidence that vitamin D supplementation drives the progression of Alzheimer's disease

ARTS repository - University of Groningen

   University of GroningenThere is no evidence that vitamin D supplementation drives the progression of Alzheimer'sdiseaseGombart, Adrian F.; Michels, Alexander J.; Eggersdorfer, ManfredPublished in:Aging CellDOI:10.1111/acel.13758IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite fromit. Please check the document version below.Document VersionPublisher's PDF, also known as Version of recordPublication date:2023Link to publication in University of Groningen/UMCG research databaseCitation for published version (APA):Gombart, A. F., Michels, A. J., & Eggersdorfer, M. (2023). There is no evidence that vitamin Dsupplementation drives the progression of Alzheimer's disease. Aging Cell, 22(1), Article e13758.https://doi.org/10.1111/acel.13758CopyrightOther than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of theauthor(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).The publication may also be distributed here under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license.More information can be found on the University of Groningen website: https://www.rug.nl/library/open-access/self-archiving-pure/taverne-amendment.Take-down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons thenumber of authors shown on this cover page is limited to 10 maximum.Aging Cell. 2023;22:e13758. | 1 of 3https://doi.org/10.1111/acel.13758wileyonlinelibrary.com/journal/acelReceived: 23 October 2022 | Accepted: 5 December 2022DOI: 10.1111/acel.13758COMMENTA RYThere is no evidence that vitamin D supplementation drives theprogression of Alzheimer's diseaseAdrian F. Gombart1 | Alexander J. Michels2 | Manfred Eggersdorfer31Department of Biochemistry and Biophysics, Linus Pauling Institute, Oregon State University, Corvallis, Oregon, USA2Linus Pauling Institute, Oregon State University, Corvallis, Oregon, USA3Department of Internal Medicine, University Medical Center Groningen, Groningen, The NetherlandsCorrespondenceManfred Eggersdorfer, Department of Internal Medicine, University Medical Center Groningen, Groningen, The Netherlands.Email: dr.eggersdorfer@gmail.comIf there is anything the last few decades have taught us, it is thatresearchers must properly conduct studies on vitamin supple-ments before they can make health claims. In a recent paper by Laiet al. (2022), the authors state, “vitamin D supplementation wors-ens Alzheimer's progression” without sufficient evidence to supportthese conclusions. While certain findings are scientifically interest-ing, readers must understand substantial limitations in the approachand methodology utilized in the paper limit conclusions one canmake about the role of vitamin D in brain health and Alzheimer'sdisease (AD).Before proceeding further, it is important for readers to under-stand that there are three different forms of vitamin D pertinentto this discussion. Cholecalciferol is the form of vitamin D3 synthe-sized in the skin upon exposure to UVB rays that typically comefrom sunlight. It is also the form found in dietary supplements. Theliver converts cholecalciferol to calcidiol (25-hydroxyvitamin D3),the circulating form used by clinicians to determine vitamin D sta-tus. Certain cells in the body will then convert calcidiol to calcitriol(1,25-dihydroxyvitamin D3), the “active” form of vitamin D in thebody (Bikle, 2000).Calcitriol is a high-affinity, potent ligand for the vitamin D recep-tor (VDR) and regulates most VDR-dependent gene transcription.The body only produces calcitriol under certain physiological condi-tions, including low serum calcium levels or immune activation, andtightly controls its synthesis and catabolism to limit its physiologicaleffects. On the other hand, cholecalciferol and calcidiol are consid-ered inactive forms of vitamin D3, as they are low-affinity ligandsfor VDR (Bikle, 2000). Because these three forms are not function-ally or physiologically equivalent, referring to them all as “vitaminD” creates a great deal of confusion, especially since cholecalciferolis found in vitamin D supplements or fortified foods and beverages,but calcitriol is appropriately classified as a drug (Vieth, 2020).The study by Lai et al. begins with data from neuronal cell culture.Here, the authors demonstrate that treatment with both calcidioland calcitriol increases apoptosis and autophagy in undifferentiatedSH-SY5Y cells upon exposure to Aβ42. SH-SY5Y is a neuroblastomacell line typically used in experiments after differentiation into a ho-mogeneous, more mature neuron-like cell, making them useful forAD research (Agholme et al., 2019). Prior reports show calcitriolprotects differentiated SH-SY5Y cells against Aβ(1–42) peptide cy-totoxicity (Vieth, 2020), although others have reported protection ofundifferentiated SH-SY5Y cells from Aβ(25–35) toxicity upon treat-ment with calcitriol (Lin, Chang, et al., 2020). While the study by Laiet al. reports contradictory findings, the authors do not discuss themin the context of the greater literature base, so it is unclear whatcould have explained these divergent responses.Encouraged by their cell culture findings, the authors performeda vitamin D (cholecalciferol) feeding study in an APP/PS1 transgenicmouse model. This model, like most murine models for AD, recapit-ulates a rare form of AD that mirrors limited aspects of human ADpathology. It does not represent normal cognitive decline or evencommonly seen forms of AD in humans. These animals also have dif-ficulties maintaining vitamin D status, as evidenced by lower serumcalcidiol levels compared to wild-type controls when maintained ona 600IU/kg cholecalciferol diet. Feeding the mice a high vitaminD diet containing 8044IU/kg cholecalciferol starting at the age of4.5 months restored serum calcidiol levels. However, after 3 monthsof supplementation, the authors observed “more severe Aβ plaquedeposits and reactive gliosis in the hippocampus compared to thecontrols,” an increased expression of pro-degenerative factors in theThis is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium,provided the original work is properly cited.© 2022 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd. 14749726, 2023, 1, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/acel.13758 by Bibliotheek Rijksuniversiteit, Wiley Online Library on [13/01/2023]. 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 License2 of 3 | COMMENTARYhippocampus, and worse cognitive functioning in the Morris watermaze.These findings are at odds with prior results in which vitamin Dsupplementation or treatment with calcitriol in several other mousemodels of AD reduced amyloid burden and improved cognition (Durket al., 2014; Lin, Lin, et al., 2020; Morello et al., 2018; Yu et al., 2011).In the 5XFADmousemodel, for example, female mice fed a high vita-min D (as cholecalciferol) diet (7500IU/kg) had fewer plaques in thefrontal cortex, hippocampus and neocortex, decreased astrogliosis,and cognitive defects as compared to the untreated mice (Landelet al., 2016). Researchers also observed similar effects of vitaminD supplementation in the AβPP (Durk et al., 2014) and the 3xTg-AD(Landel et al., 2016) transgenic mouse models. In Tg2576 andTgCRND8 mice, calcitriol administration decreased plaque burdenand improved cognitive function (Lin, Lin, et al., 2020). Furthermore,intraperitoneal injection of calcitriol also protected Long-Evans ratsfrom neuronal degeneration after intrahippocampal injection of ag-gregated Aβ(1–42; Pierucci et al., 2017). Again, the authors do notadequately discuss their findings in the context of the prior litera-ture. The findings from this and prior studies underscore the impor-tance of using multiple animal models to evaluate potential therapiesand translate findings to humans (Drummond & Wisniewski, 2017).The second half of the paper is a retrospective, population-basedlongitudinal study that attempts to quantify the risk for dementia andmortality in older adults taking vitamin D3 supplements. Accordingto the authors, their analysis indicates prolonged supplementationworsens the progression of AD by increasing dementia and mortal-ity risk. However, this is a completely inaccurate interpretation ofthe data. While described as “taking vitamin D3 supplements duringthe period 2000-2009”, the participant data comes from Taiwan'sNational Health Insurance Research Database that describes the useof calcitriol, a prescription medication—not a dietary supplement.Physicians prescribe calcitriol to increase calcium levels in patientswhose kidneys or parathyroid glands are not functioning normally.A prescription for calcitriol is not indicative of good health, as theindividuals taking calcitriol often have one or more comorbidities,such as osteoporosis, thyroid disorders, diabetes, hyperlipidemia,and hypertension. Each of these comorbidities indicates a predispo-sition toward dementia. Calcitriol is also often prescribed to patientswith chronic kidney disease, who are already prone to cognitivedecline and AD (Zhang et al., 2020). Considering the potent natureof calcitriol, it cannot be equated to taking vitamin D3 as a dietarysupplement.Of note, calcitriol overuse is associated with an increased risk ofhypercalcemia. Hypercalcemia has been associated with dementiaand changes in cognition (de Oliveira Martins Duarte et al., 2019;Lourida et al., 2015; Walker & Silverberg, 2018). Prolonged elevationin serum calcium levels, even if not to the level of hypercalcemia, canpredict cognitive decline and conversion from nondemented statusto AD (Ma et al., 2021). Since Lai et al. found that only medium-to-long-term calcitriol use (but not short-term use) was associated withincreased dementia or mortality risk, it is possible what the authorsreported were side effects of a prolonged drug regimen, not thephysiological effects associated with vitamin supplementation.In contrast to the authors' conclusions, the current body ofevidence from human clinical studies supports the role of vitaminD in cognitive health. Observational research shows that a higher25(OH)D3 (calcidiol) status is associated with a lower risk for ADand all-cause dementia (DeLuca et al., 2013; Littlejohns et al., 2014;Mayne & Burne, 2019). Randomized controlled trials with vitamin D3(cholecalciferol) supplementation have reported improved AD bio-measures and cognitive function (Jia et al., 2019). In older adults,vitamin D3 supplementation either improved or had no associa-tion with declines in cognitive function (Kang et al., 2021; Navaleet al., 2022; Rossom et al., 2012; Tong et al., 2020).While there are clearly opportunities for more research on therole of vitamin D supplementation in cognitive health, the authors'conclusions that “vitamin D supplementation worsens Alzheimer'sprogression” is not justified. Conflating the data from cell culture, amurine model system and a retrospective epidemiological observa-tion using prescription calcitriol reaches this flawed conclusion andlies in stark contrast to the large body of evidence that vitamin Dstatus and vitamin D supplementation support cognitive health. Thefindings of this paper should have been placed in the proper con-text before these inflammatory statements on AD were released forpublic view.AUTHOR CONTRIBUTIONSAll authors designed the manuscript and read and approved the finalmanuscript.FUNDING INFORMATIONThe development of the paper received no external funding.CONFLICT OF INTERESTAFG has received research funding from Bayer Consumer Care andhas acted as an advisor/consultant for and has received reimburse-ment for travel and/or speaking from Bayer Consumer Care, GSK,DSM, Kellogg's, and The Coca-Cola Company. AJM consults for di-etary supplement companies. ME is president of the Gesellschaftfür Angewandte Vitaminforschung (Germany), is a member of thescientific board of PM International, and consults for companies inthe nutrition and supplement field.DATA AVAILABILITY STATEMENTNone.ORCIDManfred Eggersdorfer https://orcid.org/0000-0002-5314-5110REFERENCESAgholme, L., Lindström, T., Kågedal, K., Marcusson, J., & Hallbeck, M.(2019). An in vitro model for neuroscience: Differentiation ofSH-SY5Y cells into cells with morphological and biochemical 14749726, 2023, 1, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/acel.13758 by Bibliotheek Rijksuniversiteit, Wiley Online Library on [13/01/2023]. 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| 3 of 3COMMENTARYcharacteristics of mature neurons. Journal of Alzheimer's Disease,20(4), 1069–1082.Bikle, D. (2000). Vitamin D: Production, metabolism, and mechanismsof action. [Updated 2021 Dec 31]. In K. R. Feingold, B. Anawalt, A.Boyce, G. Chrousos, W. W. de Herder, K. Dhatariya, K. Dungan, J.M. Hershman, J. Hershman, S. Kalra, G. Kaltsas, C. Koch, P. Kopp,M. Korbonits, C. S. Kovacs, W. Kuohung, B. Laferrère, M. Levy, E. A.McGee, … D. P. Wilson (Eds.), Endotext [Internet]. MDText.com, Inc.de Oliveira Martins Duarte, J., Pereira, P., Lopes, J. N. G., Goes, A. T. L.,Duran, D. C., Sobral, A., Rita, H. J. B., & Costa, J. A. S. E. (2019). Areversible case of rapidly progressive dementia-hypercalcemia dueto hyperparathyroidism. Clinical Case Reports, 7(12), 2571–2574.DeLuca, G. C., Kimball, S. M., Kolasinski, J., Ramagopalan, S. V., & Ebers,G. C. (2013). Review: The role of vitamin D in nervous systemhealth and disease. Neuropathology and Applied Neurobiology, 39(5),458–484.Drummond,E.,&Wisniewski, T. (2017).Alzheimer'sdisease:Experimentalmodels and reality. Acta Neuropathologica, 133(2), 155–175.Durk, M. R., Han, K., Chow, E. C., Ahrens, R., Henderson, J. T., Fraser, P.E., & Pang, K. S. (2014). 1alpha,25-Dihydroxyvitamin D3 reducescerebral amyloid-beta accumulation and improves cognition inmouse models of Alzheimer's disease. The Journal of Neuroscience,34(21), 7091–7101.Jia, J., Hu, J., Huo, X., Miao, R., Zhang, Y., & Ma, F. (2019). Effects ofvitamin D supplementation on cognitive function and blood Aβ-related biomarkers in older adults with Alzheimer's disease. Journalof Neurology, Neurosurgery, and Psychiatry, 90(12), 1347–1352.Kang, J. H., Vyas, C. M., Okereke, O. I., Ogata, S., Albert, M., Lee, I. M.,D'Agostino, D., Buring, J. E., Cook, N. R., Grodstein, F., & Manson,J. A. E. (2021). Effect of vitamin D on cognitive decline: Resultsfrom two ancillary studies of the VITAL randomized trial. ScientificReports, 11(1), 23253.Lai, R. H., Hsu, C. C., Yu, B. H., Lo, Y. R., Hsu, Y. Y., Chen, M. H., & Juang,J. L. (2022). Vitamin D supplementation worsens Alzheimer's pro-gression: Animal model and human cohort studies. Aging Cell, 21(8),e13670.Landel, V., Millet, P., Baranger, K., Loriod, B., & Feron, F. (2016). VitaminD interacts with Esr1 and Igf1 to regulate molecular pathways rel-evant to Alzheimer's disease.Molecular Neurodegeneration, 11, 22.Lin, C. I., Chang, Y. C., Kao, N. J., Lee, W. J., Cross, T. W., & Lin, S. H.(2020). 1,25(OH)2D3 alleviates Abeta(25-35)-induced tau hyper-phosphorylation, excessive reactive oxygen species, and apop-tosis through interplay with glial cell line-derived neurotrophicfactor signaling in SH-SY5Y cells. International Journal of MolecularSciences, 21(12), 4215.Lin, F. Y., Lin, Y. F., Lin, Y. S., Yang, C. M.,Wang, C. C., & Hsiao, Y. H. (2020).Relative D3 vitamin deficiency and consequent cognitive impair-ment in an animal model of Alzheimer's disease: Potential involve-ment of collapsin response mediator protein-2. Neuropharmacology,164, 107910.Littlejohns, T. J., Henley, W. E., Lang, I. A., Annweiler, C., Beauchet, O.,Chaves, P. H. M., Fried, L., Kestenbaum, B. R., Kuller, L. H., Langa, K.M., Lopez, O. L., Kos, K., Soni, M., & Llewellyn, D. J. (2014). VitaminD and the risk of dementia and Alzheimer disease. Neurology,83(10), 920–928.Lourida, I., Thompson-Coon, J., Dickens, C. M., Soni, M., Kuzma, E.,Kos, K., & Llewellyn, D. J. (2015). Parathyroid hormone, cognitivefunction and dementia: A systematic review. PLoS One, 10(5),e0127574.Ma, L. Z., Wang, Z. X., Wang, Z. T., Hou, X. H., Shen, X. N., Ou, Y. N., Dong,Q., Tan, L., & Yu, J. T. (2021). Serum calcium predicts cognitive de-cline and clinical progression of Alzheimer's disease. NeurotoxicityResearch, 39(3), 609–617.Mayne, P., & Burne, T. H. J. (2019). Vitamin D in synaptic plasticity, cogni-tive function, and neuropsychiatric illness. Trends in Neurosciences,42(4), 293–306.Morello, M., Landel, V., Lacassagne, E., Baranger, K., Annweiler, C.,Feron, F., & Millet, P. (2018). Vitamin D improves neurogenesisand cognition in a mouse model of Alzheimer's disease. MolecularNeurobiology, 55(8), 6463–6479.Navale, S., Mulugeta, A., Zhou, A., Llewellyn, D. J., & Hyppönen, E. (2022).Vitamin D and brain health – An observational and Mendelian ran-domization study. The American Journal of Clinical Nutrition, 116,531–540.Pierucci, F., Garcia-Gil, M., Frati, A., Bini, F., Martinesi, M., Vannini, E.,Mainardi, M., Luzzati, F., Peretto, P., Caleo, M., & Meacci, E. (2017).Vitamin D3 protects against Abeta peptide cytotoxicity in differ-entiated human neuroblastoma SH- SY5Y cells: A role for S1P1/p38MAPK/ATF4 axis. Neuropharmacology, 116, 328–342.Rossom, R. C., Espeland, M. A., Manson, J. E., Dysken, M. W., Johnson,K. C., Lane, D. S., LeBlanc, E. S., Lederle, F. A., Masaki, K. H., &Margolis, K. L. (2012). Calcium and vitamin D supplementation andcognitive impairment in the women's health initiative. Journal of theAmerican Geriatrics Society, 60(12), 2197–2205.Tong, Y., Wang, H. W., Ying, X., Chen, C. C., Keran, D., Jingya, J., & Fei,M. (2020). Vitamin D supplementation improves cognitive functionthrough reducing oxidative stress regulated by telomere length inolder adults with mild cognitive impairment. Journal of Alzheimer'sDisease, 78(4), 1509–1518.Vieth, R. (2020). Vitamin D supplementation: cholecalciferol, calcife-diol, and calcitriol. European Journal of Clinical Nutrition, 74(11),1493–1497.Walker, M. D., & Silverberg, S. J. (2018). Primary hyperparathyroidism.Nature Reviews. Endocrinology, 14(2), 115–125.Yu, J., Gattoni-Celli, M., Zhu, H., Bhat, N. R., Sambamurti, K., Gattoni-Celli, S., & Kindy, M. S. (2011). Vitamin D3-enriched diet correlateswith a decrease of amyloid plaques in the brain of AbetaPP trans-genic mice. Journal of Alzheimer's Disease, 25(2), 295–307.Zhang, C. Y., He, F. F., Su, H., Zhang, C., & Meng, X. F. (2020). Associationbetween chronic kidney disease and Alzheimer's disease: An up-date.Metabolic Brain Disease, 35(6), 883–894.How to cite this article: Gombart, A. F., Michels, A. J., &Eggersdorfer, M. (2023). There is no evidence that vitamin Dsupplementation drives the progression of Alzheimer'sdisease. Aging Cell, 22, e13758. https://doi.org/10.1111/acel.13758 14749726, 2023, 1, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/acel.13758 by Bibliotheek Rijksuniversiteit, Wiley Online Library on [13/01/2023]. 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

Adrian F. Gombart

Alexander J. Michels

Manfred Eggersdorfer

Crossref

University of Groningen

   University of GroningenThere is no evidence that vitamin D supplementation drives the progression of Alzheimer'sdiseaseGombart, Adrian F.; Michels, Alexander J.; Eggersdorfer, ManfredPublished in:Aging CellDOI:10.1111/acel.13758IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite fromit. Please check the document version below.Document VersionPublisher's PDF, also known as Version of recordPublication date:2023Link to publication in University of Groningen/UMCG research databaseCitation for published version (APA):Gombart, A. F., Michels, A. J., & Eggersdorfer, M. (2023). There is no evidence that vitamin Dsupplementation drives the progression of Alzheimer's disease. Aging Cell, 22(1), [e13758].https://doi.org/10.1111/acel.13758CopyrightOther than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of theauthor(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).The publication may also be distributed here under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license.More information can be found on the University of Groningen website: https://www.rug.nl/library/open-access/self-archiving-pure/taverne-amendment.Take-down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons thenumber of authors shown on this cover page is limited to 10 maximum.Aging Cell. 2023;22:e13758. | 1 of 3https://doi.org/10.1111/acel.13758wileyonlinelibrary.com/journal/acelReceived: 23 October 2022 | Accepted: 5 December 2022DOI: 10.1111/acel.13758COMMENTA RYThere is no evidence that vitamin D supplementation drives theprogression of Alzheimer's diseaseAdrian F. Gombart1 | Alexander J. Michels2 | Manfred Eggersdorfer31Department of Biochemistry and Biophysics, Linus Pauling Institute, Oregon State University, Corvallis, Oregon, USA2Linus Pauling Institute, Oregon State University, Corvallis, Oregon, USA3Department of Internal Medicine, University Medical Center Groningen, Groningen, The NetherlandsCorrespondenceManfred Eggersdorfer, Department of Internal Medicine, University Medical Center Groningen, Groningen, The Netherlands.Email: dr.eggersdorfer@gmail.comIf there is anything the last few decades have taught us, it is thatresearchers must properly conduct studies on vitamin supple-ments before they can make health claims. In a recent paper by Laiet al. (2022), the authors state, “vitamin D supplementation wors-ens Alzheimer's progression” without sufficient evidence to supportthese conclusions. While certain findings are scientifically interest-ing, readers must understand substantial limitations in the approachand methodology utilized in the paper limit conclusions one canmake about the role of vitamin D in brain health and Alzheimer'sdisease (AD).Before proceeding further, it is important for readers to under-stand that there are three different forms of vitamin D pertinentto this discussion. Cholecalciferol is the form of vitamin D3 synthe-sized in the skin upon exposure to UVB rays that typically comefrom sunlight. It is also the form found in dietary supplements. Theliver converts cholecalciferol to calcidiol (25-hydroxyvitamin D3),the circulating form used by clinicians to determine vitamin D sta-tus. Certain cells in the body will then convert calcidiol to calcitriol(1,25-dihydroxyvitamin D3), the “active” form of vitamin D in thebody (Bikle, 2000).Calcitriol is a high-affinity, potent ligand for the vitamin D recep-tor (VDR) and regulates most VDR-dependent gene transcription.The body only produces calcitriol under certain physiological condi-tions, including low serum calcium levels or immune activation, andtightly controls its synthesis and catabolism to limit its physiologicaleffects. On the other hand, cholecalciferol and calcidiol are consid-ered inactive forms of vitamin D3, as they are low-affinity ligandsfor VDR (Bikle, 2000). Because these three forms are not function-ally or physiologically equivalent, referring to them all as “vitaminD” creates a great deal of confusion, especially since cholecalciferolis found in vitamin D supplements or fortified foods and beverages,but calcitriol is appropriately classified as a drug (Vieth, 2020).The study by Lai et al. begins with data from neuronal cell culture.Here, the authors demonstrate that treatment with both calcidioland calcitriol increases apoptosis and autophagy in undifferentiatedSH-SY5Y cells upon exposure to Aβ42. SH-SY5Y is a neuroblastomacell line typically used in experiments after differentiation into a ho-mogeneous, more mature neuron-like cell, making them useful forAD research (Agholme et al., 2019). Prior reports show calcitriolprotects differentiated SH-SY5Y cells against Aβ(1–42) peptide cy-totoxicity (Vieth, 2020), although others have reported protection ofundifferentiated SH-SY5Y cells from Aβ(25–35) toxicity upon treat-ment with calcitriol (Lin, Chang, et al., 2020). While the study by Laiet al. reports contradictory findings, the authors do not discuss themin the context of the greater literature base, so it is unclear whatcould have explained these divergent responses.Encouraged by their cell culture findings, the authors performeda vitamin D (cholecalciferol) feeding study in an APP/PS1 transgenicmouse model. This model, like most murine models for AD, recapit-ulates a rare form of AD that mirrors limited aspects of human ADpathology. It does not represent normal cognitive decline or evencommonly seen forms of AD in humans. These animals also have dif-ficulties maintaining vitamin D status, as evidenced by lower serumcalcidiol levels compared to wild-type controls when maintained ona 600IU/kg cholecalciferol diet. Feeding the mice a high vitaminD diet containing 8044IU/kg cholecalciferol starting at the age of4.5 months restored serum calcidiol levels. However, after 3 monthsof supplementation, the authors observed “more severe Aβ plaquedeposits and reactive gliosis in the hippocampus compared to thecontrols,” an increased expression of pro-degenerative factors in theThis is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium,provided the original work is properly cited.© 2022 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd. 14749726, 2023, 1, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/acel.13758 by Bibliotheek Rijksuniversiteit, Wiley Online Library on [13/01/2023]. 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 License2 of 3 | COMMENTARYhippocampus, and worse cognitive functioning in the Morris watermaze.These findings are at odds with prior results in which vitamin Dsupplementation or treatment with calcitriol in several other mousemodels of AD reduced amyloid burden and improved cognition (Durket al., 2014; Lin, Lin, et al., 2020; Morello et al., 2018; Yu et al., 2011).In the 5XFADmousemodel, for example, female mice fed a high vita-min D (as cholecalciferol) diet (7500IU/kg) had fewer plaques in thefrontal cortex, hippocampus and neocortex, decreased astrogliosis,and cognitive defects as compared to the untreated mice (Landelet al., 2016). Researchers also observed similar effects of vitaminD supplementation in the AβPP (Durk et al., 2014) and the 3xTg-AD(Landel et al., 2016) transgenic mouse models. In Tg2576 andTgCRND8 mice, calcitriol administration decreased plaque burdenand improved cognitive function (Lin, Lin, et al., 2020). Furthermore,intraperitoneal injection of calcitriol also protected Long-Evans ratsfrom neuronal degeneration after intrahippocampal injection of ag-gregated Aβ(1–42; Pierucci et al., 2017). Again, the authors do notadequately discuss their findings in the context of the prior litera-ture. The findings from this and prior studies underscore the impor-tance of using multiple animal models to evaluate potential therapiesand translate findings to humans (Drummond & Wisniewski, 2017).The second half of the paper is a retrospective, population-basedlongitudinal study that attempts to quantify the risk for dementia andmortality in older adults taking vitamin D3 supplements. Accordingto the authors, their analysis indicates prolonged supplementationworsens the progression of AD by increasing dementia and mortal-ity risk. However, this is a completely inaccurate interpretation ofthe data. While described as “taking vitamin D3 supplements duringthe period 2000-2009”, the participant data comes from Taiwan'sNational Health Insurance Research Database that describes the useof calcitriol, a prescription medication—not a dietary supplement.Physicians prescribe calcitriol to increase calcium levels in patientswhose kidneys or parathyroid glands are not functioning normally.A prescription for calcitriol is not indicative of good health, as theindividuals taking calcitriol often have one or more comorbidities,such as osteoporosis, thyroid disorders, diabetes, hyperlipidemia,and hypertension. Each of these comorbidities indicates a predispo-sition toward dementia. Calcitriol is also often prescribed to patientswith chronic kidney disease, who are already prone to cognitivedecline and AD (Zhang et al., 2020). Considering the potent natureof calcitriol, it cannot be equated to taking vitamin D3 as a dietarysupplement.Of note, calcitriol overuse is associated with an increased risk ofhypercalcemia. Hypercalcemia has been associated with dementiaand changes in cognition (de Oliveira Martins Duarte et al., 2019;Lourida et al., 2015; Walker & Silverberg, 2018). Prolonged elevationin serum calcium levels, even if not to the level of hypercalcemia, canpredict cognitive decline and conversion from nondemented statusto AD (Ma et al., 2021). Since Lai et al. found that only medium-to-long-term calcitriol use (but not short-term use) was associated withincreased dementia or mortality risk, it is possible what the authorsreported were side effects of a prolonged drug regimen, not thephysiological effects associated with vitamin supplementation.In contrast to the authors' conclusions, the current body ofevidence from human clinical studies supports the role of vitaminD in cognitive health. Observational research shows that a higher25(OH)D3 (calcidiol) status is associated with a lower risk for ADand all-cause dementia (DeLuca et al., 2013; Littlejohns et al., 2014;Mayne & Burne, 2019). Randomized controlled trials with vitamin D3(cholecalciferol) supplementation have reported improved AD bio-measures and cognitive function (Jia et al., 2019). In older adults,vitamin D3 supplementation either improved or had no associa-tion with declines in cognitive function (Kang et al., 2021; Navaleet al., 2022; Rossom et al., 2012; Tong et al., 2020).While there are clearly opportunities for more research on therole of vitamin D supplementation in cognitive health, the authors'conclusions that “vitamin D supplementation worsens Alzheimer'sprogression” is not justified. Conflating the data from cell culture, amurine model system and a retrospective epidemiological observa-tion using prescription calcitriol reaches this flawed conclusion andlies in stark contrast to the large body of evidence that vitamin Dstatus and vitamin D supplementation support cognitive health. Thefindings of this paper should have been placed in the proper con-text before these inflammatory statements on AD were released forpublic view.AUTHOR CONTRIBUTIONSAll authors designed the manuscript and read and approved the finalmanuscript.FUNDING INFORMATIONThe development of the paper received no external funding.CONFLICT OF INTERESTAFG has received research funding from Bayer Consumer Care andhas acted as an advisor/consultant for and has received reimburse-ment for travel and/or speaking from Bayer Consumer Care, GSK,DSM, Kellogg's, and The Coca-Cola Company. AJM consults for di-etary supplement companies. ME is president of the Gesellschaftfür Angewandte Vitaminforschung (Germany), is a member of thescientific board of PM International, and consults for companies inthe nutrition and supplement field.DATA AVAILABILITY STATEMENTNone.ORCIDManfred Eggersdorfer https://orcid.org/0000-0002-5314-5110REFERENCESAgholme, L., Lindström, T., Kågedal, K., Marcusson, J., & Hallbeck, M.(2019). An in vitro model for neuroscience: Differentiation ofSH-SY5Y cells into cells with morphological and biochemical 14749726, 2023, 1, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/acel.13758 by Bibliotheek Rijksuniversiteit, Wiley Online Library on [13/01/2023]. 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| 3 of 3COMMENTARYcharacteristics of mature neurons. Journal of Alzheimer's Disease,20(4), 1069–1082.Bikle, D. (2000). 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Associationbetween chronic kidney disease and Alzheimer's disease: An up-date.Metabolic Brain Disease, 35(6), 883–894.How to cite this article: Gombart, A. F., Michels, A. J., &Eggersdorfer, M. (2023). There is no evidence that vitamin Dsupplementation drives the progression of Alzheimer'sdisease. Aging Cell, 22, e13758. https://doi.org/10.1111/acel.13758 14749726, 2023, 1, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/acel.13758 by Bibliotheek Rijksuniversiteit, Wiley Online Library on [13/01/2023]. 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

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There is no evidence that vitamin D supplementation drives the progression of Alzheimer's disease

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