Background and Aims: The impact of statin on dementia risk reduction has been a subject of debate over the last decade, but the evidence remains inconclusive. Therefore, we performed a meta-analysis of relevant observational studies to quantify the magnitude of the association between statin therapy and the risk of dementia. Methods: We systematically searched for relevant studies published from January 2000 to March 2018 using EMBASE, Google, Google Scholar, PubMed, Scopus, and Web of Science. Two authors performed study selection, data abstraction, and risk of bias assessment. We then extracted data from the selected studies and performed meta-analysis of observational studies using a random-effects model. Subgroup and sensitivity analyses were also conducted. Results: A total of 30 observational studies, including 9,162,509 participants (84,101 dementia patients), met the eligibility criteria. Patients with statin had a lower all-caused dementia risk than those without statin (risk ratio [RR] 0.83, 95% CI 0.79–0.87, I2 = 57.73%). The overall pooled reduction of Alzheimer disease in patients with statin use was RR 0.69 (95% CI 0.60–0.80, p < 0.0001), and the overall pooled RR of statin use and vascular dementia risk was RR 0.93 (95% CI 0.74–1.16, p = 0.54). Conclusion: This study suggests that the use of statin is significantly associated with a decreased risk of dementia. Future studies measuring such outcomes would provide useful information to patients, clinicians, and policymakers. Until further evidence is established, clinicians need to make sure that statin use should remain restricted to the treatment of cardiovascular disease.

Journal Section:
Editor's choice
Keywords:
Statin, Dementia, Alzheimer, Vascular dementia, Cardiac disease, Meta-analysis
1.
Williams JW, Plassman BL, Burke J, Benjamin S. Preventing Alzheimer’s disease and cognitive decline. Evid Rep Technol Assess (Full Rep). 2010 Apr;193(193):1–727.
2.
Prince MJ, Wu F, Guo Y, Gutierrez Robledo LM, O’Donnell M, Sullivan R, et al. The burden of disease in older people and implications for health policy and practice. Lancet. 2015 Feb;385(9967):549–62.
3.
Baumgart M, Snyder HM, Carrillo MC, Fazio S, Kim H, Johns H. Summary of the evidence on modifiable risk factors for cognitive decline and dementia: A population-based perspective. Alzheimers Dement. 2015 Jun;11(6):718–26.
4.
Wang Y-C, Tai P-A, Poly TN, Islam MM, Yang H-C, Wu C-C, Li Y-CJ. Increased risk of dementia in patients with antidepressants: A meta-analysis of observational studies. Behav Neurol. 2018 Jul;2018:5315098.
5.
Pahan K. Lipid-lowering drugs. Cell Mol Life Sci. 2006 May;63(10):1165–78.
6.
Kurinami H, Sato N, Shinohara M, Takeuchi D, Takeda S, Shimamura M, et al. Prevention of amyloid β-induced memory impairment by fluvastatin, associated with the decrease in amyloid β accumulation and oxidative stress in amyloid β injection mouse model. Int J Mol Med. 2008 May;21(5):531–7.
7.
Tong XK, Nicolakakis N, Fernandes P, Ongali B, Brouillette J, Quirion R, et al. Simvastatin improves cerebrovascular function and counters soluble amyloid-beta, inflammation and oxidative stress in aged APP mice. Neurobiol Dis. 2009 Sep;35(3):406–14.
8.
Thal DR, Griffin WS, de Vos RA, Ghebremedhin E. Cerebral amyloid angiopathy and its relationship to Alzheimer’s disease. Acta Neuropathol. 2008 Jun;115(6):599–609.
9.
Iadecola C. Neurovascular regulation in the normal brain and in Alzheimer’s disease. Nat Rev Neurosci. 2004 May;5(5):347–60.
10.
Zhou B, Teramukai S, Fukushima M. Prevention and treatment of dementia or Alzheimer’s disease by statins: a meta-analysis. Dement Geriatr Cogn Disord. 2007;23(3):194–201.
11.
Song Y, Nie H, Xu Y, Zhang L, Wu Y. Association of statin use with risk of dementia: a meta-analysis of prospective cohort studies. Geriatr Gerontol Int. 2013 Oct;13(4):817–24.
12.
Wong WB, Lin VW, Boudreau D, Devine EB. Statins in the prevention of dementia and Alzheimer’s disease: a meta-analysis of observational studies and an assessment of confounding. Pharmacoepidemiol Drug Saf. 2013 Apr;22(4):345–58.
13.
Rojas-Fernandez C, Hudani Z, Bittner V. Statins and cognitive side effects: what cardiologists need to know. Cardiol Clin. 2015 May;33(2):245–56.
14.
Chu CS, Tseng PT, Stubbs B, Chen TY, Tang CH, Li DJ, et al. Use of statins and the risk of dementia and mild cognitive impairment: A systematic review and meta-analysis. Sci Rep. 2018 Apr;8(1):5804.
15.
Frieden TR. Evidence for health decision making – beyond randomized, controlled trials. N Engl J Med. 2017 Aug;377(5):465–75.
16.
Islam MM, Yang HC, Nguyen PA, Poly TN, Huang CW, Kekade S, et al. Exploring association between statin use and breast cancer risk: an updated meta-analysis. Arch Gynecol Obstet. 2017 Dec;296(6):1043–53.
17.
Islam MM, Iqbal U, Walther B, Atique S, Dubey NK, Nguyen PA, et al. Benzodiazepine use and risk of dementia in the elderly population: a systematic review and meta-analysis. Neuroepidemiology. 2016;47(3-4):181–91.
18.
Poly TN, Islam MM, Walther BA, Yang HC, Nguyen PA, Huang CW, et al. Exploring the association between statin use and the risk of Parkinson’s disease: a meta-analysis of observational studies. Neuroepidemiology. 2017;49(3-4):142–51.
19.
Poly TN, Islam MM, Yang HC, Wu CC, Li YJ. Proton pump inhibitors and risk of hip fracture: a meta-analysis of observational studies. Osteoporos Int. 2019 Jan;30(1):103–14.
20.
DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials. 1986 Sep;7(3):177–88.
21.
Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ. 2003 Sep;327(7414):557–60.
22.
Higgins JP, Thompson SG, Spiegelhalter DJ. A re-evaluation of random-effects meta-analysis. J R Stat Soc Ser A Stat Soc. 2009 Jan;172(1):137–59.
23.
Chao TF, Liu CJ, Chen SJ, Wang KL, Lin YJ, Chang SL, et al. Statins and the risk of dementia in patients with atrial fibrillation: A nationwide population-based cohort study. Int J Cardiol. 2015 Oct;196:91–7.
24.
Chitnis AS, Aparasu RR, Chen H, Kunik ME, Schulz PE, Johnson ML. Use of statins and risk of dementia in heart failure: a retrospective cohort study. Drugs Aging. 2015 Sep;32(9):743–54.
25.
Chuang CS, Lin CL, Lin MC, Sung FC, Kao CH. Decreased prevalence of dementia associated with statins: a national population-based study. Eur J Neurol. 2015 Jun;22(6):912–8.
26.
Hendrie HC, Hake A, Lane K, Purnell C, Unverzagt F, Smith-Gamble V, et al. Statin use, incident dementia and Alzheimer disease in elderly African Americans. Ethn Dis. 2015 Aug;25(3):345–54.
27.
Lin FC, Chuang YS, Hsieh HM, Lee TC, Chiu KF, Liu CK, et al. Early statin use and the progression of Alzheimer disease: a total population-based case-control study. Medicine (Baltimore). 2015 Nov;94(47):e2143.
28.
Chen PY, Liu SK, Chen CL, Wu CS. Long-term statin use and dementia risk in Taiwan. J Geriatr Psychiatry Neurol. 2014 Sep;27(3):165–71.
29.
Chen JM, Chang CW, Chang TH, Hsu CC, Horng JT, Sheu WH. Effects of statins on incident dementia in patients with type 2 DM: a population-based retrospective cohort study in Taiwan. PLoS One. 2014 Feb;9(2):e88434.
30.
Chou CY, Chou YC, Chou YJ, Yang YF, Huang N. Statin use and incident dementia: a nationwide cohort study of Taiwan. Int J Cardiol. 2014 May;173(2):305–10.
31.
Haag MD, Hofman A, Koudstaal PJ, Stricker BH, Breteler MM. Statins are associated with a reduced risk of Alzheimer disease regardless of lipophilicity. The Rotterdam Study. J Neurol Neurosurg Psychiatry. 2009 Jan;80(1):13–7.
32.
Smeeth L, Douglas I, Hall AJ, Hubbard R, Evans S. Effect of statins on a wide range of health outcomes: a cohort study validated by comparison with randomized trials. Br J Clin Pharmacol. 2009 Jan;67(1):99–109.
33.
Cramer C, Haan MN, Galea S, Langa KM, Kalbfleisch JD. Use of statins and incidence of dementia and cognitive impairment without dementia in a cohort study. Neurology. 2008 Jul;71(5):344–50.
34.
Li G, Larson EB, Sonnen JA, Shofer JB, Petrie EC, Schantz A, et al. Statin therapy is associated with reduced neuropathologic changes of Alzheimer disease. Neurology. 2007 Aug;69(9):878–85.
35.
Rea TD, Breitner JC, Psaty BM, Fitzpatrick AL, Lopez OL, Newman AB, et al. Statin use and the risk of incident dementia: the Cardiovascular Health Study. Arch Neurol. 2005 Jul;62(7):1047–51.
36.
Li G, Higdon R, Kukull WA, Peskind E, Van Valen Moore K, Tsuang D, et al. Statin therapy and risk of dementia in the elderly: a community-based prospective cohort study. Neurology. 2004 Nov;63(9):1624–8.
37.
Ancelin ML, Carrière I, Barberger-Gateau P, Auriacombe S, Rouaud O, Fourlanos S, et al. Lipid lowering agents, cognitive decline, and dementia: the three-city study. J Alzheimers Dis. 2012;30(3):629–37.
38.
Arvanitakis Z, Schneider JA, Wilson RS, Bienias JL, Kelly JF, Evans DA, et al. Statins, incident Alzheimer disease, change in cognitive function, and neuropathology. Neurology. 2008 May;70(19 Pt 2):1795–802.
39.
Bettermann K, Arnold AM, Williamson J, Rapp S, Sink K, Toole JF, et al. Statins, risk of dementia, and cognitive function: secondary analysis of the ginkgo evaluation of memory study. J Stroke Cerebrovasc Dis. 2012 Aug;21(6):436–44.
40.
Beydoun MA, Beason-Held LL, Kitner-Triolo MH, Beydoun HA, Ferrucci L, Resnick SM, et al. Statins and serum cholesterol’s associations with incident dementia and mild cognitive impairment. J Epidemiol Community Health. 2011 Nov;65(11):949–57.
41.
Li G, Shofer JB, Rhew IC, Kukull WA, Peskind ER, McCormick W, et al. Age-varying association between statin use and incident Alzheimer’s disease. J Am Geriatr Soc. 2010 Jul;58(7):1311–7.
42.
Sparks DL, Sabbagh M, Connor D, Soares H, Lopez J, Stankovic G, et al. Statin therapy in Alzheimer’s disease. Acta Neurol Scand Suppl. 2006;185:78–86.
43.
Zamrini E, McGwin G, Roseman JM. Association between statin use and Alzheimer’s disease. Neuroepidemiology. 2004 Jan-Apr;23(1-2):94–8.
44.
Jick H, Zornberg GL, Jick SS, Seshadri S, Drachman DA. Statins and the risk of dementia. Lancet. 2000 Nov;356(9242):1627–31.
45.
Szwast SJ, Hendrie HC, Lane KA, Gao S, Taylor SE, Unverzagt F, et al. Association of statin use with cognitive decline in elderly African Americans. Neurology. 2007 Nov;69(19):1873–80.
46.
Zandi PP, Sparks DL, Khachaturian AS, Tschanz J, Norton M, Steinberg M, et al.; Cache County Study investigators. Do statins reduce risk of incident dementia and Alzheimer disease? The Cache County Study. Arch Gen Psychiatry. 2005 Feb;62(2):217–24.
47.
Green RC, McNagny SE, Jayakumar P, Cupples LA, Benke K, Farrer LA; MIRAGE Study Group. Statin use and the risk of Alzheimer’s disease: the MIRAGE study. Alzheimers Dement. 2006 Apr;2(2):96–103.
48.
Reitz C, Tang MX, Luchsinger J, Mayeux R. Relation of plasma lipids to Alzheimer disease and vascular dementia. Arch Neurol. 2004 May;61(5):705–14.
49.
Parikh NM, Morgan RO, Kunik ME, Chen H, Aparasu RR, Yadav RK, et al. Risk factors for dementia in patients over 65 with diabetes. Int J Geriatr Psychiatry. 2011 Jul;26(7):749–57.
50.
Hippisley-Cox J, Coupland C. Unintended effects of statins in men and women in England and Wales: population based cohort study using the QResearch database. BMJ. 2010 May;340:c2197.
51.
Wolozin B, Wang SW, Li NC, Lee A, Lee TA, Kazis LE. Simvastatin is associated with a reduced incidence of dementia and Parkinson’s disease. BMC Med. 2007 Jul;5(1):20.
52.
Rockwood K, Kirkland S, Hogan DB, MacKnight C, Merry H, Verreault R, et al. Use of lipid-lowering agents, indication bias, and the risk of dementia in community-dwelling elderly people. Arch Neurol. 2002 Feb;59(2):223–7.
53.
Zhang X, Wen J, Zhang Z. Statins use and risk of dementia: A dose-response meta analysis. Medicine (Baltimore). 2018 Jul;97(30):e11304.
54.
Zhu XC, Dai WZ, Ma T. Overview the effect of statin therapy on dementia risk, cognitive changes and its pathologic change: a systematic review and meta-analysis. Ann Transl Med. 2018 Nov;6(22):435.
55.
Zhou Q, Liao JK. Pleiotropic effects of statins. - Basic research and clinical perspectives -. Circ J. 2010 May;74(5):818–26.
56.
Giannopoulos S, Katsanos AH, Tsivgoulis G, Marshall RS. Statins and cerebral hemodynamics. J Cereb Blood Flow Metab. 2012 Nov;32(11):1973–6.
57.
Yarchoan M, Xie SX, Kling MA, Toledo JB, Wolk DA, Lee EB, et al. Cerebrovascular atherosclerosis correlates with Alzheimer pathology in neurodegenerative dementias. Brain. 2012 Dec;135(Pt 12):3749–56.
58.
Birkenhager W, Cheung B, Kumana C, Jick H, Blauw G, Kast R, et al. Dementia and statins. LANCET-LONDON; 2001. pp. 880–1.
59.
Vaughan CJ. Prevention of stroke and dementia with statins: effects beyond lipid lowering. Am J Cardiol. 2003 Feb;91(4 4A):23B–9B.
60.
Shah NP, Swiger KJ, Martin SS. Impact on cognitive function-are all statins the same? Curr Atheroscler Rep. 2015 Jan;17(1):466.
61.
Power MC, Rawlings A, Sharrett AR, Bandeen-Roche K, Coresh J, Ballantyne CM, et al. Association of midlife lipids with 20-year cognitive change: A cohort study. Alzheimers Dement. 2018 Feb;14(2):167–77.
62.
Hamelin BA, Turgeon J. Hydrophilicity/lipophilicity: relevance for the pharmacology and clinical effects of HMG-CoA reductase inhibitors. Trends Pharmacol Sci. 1998 Jan;19(1):26–37.
63.
Langham S, Langham J, Goertz HP, Ratcliffe M. Large-scale, prospective, observational studies in patients with psoriasis and psoriatic arthritis: A systematic and critical review. BMC Med Res Methodol. 2011 Mar;11(1):32.
64.
Gopalakrishnan S, Ganeshkumar P. Systematic reviews and meta-analysis: understanding the best evidence in primary healthcare. J Family Med Prim Care. 2013 Jan;2(1):9–14.
65.
Angus DC. Fusing randomized trials with big data: the key to self-learning health care systems? JAMA. 2015 Aug;314(8):767–8.
66.
Grimes DA, Schulz KF. False alarms and pseudo-epidemics: the limitations of observational epidemiology. Obstet Gynecol. 2012 Oct;120(4):920–7.
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