Comparative Effectiveness of Different Statins on the Risk of Incident Dementia and the Impact of Gender and Exposure time on Risk Reduction: A Meta-analysis of Observational Studies.
DOI:
https://doi.org/10.37376/ljst.v14i2.7205Keywords:
A Meta-analysis, statins, dementia, gender, exposure timeAbstract
The impact of statins in the prevention of dementia has been a point of debate recently however, the evidence remains controversial. For this reason, we conducted this meta-analysis of relevant observational studies to assess the relationship between statin therapy and the reduction of dementia risk
Methods:
We systematically searched for relevant studies published from 2000 to 2021 using different scientific search engines. Seventeen original articles, which represent observational studies about the prophylactic effect of statin medications in reducing the risk of all-cause dementia were chosen. We then extracted data from the selected studies and performed meta-analysis of these studies using random effects model. Subgroup and sensitivity analyses were also conducted.
Results:
About 4,241,469 Participants met the eligibility criteria. Statin users had lowered all caused dementia risk than those non-statin users (RR from 17 studies RR= 0.745, 95% CI = 0.653- 0.849, P =0.000). In subgroup analyses, statins reduced the risk of dementia in both males and females (RR= 0.902, 95%, CI=0.872-0.932, P= 0.00), (RR= 0.889, 95%, CI= 0.794- 0.995, P= 0.04). Moreover, testing different statin formulae has shown that atorvastatin and rosuvastatin have significant effects (aRR=0.686, 95%CI=0.488-0.965, p-value=0.030) and (RR=0.695, 95%CI= 0.553-0.873, p-value=0.002). While simvastatin showed a non-significant effect (an RR= 0.900; 95%, CI=0.792-1.024; P=0.109). concerning exposure time, using statin for more than one year tends to show a significant influence on the risk of dementia (RR= 0.576; 95%, CI= 0.367- 0.903; P= 0.016).
Conclusion:
This analytical study revealed the great value of using statins in both males and females who are at higher risk of developing dementia. It is highly recommended for conducting a clinical study on high-risk Libyan patients.
Downloads
References
Ancelin, M.-L., Carrière, I., Barberger-Gateau, P., Auriacombe, S., Rouaud, O., Fourlanos, S., Berr, C., Dupuy, A.-M., Ritchie, K., (2012) Lipid-lowering agents, cognitive decline, and dementia: the three-city study. J Alzheimers Dis 30, 629–637. doi:10.3233/JAD-2012-120064
Bettermann, K., Arnold, A.M., Williamson, J., Rapp, S., Sink, K., Toole, J.F., Carlson, M.C., Yasar, S., Dekosky, S., Burke, G.L., 2012. Statins, risk of dementia, and cognitive function: secondary analysis of the ginkgo evaluation of memory study. J. Stroke Cerebrovasc. Dis. 21, 436–444. doi: 10.1016/j.jstrokecerebrovasdis.2010.11.002
Bottorff, M., Hansten, P., 2000. Long-term safety of hepatic hydroxymethyl glutaryl coenzyme A reductase inhibitors: the role of metabolism-monograph for physicians. Arch. Intern. Med. 160, 2273–2280. doi:10.1001/archinte.160.15.2273
Chang, C.-F., Liou, Y.-S., Lin, T.-K., Ma, S., Hu, Y.-R., Chen, H.-Y., Jong, G.-P., 2019. High exposure to statins decreases the risk of new-onset dementia: A nationwide population-based longitudinal cohort study. Medicine (Baltimore) 98, e16931. doi:10.1097/MD.0000000000016931
Chao, T.-F., Liu, C.-J., Chen, S.-J., Wang, K.-L., Lin, Y.-J., Chang, S.-L., Lo, L.-W., Hu, Y.-F., Tuan, T.-C., Chen, T.-J., Lip, G.Y.H., Chiang, C.-E., Chen, S.-A., 2015. Statins and the risk of dementia in patients with atrial fibrillation: A nationwide population-based cohort study. Int. J. Cardiol. 196, 91–97. doi: 10.1016/j.ijcard.05.159
Chen, J.-M., Chang, C.-W., Chang, T.-H., Hsu, C.-C., Horng, J.-T., Sheu, W.H.-H., 2014. Effects of statins on incident dementia in patients with type 2 DM: a population-based retrospective cohort study in Taiwan. PLoS ONE 9, e88434. doi: 10.1371/journal.pone.0088434
Chen, P.-Y., Liu, S.-K., Chen, C.-L., Wu, C.-S., 2014. Long-term statin uses and dementia risk in Taiwan. J. Geriatr. Psychiatry Neurol. 27, 165–171. doi:10.1177/0891988714522702
Chitnis, A.S., Aparasu, R.R., Chen, H., Kunik, M.E., Schulz, P.E., Johnson, M.L., 2015. Use of statins and risk of dementia in heart failure: A retrospective cohort study. Drugs Aging 32, 743–754. doi:10.1007/s40266-015-0295-4
Cordle, A., Landreth, G., 2005. 3-Hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors attenuate beta-amyloid-induced microglial inflammatory responses. J. Neurosci. 25, 299–307. doi:10.1523/JNEUROSCI.2544-04.
Cordy, J.M., Hussain, I., Dingwall, C., Hooper, N.M., Turner, A.J., 2003. Exclusively targeting beta-secretase to lipid rafts by GPI-anchor addition up-regulates beta-site processing of the amyloid precursor protein. Proc Natl Acad Sci USA 100, 11735–11740. doi:10.1073/pnas.1635130100
Cramer, C., Haan, M.N., Galea, S., Langa, K.M., Kalbfleisch, J.D., 2008. Use of statins and incidence of dementia and cognitive impairment without dementia in a cohort study. Neurology 71, 344–350. doi: 10.1212/01.wnl.0000319647.15752.7b
Egger M, Davey SG, Schneider M, Minder C.1997. Bias in meta-analysis was detected by a simple, graphical test. BMJ 315 (7109), 629–634.
Faubion, S.S., Kapoor, E., Moyer, A.M., Hodis, H.N., Miller, V.M., 2019. Statin therapy: does sex matter? Menopause 26, 1425–1435. doi:10.1097/GME.0000000000001412
Hajjar, I., Schumpert, J., Hirth, V., Wieland, D., Eleazer, G.P., 2002. The impact of the use of statins on the prevalence of dementia and the progression of cognitive impairment. J. Gerontol. A Biol. Sci. Med. Sci. 57, M414-8. doi:10.1093/gerona/57.7.m414
Hammad, M.A., Syed Sulaiman, S.A., Aziz, N.A., Mohamed Noor, D.A., 2019. Evaluation of statins impacts on cognitive function among diabetic patients. Diabetes & Metabolic Syndrome: Clinical Research & Reviews 13, 1797–1803. doi: 10.1016/j.dsx.2019.04.006
Hendrie, H.C., 1998. Epidemiology of dementia and Alzheimer’s disease. Am. J. Geriatr. Psychiatry 6, S3-18. doi:10.1097/00019442-199821001-00002
Hooff, G.P., Wood, W.G., Müller, W.E., Eckert, G.P., 2010. Isoprenoids, small GTPases, and Alzheimer’s disease. Biochim. Biophys. Acta 1801, 896–905. doi: 10.1016/j.bbalip.2010.03.014
Hosaka, A., Araki, W., Oda, A., Tomidokoro, Y., Tamaoka, A., 2013. Statins reduce amyloid β-peptide production by modulating amyloid precursor protein maturation and phosphorylation through a cholesterol-independent mechanism in cultured neurons. Neurochem. Res. 38, 589–600. doi:10.1007/s11064-012-0956-1
Jick, H., Zornberg, G.L., Jick, S.S., Seshadri, S., Drachman, D.A., 2000. Statins and the risk of dementia. Lancet 356, 1627–1631. doi:10.1016/s0140-6736(00)03155-x
Kim, M.-Y., Jung, M., Noh, Y., Shin, S., Hong, C.H., Lee, S., Jung, Y.-S., 2020. Impact of Statin Use on Dementia Incidence in Elderly Men and Women with Ischemic Heart Disease. Biomedicines 8. doi:10.3390/biomedicines8020030
Lee, J.W., Choi, E.A., Kim, Y.S., Kim, Y., You, H.S., Han, Y.E., Kim, H.S., Bae, Y.J., Kim, J., Kang, H.T., 2020. Statin exposure and the risk of dementia in individuals with hypercholesterolaemia. J. Intern. Med. 288, 689–698. doi:10.1111/joim.13134
Li, G., Higdon, R., Kukull, W.A., Peskind, E., Van Valen Moore, K., Tsuang, D., van Belle, G., McCormick, W., Bowen, J.D., Teri, L., Schellenberg, G.D., Larson, E.B., 2004. Statin therapy and risk of dementia in the elderly: a community-based prospective cohort study. Neurology 63, 1624–1628. doi: 10.1212/01.wnl.0000142963.90204.58
Li, G., Shofer, J.B., Rhew, I.C., Kukull, W.A., Peskind, E.R., McCormick, W., Bowen, J.D., Schellenberg, G.D., Crane, P.K., Breitner, J.C.S., Larson, E.B., 2010. Age-varying association between statin use and incident Alzheimer’s disease. J. Am. Geriatr. Soc. 58, 1311–1317. doi:10.1111/j.1532-5415.2010. 02906.x
Mahley, R.W., 2016. Apolipoprotein E: from cardiovascular disease to neurodegenerative disorders. J. Mol. Med. 94, 739–746. doi:10.1007/s00109-016-1427-y
McFarlane, O., Kędziora-Kornatowska, K., 2020. Cholesterol and dementia: A long and complicated relationship. Curr. Aging Sci. 13, 42–51. doi:10.2174/1874609812666190917155400
O’Brien, J.T., Thomas, A., 2015. Vascular dementia. Lancet 386, 1698–1706. doi:10.1016/S0140-6736(15)00463-8
Pan, M.-L., Hsu, C.-C., Chen, Y.-M., Yu, H.-K., Hu, G.-C., 2018. Statin Use and the Risk of Dementia in Patients with Stroke: A Nationwide Population-Based Cohort Study. J. Stroke Cerebrovasc. Dis. 27, 3001–3007. doi: 10.1016/j.jstrokecerebrovasdis.2018.06.036
Poly, T.N., Islam, M.M., Walther, B.A., Yang, H.-C., Wu, C.-C., Lin, M.-C., Li, Y.-C., 2020. Association between Use of Statin and Risk of Dementia: A Meta-Analysis of Observational Studies. Neuroepidemiology 54, 214–226. doi:10.1159/000503105
Rea, T.D., Breitner, J.C., Psaty, B.M., Fitzpatrick, A.L., Lopez, O.L., Newman, A.B., Hazzard, W.R., Zandi, P.P., Burke, G.L., Lyketsos, C.G., Bernick, C., Kuller, L.H., 2005. Statin use and the risk of incident dementia: the Cardiovascular Health Study. Arch. Neurol. 62, 1047–1051. doi:10.1001/archneur.62.7.1047
Refolo, L.M., Pappolla, M.A., LaFrancois, J., Malester, B., Schmidt, S.D., Thomas-Bryant, T., Tint, G.S., Wang, R., Mercken, M., Petanceska, S.S., Duff, K.E., 2001. A cholesterol-lowering drug reduces beta-amyloid pathology in a transgenic mouse model of Alzheimer’s disease. Neurobiol. Dis. 8, 890–899. doi:10.1006/nbdi.2001.0422
Reitz, C., 2012. Dyslipidemia and dementia: current epidemiology, genetic evidence, and mechanisms behind the associations. J Alzheimers Dis 30 Suppl 2, S127-45. doi:10.3233/JAD-2011-110599
Shie, F.-S., Jin, L.-W., Cook, D.G., Leverenz, J.B., LeBoeuf, R.C., 2002. Diet-induced hypercholesterolemia enhances brain Aβ accumulation in transgenic mice. NeuroReport 13.
Smeeth, L., Douglas, I., Hall, A.J., Hubbard, R., Evans, S., 2009. Effect of statins on a wide range of health outcomes: a cohort study validated by comparison with randomized trials. Br. J. Clin. Pharmacol. 67, 99–109. doi:10.1111/j.1365-2125.2008.03308.x
Smiderle, L., Fiegenbaum, M., Hutz, M.H., Van Der Sand, C.R., Van Der Sand, L.C., Ferreira, M.E.W., Pires, R.C., Almeida, S., 2016. ESR1 polymorphisms and statin therapy: a sex-specific approach. Pharmacogenomics J. 16, 507–513. doi:10.1038/tpj.2015.60
Solomon, A., Kivipelto, M., Wolozin, B., Zhou, J., Whitmer, R.A., 2009. Midlife serum cholesterol and increased risk of Alzheimer’s and vascular dementia three decades later. Dement. Geriatr. Cogn. Disord. 28, 75–80. doi:10.1159/000231980
Song, Y., Nie, H., Xu, Y., Zhang, L., Wu, Y., 2013. Association of statin use with risk of dementia: a meta-analysis of prospective cohort studies. Geriatr. Gerontol. Int. 13, 817–824. doi:10.1111/ggi.12044
Sparks, D.L., Sabbagh, M.N., Connor, D.J., Lopez, J., Launer, L.J., Browne, P., Wasser, D., Johnson-Traver, S., Lochhead, J., Ziolwolski, C., 2005. Atorvastatin for the treatment of mild to moderate Alzheimer disease: preliminary results. Arch. Neurol. 62, 753–757. doi:10.1001/archneur.62.5.753
Thomas D. Rea, John C. Breitner, Bruce M. Psaty, Annette L. Fitzpatrick,Oscar L. Lopez, Anne B. Newman, William R. Hazzard, Peter P. Zandi, Gregory L. Burke, Constantine G. Lyketsos, Charles Bernick, Lewis H. Kuller.,2005. Statin Use and the Risk of Incident Dementia. Arch Neurol.62,753-757 Jul;62(7):1047-51. doi: 10.1001/archneur.62.7.1047.
Torrandell-Haro, G., Branigan, G.L., Vitali, F., Geifman, N., Zissimopoulos, J.M., Brinton, R.D., 2020. Statin therapy and risk of Alzheimer’s and age-related neurodegenerative diseases. Alzheimers Dement (N Y) 6, e12108. doi:10.1002/trc2.12108
Verghese, P.B., Castellano, J.M., Garai, K., Wang, Y., Jiang, H., Shah, A., Bu, G., Frieden, C., Holtzman, D.M., 2013. ApoE influences amyloid-β (Aβ) clearance despite minimal apoE/Aβ association in physiological conditions. Proc Natl Acad Sci USA 110, E1807-16. doi:10.1073/pnas.1220484110
Wells GA, Shea B, O 'Connell D, Peterson Welch V, Losos M, Tugwell P. 2009. The Newcastle-Ottawa Scale (NOS) for assessing the quality if nonrandomized studies in meta-analyses. Available from: URL: http://www.ohri.ca/programs/clinical_epidemiology/oxford.htm
Wolozin, B., Kellman, W., Ruosseau, P., Celesia, G.G., Siegel, G., 2000. Decreased prevalence of Alzheimer's disease associated with 3-hydroxy-3-methyglutaryl coenzyme A reductase inhibitors. Arch. Neurol. 57, 1439–1443. doi:10.1001/archneur.57.10.1439
Wolozin, B., Wang, S.W., Li, N.-C., Lee, A., Lee, T.A., Kazis, L.E., 2007. Simvastatin is associated with a reduced incidence of dementia and Parkinson’s disease. BMC Med. 5, 20. doi:10.1186/1741-7015-5-20
Wong, W.B., Lin, V.W., Boudreau, D., Devine, E.B., 2013. Statins in the prevention of dementia and Alzheimer’s disease: a meta-analysis of observational studies and an assessment of confounding. Pharmacoepidemiol. Drug Saf. 22, 345–358. doi:10.1002/pds.3381
Wu, C.K., Yang, Y.H., Lin, T.T., Tsai, C.T., Hwang, J.J., Lin, J.L., Chen, P.C., Chiang, F.T., Lin, L.Y., 2015. Statin use reduces the risk of dementia in elderly patients: a nationwide data survey and propensity analysis. J. Intern. Med. 277, 343–352. doi:10.1111/joim.12262
Zamrini, E., McGwin, G., Roseman, J.M., 2004. Association between statin use and Alzheimer’s disease. Neuroepidemiology 23, 94–98. doi:10.1159/000073981
Zandi, P.P., Sparks, D.L., Khachaturian, A.S., Tschanz, J., Norton, M., Steinberg, M., Welsh-Bohmer, K.A., Breitner, J.C.S., 2005. Cache County Study investigators, Do statins reduce risk of incident dementia and Alzheimer's disease? The Cache County Study. Arch. Gen. Psychiatry 62, 217–224. doi:10.1001/archpsyc.62.2.217
Zhou, B., Teramukai, S., Fukushima, M., 2007. Prevention and treatment of dementia or Alzheimer’s disease by statins: a meta-analysis. Dement. Geriatr. Cogn. Disord. 23, 194–201. doi:10.1159/000099037
Zingel, R., Bohlken, J., Riedel-Heller, S., Barth, S., Kostev, K., 2021. Association Between Low-Density Lipoprotein Cholesterol Levels, Statin Use, and Dementia in Patients followed in German General Practices. J Alzheimers Dis 79, 37–46. doi:10.3233/JAD-201176
Zissimopoulos, J.M., Barthold, D., Brinton, R.D., Joyce, G., 2017. Sex and race differences in the association between statin use and the incidence of Alzheimer's disease. JAMA Neurol. 74, 225–232. doi:10.1001/jamaneurol.2016.3783
Downloads
Published
How to Cite
Issue
Section
License
Copyright (c) 2025 Libyan Journal of Science &Technology

This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.