Calcium supplementation and risk of dementia in women with cerebrovascular disease
Abstract
Objective:
To determine whether calcium supplementation is associated with the development of dementia in women after a 5-year follow-up.
Methods:
This was a longitudinal population-based study. The sample was derived from the Prospective Population Study of Women and H70 Birth Cohort Study in Gothenburg, Sweden, and included 700 dementia-free women aged 70–92 years. At baseline in 2000–2001, and at follow-up in 2005–2006, the women underwent comprehensive neuropsychiatric and somatic examinations. A CT scan was performed in 447 participants at baseline. Information on the use and dosage of calcium supplements was collected. Dementia was diagnosed according to DSM-III-R criteria.
Results:
Women treated with calcium supplements (n = 98) were at a higher risk of developing dementia (odds ratio [OR] 2.10, 95% confidence interval [CI] 1.01–4.37, p = 0.046) and the subtype stroke-related dementia (vascular dementia and mixed dementia) (OR 4.40, 95% CI 1.54–12.61, p = 0.006) than women not given supplementation (n = 602). In stratified analyses, calcium supplementation was associated with the development of dementia in groups with a history of stroke (OR 6.77, 95% CI 1.36–33.75, p = 0.020) or presence of white matter lesions (OR 2.99, 95% CI 1.28–6.96, p = 0.011), but not in groups without these conditions.
Conclusions:
Calcium supplementation may increase the risk of developing dementia in elderly women with cerebrovascular disease. Because our sample was relatively small and the study was observational, these findings need to be confirmed.
Get full access to this article
View all available purchase options and get full access to this article.
REFERENCES
1.
Skoog I, Nilsson L, Palmertz B, Andreasson LA, Svanborg A. A population-based study of dementia in 85-year-olds. N Engl J Med 1993;328:153–158.
2.
Bauer DC. Clinical practice: calcium supplements and fracture prevention. N Engl J Med 2013;369:1537–1543.
3.
Reid IR, Bristow SM, Bolland MJ. Calcium supplements: benefits and risks. J Intern Med 2015;278:354–368.
4.
Wang X, Chen H, Ouyang Y, et al. Dietary calcium intake and mortality risk from cardiovascular disease and all causes: a meta-analysis of prospective cohort studies. BMC Med 2014;12:158.
5.
Wang L, Manson JE, Song Y, Sesso HD. Systematic review: vitamin D and calcium supplementation in prevention of cardiovascular events. Ann Intern Med 2010;152:315–323.
6.
Bolland MJ, Grey A, Avenell A, Gamble GD, Reid IR. Calcium supplements with or without vitamin D and risk of cardiovascular events: reanalysis of the Women's Health Initiative limited access dataset and meta-analysis. BMJ 2011;342:d2040.
7.
Lewis JR, Calver J, Zhu K, Flicker L, Prince RL. Calcium supplementation and the risks of atherosclerotic vascular disease in older women: results of a 5-year RCT and a 4.5-year follow-up. J Bone Miner Res 2011;26:35–41.
8.
Hsia J, Heiss G, Ren H, et al. Calcium/vitamin D supplementation and cardiovascular events. Circulation 2007;115:846–854.
9.
Walker MD, Silverberg SJ. Cardiovascular aspects of primary hyperparathyroidism. J Endocrinol Invest 2008;31:925–931.
10.
Kloppenborg RP, van den Berg E, Kappelle LJ, Biessels GJ. Diabetes and other vascular risk factors for dementia: which factor matters most? A systematic review. Eur J Pharmacol 2008;585:97–108.
11.
Skoog I, Gustafson D. Hypertension, hypertension-clustering factors and Alzheimer's disease. Neurol Res 2003;25:675–680.
12.
Chung JW, Ryu WS, Kim BJ, Yoon BW. Elevated calcium after acute ischemic stroke: association with a poor short-term outcome and long-term mortality. J Stroke 2015;17:54–59.
13.
Kern S, Skoog I, Ostling S, Kern J, Borjesson-Hanson A. Does low-dose acetylsalicylic acid prevent cognitive decline in women with high cardiovascular risk? A 5-year follow-up of a non-demented population-based cohort of Swedish elderly women. BMJ Open 2012;2:1286–1288.
14.
Karlsson B, Klenfeldt IF, Sigstrom R, et al. Prevalence of social phobia in non-demented elderly from a Swedish population study. Am J Geriatr Psychiatry 2009;17:127–135.
15.
Simoni M, Pantoni L, Pracucci G, et al. Prevalence of CT-detected cerebral abnormalities in an elderly Swedish population sample. Acta Neurol Scand 2008;118:260–267.
16.
Skoog I, Palmertz B, Andreasson LA. The prevalence of white-matter lesions on computed tomography of the brain in demented and nondemented 85-year-olds. J Geriatr Psychiatry Neurol 1994;7:169–175.
17.
American Psychological Association. Diagnostic and Statistical Manual of Mental Disorders, 3rd ed Washington, DC: American Psychological Association; 1987.
18.
McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM. Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease. Neurology 1984;34:939–944.
19.
Guo X, Waern M, Sjogren K, et al. Midlife respiratory function and incidence of Alzheimer's disease: a 29-year longitudinal study in women. Neurobiol Aging 2007;28:343–350.
20.
Roman GC, Tatemichi TK, Erkinjuntti T, et al. Vascular dementia: diagnostic criteria for research studies: report of the NINDS-AIREN International Workshop. Neurology 1993;43:250–260.
21.
Ostling S, Gustafson D, Blennow K, Borjesson-Hanson A, Waern M. Psychotic symptoms in a population-based sample of 85-year-old individuals with dementia. J Geriatr Psychiatry Neurol 2011;24:3–8.
22.
Moyer VA; US Preventive Services Task Force. Vitamin D and calcium supplementation to prevent fractures in adults: US Preventive Services Task Force recommendation statement. Ann Intern Med 2013;158:691–696.
23.
Augat P, Weyand D, Panzer S, Klier T. Osteoporosis prevalence and fracture characteristics in elderly female patients with fractures. Arch Orthop Trauma Surg 2010;130:1405–1410.
24.
Vermeer SE, Prins ND, den Heijer T, Hofman A, Koudstaal PJ, Breteler MM. Silent brain infarcts and the risk of dementia and cognitive decline. N Engl J Med 2003;348:1215–1222.
25.
Linden T, Skoog I, Fagerberg B, Steen B, Blomstrand C. Cognitive impairment and dementia 20 months after stroke. Neuroepidemiology 2004;23:45–52.
26.
Pantoni L, Garcia JH. Pathogenesis of leukoaraiosis: a review. Stroke 1997;28:652–659.
27.
Bolland MJ, Avenell A, Baron JA, et al. Effect of calcium supplements on risk of myocardial infarction and cardiovascular events: meta-analysis. BMJ 2010;341:c3691.
28.
Hotchkiss RS, Strasser A, McDunn JE, Swanson PE. Cell death. N Engl J Med 2009;361:1570–1583.
29.
Zhivotovsky B, Orrenius S. Cell cycle and cell death in disease: past, present and future. J Intern Med 2010;268:395–409.
30.
Tomonaga M, Yamanouchi H, Tohgi H, Kameyama M. Clinicopathologic study of progressive subcortical vascular encephalopathy (Binswanger type) in the elderly. J Am Geriatr Soc 1982;30:524–529.
31.
Abedin M, Tintut Y, Demer LL. Vascular calcification: mechanisms and clinical ramifications. Arterioscler Thromb Vasc Biol 2004;24:1161–1170.
32.
Umesawa M, Iso H, Ishihara J, et al. Dietary calcium intake and risks of stroke, its subtypes, and coronary heart disease in Japanese: the JPHC Study Cohort I. Stroke 2008;39:2449–2456.
33.
Rossom RC, Espeland MA, Manson JE, et al. Calcium and vitamin D supplementation and cognitive impairment in the women's health initiative. J Am Geriatr Soc 2012;60:2197–2205.
34.
Payne ME, McQuoid DR, Steffens DC, Anderson JJ. Elevated brain lesion volumes in older adults who use calcium supplements: a cross-sectional clinical observational study. Br J Nutr 2014;112:220–227.
35.
Afzal S, Bojesen SE, Nordestgaard BG. Reduced 25-hydroxyvitamin D and risk of Alzheimer's disease and vascular dementia. Alzheimers Dement 2014;10:296–302.
36.
Bolland MJ, Grey A, Gamble GD, Reid IR. The effect of vitamin D supplementation on skeletal, vascular, or cancer outcomes: a trial sequential meta-analysis. Lancet Diabetes Endocrinol 2014;2:307–320.
37.
Jacobs DR Jr, Hohe C, Mursu J, Robien K, Folsom AR. Whole grain intake, incident hip fracture and presumed frailty in the Iowa Women's Health Study. Br J Nutr 2010;104:1537–1543.
38.
Gudmundsson P, Olesen PJ, Simoni M, et al. White matter lesions and temporal lobe atrophy related to incidence of both dementia and major depression in 70-year-olds followed over 10 years. Eur J Neurol 2015;22:781–788, e49–e50.
39.
Lopez OL, Becker JT, Jungreis CA, et al. Computed tomography—but not magnetic resonance imaging—identified periventricular white-matter lesions predict symptomatic cerebrovascular disease in probable Alzheimer's disease. Arch Neurol 1995;52:659–664.
40.
Beynon R, Sterne JA, Wilcock G, et al. Is MRI better than CT for detecting a vascular component to dementia? A systematic review and meta-analysis. BMC Neurol 2012;12:33.
Information & Authors
Information
Published In
Copyright
© 2016 American Academy of Neurology.
Publication History
Received: January 16, 2016
Accepted: July 5, 2016
Published online: August 17, 2016
Published in print: October 18, 2016
Disclosure
The authors report no disclosures relevant to the manuscript. Go to Neurology.org for full disclosures.
Study Funding
This study was supported by grants from The Swedish Research Council (11267, 2005-8460, 825-2007-7462, 825-2012-5041, 2013-8717, 2013-61X-14002, 2015-02830); the Torsten Söderbergs Stiftelse at the Royal Swedish Academy of Sciences; Swedish Research Council for Health, Working Life and Wellfare (nos. 2001-2646, 2001-2835, 2003-0234, 2004-0150, 2006-0020, 2008-1229, 2004-0145, 2006-0596, 2008-1111, 2010-0870, AGECAP 2013-2300, 2013-2496, Epilife 2006-1506); Swedish Brain Power; The Alzheimer's Association Zenith Award (ZEN-01-3151); The Alzheimer's Association Stephanie B. Overstreet Scholars (IIRG-00-2159); The Knut and Alice Wallenberg Foundation; Sahlgrenska University Hospital (ALF); The Emil and Maria Palm Foundation; The Bank of Sweden Tercentenary Foundation; EU FP7 project LipiDiDiet; Grant Agreement 211696; Konung Gustaf V:s och Drottning Victorias Frimurarestiftelse; Eivind och Elsa K:son Sylvans Stiftelse; Stiftelsen Söderström-Königska Sjukhemmet; Stiftelsen för Gamla Tjänarinnor; Handlanden Hjalmar Svenssons Forskningsfond; Stiftelsen Längmanska Kulturfonden; Epilife Small Grant; and Stiftelsen Demensfonden. None of the funders was involved in the design or interpretation of the study. The funding sources had no involvement in study design; the collection, analysis, or interpretation of data; the writing of the paper; or the decision to submit the paper for publication.
Authors
Author Contributions
Jürgen Kern and Silke Kern analyzed and interpreted the data, conducted the literature search, and wrote the paper. Kaj Blennow, Henrik Zetterberg, Margda Waern, Xinxin Guo, and Anne Börjesson-Hanson contributed with the analysis and interpretation of the data and revised the article critically for important intellectual content. Ingmar Skoog and Svante Östling conceived and designed the study, refined the study methods, were involved in analysis and interpretation of the data, and revised the article critically for important intellectual content. The corresponding author attests that the authors had access to all the study data, take responsibility for the accuracy of the analysis, and had authority over manuscript preparation and the decision to submit the manuscript for publication. All authors gave final approval of the version to be published. The corresponding author affirms that he has listed everyone who contributed significantly to the work.
Metrics & Citations
Metrics
Citations
Download Citations
If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Select your manager software from the list below and click Download.
Cited By
- Essential Nutrients and White Matter Hyperintensities: A Two-Sample Mendelian Randomization Study, Biomedicines, 12, 4, (810), (2024).https://doi.org/10.3390/biomedicines12040810
- Associations between plasma metal elements and risk of cognitive impairment among Chinese older adults, Frontiers in Aging Neuroscience, 16, (2024).https://doi.org/10.3389/fnagi.2024.1353286
- Micronutrients for Dementia Prevention, Nutrition in Brain Aging and Dementia, (151-165), (2024).https://doi.org/10.1007/978-981-97-4117-5_7
- Metals in Alzheimer’s Disease, Biomedicines, 11, 4, (1161), (2023).https://doi.org/10.3390/biomedicines11041161
- Oral calcium and vitamin D supplements differentially alter exploratory, anxiety-like behaviors and memory in male rats, PLOS ONE, 18, 8, (e0290106), (2023).https://doi.org/10.1371/journal.pone.0290106
- Habitual glucosamine use, APOE genotypes, and risk of incident cause-specific dementia in the older population, Alzheimer's Research & Therapy, 15, 1, (2023).https://doi.org/10.1186/s13195-023-01295-6
- Cerebrospinal fluid biomarkers of axonal and synaptic degeneration in a population-based sample, Alzheimer's Research & Therapy, 15, 1, (2023).https://doi.org/10.1186/s13195-023-01193-x
- Causal association of genetically determined circulating vitamin D metabolites and calcium with multiple sclerosis in participants of European descent, European Journal of Clinical Nutrition, 77, 4, (481-489), (2023).https://doi.org/10.1038/s41430-023-01260-4
- Role of calcium in Parkinson's disease, Vitamins and Minerals in Neurological Disorders, (561-577), (2023).https://doi.org/10.1016/B978-0-323-89835-5.00021-1
- A Metallomic Approach to Assess Associations of Plasma Metal Levels with Amnestic Mild Cognitive Impairment and Alzheimer’s Disease: An Exploratory Study, Journal of Clinical Medicine, 11, 13, (3655), (2022).https://doi.org/10.3390/jcm11133655
- See more
Loading...
View Options
Get Access
Login options
Check if you have access through your login credentials or your institution to get full access on this article.
Personal login Institutional LoginPurchase Options
The neurology.org payment platform is currently offline. Our technical team is working as quickly as possible to restore service.
If you need immediate support or to place an order, please call or email customer service:
- 1-800-638-3030 for U.S. customers - 8:30 - 7 pm ET (M-F)
- 1-301-223-2300 for customers outside the U.S. - 8:30 - 7 pm ET (M-F)
- [email protected]
We appreciate your patience during this time and apologize for any inconvenience.
We thank Dr. Beale for the interesting comment on our article. [1] We agree that Vitamin D is a possible confounder. However, we did not detect a modifying effect of Vtiamin D in our study. Even if existing data are not sufficient to conclude that Vitamin D reduces dementia risk, an association was found between low plasma 25-hydroxy vitamin D and an increased risk of Alzheimer disease and vascular dementia. [2] Therefore, Vitamin D supplementation might even decrease the risk of dementia. As noted in our paper, the study was observational. Thus, true cause and effect cannot be proven.
1. Kern J, Kern S, Blennow K, et al. Calcium supplementation and risk of dementia in women with cerebrovascular disease. Neurology 2016;87:1674-1680.
2. Afzal S, Bojesen SE, Nordestgaard BG. Reduced 25-hydroxyvitamin D and risk of Alzheimer's disease and vascular dementia. Alzheimers Dement 2014;10:296-302.
For disclosures, please contact the editorial office at [email protected].
Kern et al. conducted a small, observational, retrospective, longitudinal, population-based cohort study of calcium supplementation and increased dementia risk in elderly women. [1] Women who took calcium supplementation had higher odds of dementia. However, the number of individuals taking calcium supplements without vitamin D was low and compromised the reliability of the results. The sample size (n=98) in the calcium supplements group included women taking calcium supplements with 85.7% (84 of 98) also taking vitamin D. [1] The authors, recognizing vitamin D as a confounding variable, included it in regression models and stated that vitamin D did not affect the "main results." [1] However, controlling for vitamin D would not improve statistical power. Women taking calcium supplements with vitamin D should have been excluded at baseline because the dependent variable in the hypothesis was calcium supplementation alone. [1] The calcium supplement group was described as "women treated with calcium supplements," [1] but they were actually women treated with calcium supplements most of whom took vitamin D. Thus, the study hypothesis of calcium supplementation association with an increased risk of dementia was tested with a small sample size of 98 where only 14 individuals were relevant to the research question.
1. Kern J, Kern S, Blennow K, et al. Calcium supplementation and risk of dementia in women with cerebrovascular disease. Neurolog. 2016;87:1674-1680.
For disclosures, please contact the editorial office at [email protected].
We thank Dr. Rosenberg for the interesting comment. Indeed, in our article, [1] we referenced Bolland et al. for an acute (steep) increase in serum calcium being one possible mechanism. [2] This acute increase is correctly detailed by Dr. Rosenberg, just to a modest degree. However, in the pathomechanism of cell death, the acute increase in itself, not the amount of the increase, might be important especially in vulnerable neurons already compromised by cerebrovascular disease. Additionally, there are several possible mechanisms of calcium supplements in the pathogenesis of dementia.
We agree with Dr. Rosenberg that further research should look for mechanisms outside the realm of calcium pharmacokinetics.
1. Kern J, Kern S, Blennow K, et al. Calcium supplementation and risk of dementia in women with cerebrovascular disease. Neurology Epub 2016 Aug 17.
2. Bolland MJ, Avenell A, Baron JA, et al. Effect of calcium supplements on risk of myocardial infarction and cardiovascular events: meta-analysis. BMJ 2010;341:c3691.
For disclosures, please contact the editorial office at [email protected].
Kern et al. reported calcium supplementation may increase the risk of dementia in elderly women with cerebrovascular disease. [1] Among the possible mechanisms that could explain this association, the authors mentioned "the steep increase in serum calcium levels caused by the supplements." [1] This statement was referenced to a previous publication, [2] which described the supplement-induced increase in serum calcium as "modest" based on the results of an earlier study in young healthy subjects. [3] A more recent study in overweight but otherwise healthy post-menopausal women administered a single dose of 500 mg elemental calcium supplement after pre-treatment with 10 micrograms 25(OH)D3 and found that the maximal increase in serum level of ionized calcium post-dosing was in the vicinity of 0.3 mg/dL (i.e. approximately only 5% of the upper limit of this ion's normal serum concentration); this change peaked 3 to 5 hours after the supplement's ingestion. [4] Such a small increase over several hours can hardly be termed "steep." The mechanism, if any, linking the increased dementia risk with calcium supplementation should probably be looked for outside the realm of calcium's pharmacokinetics.
1. Kern J, Kern S, Blennow K, et al. Calcium supplementation and risk of dementia in women with cerebrovascular disease. Neurology Epub 2016 Aug 17.
2. Bolland MJ, Avenell A, Baron JA, et al. Effect of calcium supplements on risk of myocardial infarction and cardiovascular events: meta-analysis. BMJ 2010;341:c3691.
3. Reid IR, Schooler BA, Hannan SF, Ibbertson HK. The acute biochemical effects of four proprietary calcium preparations. Aust N Z J Med 1986;16:193-197.
4. Heaney RP, Dowell MS, Bierman J, Hale CA, Bendich A. Absorbability and cost effectiveness in calcium supplementation. J Am Coll Nutr 2001;20:239-246.
For disclosures, please contact the editorial office at [email protected].