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Effect of Statin Therapy on Cognitive Decline and Incident Dementia in Older Adults

Original Investigation

J Am Coll Cardiol, 77 (25) 3145–3156
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Abstract

Background

The neurocognitive effect of statins in older adults remain uncertain.

Objectives

The aim of this study was to investigate the associations of statin use with cognitive decline and incident dementia among older adults.

Methods

This analysis included 18,846 participants ≥65 years of age in a randomized trial of aspirin, who had no prior cardiovascular events, major physical disability, or dementia initially and were followed for 4.7 years. Outcome measures included incident dementia and its subclassifications (probable Alzheimer’s disease, mixed presentations); mild cognitive impairment (MCI) and its subclassifications (MCI consistent with Alzheimer’s disease, other MCI); and changes in domain-specific cognition, including global cognition, memory, language and executive function, psychomotor speed, and the composite of these domains. Associations of baseline statin use versus nonuse with dementia and MCI outcomes were examined using Cox proportional hazards models and with cognitive change using linear mixed-effects models, adjusting for potential confounders. The impact of statin lipophilicity on these associations was further examined, and effect modifiers were identified.

Results

Statin use versus nonuse was not associated with dementia, MCI, or their subclassifications or with changes in cognitive function scores over time (p > 0.05 for all). No differences were found in any outcomes between hydrophilic and lipophilic statin users. Baseline neurocognitive ability was an effect modifier for the associations of statins with dementia (p for interaction < 0.001) and memory change (p for interaction = 0.02).

Conclusions

In adults ≥65 years of age, statin therapy was not associated with incident dementia, MCI, or declines in individual cognition domains. These findings await confirmation from ongoing randomized trials.

  • 1. Ridker P.M., Lonn E., Paynter N.P., Glynn R., Yusuf S. "Primary prevention with statin therapy in the elderly: new meta-analyses from the contemporary JUPITER and HOPE-3 randomized trials". Circulation 2017;135:1979-1981.

    MedlineGoogle Scholar
  • 2. Bosch J., O’Donnell M., Swaminathan B., et al. "Effects of blood pressure and lipid lowering on cognition: results from the HOPE-3 study". Neurology 2019;92:e1435-e1446.

    CrossrefMedlineGoogle Scholar
  • 3. U.S. Food and Drug Administration. "FDA consumer health information: FDA expands advice on statin risks". Available at: https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-important-safety-label-changes-cholesterol-lowering-statin-drugs. Accessed April 6, 2021.

    Google Scholar
  • 4. Bellou V., Belbasis L., Tzoulaki I., Middleton L.T., Ioannidis J.P.A., Evangelou E. "Systematic evaluation of the associations between environmental risk factors and dementia: an umbrella review of systematic reviews and meta-analyses". Alzheimers Dement 2017;13:406-418.

    CrossrefMedlineGoogle Scholar
  • 5. Fink H.A., Jutkowitz E., McCarten J.R., et al. "Pharmacologic interventions to prevent cognitive decline, mild cognitive impairment, and clinical Alzheimer-type dementia: a systematic review". Ann Intern Med 2018;168:39-51.

    CrossrefMedlineGoogle Scholar
  • 6. Wong W.B., Lin V.W., Boudreau D., Devine E.B. "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;22:345-358.

    CrossrefMedlineGoogle Scholar
  • 7. Haag M.D., Hofman A., Koudstaal P.J., Stricker B.H., Breteler M.M. "Statins are associated with a reduced risk of Alzheimer disease regardless of lipophilicity. The Rotterdam Study". J Neurol Neurosurg Psychiatry 2009;80:13-17.

    CrossrefMedlineGoogle Scholar
  • 8. Arvanitakis Z., Schneider J.A., Wilson R.S., et al. "Statins, incident Alzheimer disease, change in cognitive function, and neuropathology". Neurology 2008;70:1795-1802.

    CrossrefMedlineGoogle Scholar
  • 9. McGuinness B., Craig D., Bullock R., Passmore P. "Statins for the prevention of dementia". Cochrane Database Syst Rev 2016;1:CD003160.

    Google Scholar
  • 10. Ott B.R., Daiello L.A., Dahabreh I.J., et al. "Do statins impair cognition? A systematic review and meta-analysis of randomized controlled trials". J Gen Intern Med 2015;30:348-358.

    CrossrefMedlineGoogle Scholar
  • 11. Schultz B.G., Patten D.K., Berlau D.J. "The role of statins in both cognitive impairment and protection against dementia: a tale of two mechanisms". Transl Neurodegener 2018;7:5.

    CrossrefMedlineGoogle Scholar
  • 12. Sinyavskaya L., Gauthier S., Renoux C., Dell’Aniello S., Suissa S., Brassard P. "Comparative effect of statins on the risk of incident Alzheimer disease". Neurology 2018;90:e179-e187.

    CrossrefMedlineGoogle Scholar
  • 13. Kelley B.J., Glasser S. "Cognitive effects of statin medications". CNS Drugs 2014;28:411-419.

    CrossrefMedlineGoogle Scholar
  • 14. Alsehli A.M., Olivo G., Clemensson L.E., Williams M.J., Schioth H.B. "The cognitive effects of statins are modified by age". Sci Rep 2020;10:6187.

    CrossrefMedlineGoogle Scholar
  • 15. Zissimopoulos J.M., Barthold D., Brinton R.D., Joyce G. "Sex and race differences in the association between statin use and the incidence of Alzheimer disease". JAMA Neurol 2017;74:225-232.

    CrossrefMedlineGoogle Scholar
  • 16. Zamrini E., McGwin G., Roseman J.M. "Association between statin use and Alzheimer’s disease". Neuroepidemiology 2004;23:94-98.

    CrossrefMedlineGoogle Scholar
  • 17. Samaras K., Makkar S.R., Crawford J.D., et al. "Effects of statins on memory, cognition, and brain volume in the elderly". J Am Coll Cardiol 2019;74:2554-2568.

    View ArticleGoogle Scholar
  • 18. Odden M.C., Pletcher M.J., Coxson P.G., et al. "Cost-effectiveness and population impact of statins for primary prevention in adults aged 75 years or older in the United States". Ann Intern Med 2015;162:533-541.

    CrossrefMedlineGoogle Scholar
  • 19. Nanna M.G., Navar A.M., Wang T.Y., et al. "Statin use and adverse effects among adults >75 years of age: insights from the Patient and Provider Assessment of Lipid Management (PALM) registry". J Am Heart Assoc 2018;7:e008546.

    CrossrefMedlineGoogle Scholar
  • 20. McNeil J.J., Nelson M.R., Woods R.L., et al. "Effect of aspirin on all-cause mortality in the healthy elderly". N Engl J Med 2018;379:1519-1528.

    CrossrefMedlineGoogle Scholar
  • 21. McNeil J.J., Wolfe R., Woods R.L., et al. "Effect of aspirin on cardiovascular events and bleeding in the healthy elderly". N Engl J Med 2018;379:1509-1518.

    CrossrefMedlineGoogle Scholar
  • 22. McNeil J.J., Woods R.L., Nelson M.R., et al. "Effect of aspirin on disability-free survival in the healthy elderly". N Engl J Med 2018;379:1499-1508.

    CrossrefMedlineGoogle Scholar
  • 23. Ryan J., Woods R.L., Britt C., et al. "Normative performance of healthy older individuals on the Modified Mini-Mental State (3MS) examination according to ethno-racial group, gender, age, and education level". Clin Neuropsychol 2019;33:779-797.

    CrossrefMedlineGoogle Scholar
  • 24. Schachter M. "Chemical, pharmacokinetic and pharmacodynamic properties of statins: an update". Fundam Clin Pharmacol 2005;19:117-125.

    CrossrefMedlineGoogle Scholar
  • 25. Gmitrowicz A., Kucharska A. "[Developmental disorders in the fourth edition of the American classification: Diagnostic and Statistical Manual of Mental Disorders (DSM IV—optional book)]". Psychiatr Pol 1994;28:509-521.

    MedlineGoogle Scholar
  • 26. Ryan J., Storey E., Murray A.M., et al. "Randomized placebo-controlled trial of the effects of aspirin on dementia and cognitive decline". Neurology 2020;95:e320-e331.

    CrossrefMedlineGoogle Scholar
  • 27. Jack C.R., Albert M.S., Knopman D.S., et al. "Introduction to the recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease". Alzheimers Dement 2011;7:257-262.

    CrossrefMedlineGoogle Scholar
  • 28. Albert M.S., DeKosky S.T., Dickson D., et al. "The diagnosis of mild cognitive impairment due to Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease". Alzheimers Dement 2011;7:270-279.

    CrossrefMedlineGoogle Scholar
  • 29. Schoenfeld D. "Partial residuals for the proportional hazards regression model". Biometrika 1982;69:239-241.

    CrossrefGoogle Scholar
  • 30. Abeare C.A., Hurtubise J.L., Cutler L., et al. "Introducing a forced choice recognition trial to the Hopkins Verbal Learning Test–Revised". Clin Neuropsychol. In press.

    Google Scholar
  • 31. Radloff L.S. "The CES-D scale: a self-report depression scale for research in the general population". Appl Psych Measurement 1977;1:385-401.

    CrossrefGoogle Scholar
  • 32. "ASPREE Protocol Version 9". Available at: https://aspree.org/usa/wp-content/uploads/sites/3/2014/04/ASPREE-Protocol-Version-9_-Nov2014_FINAL.pdf. Accessed April 6, 2021.

    Google Scholar
  • 33. Masse I., Bordet R., Deplanque D., et al. "Lipid lowering agents are associated with a slower cognitive decline in Alzheimer’s disease". J Neurol Neurosurg Psychiatry 2005;76:1624-1629.

    CrossrefMedlineGoogle Scholar
  • 34. Giugliano R.P., Mach F., Zavitz K., et al. "Cognitive function in a randomized trial of evolocumab". N Engl J Med 2017;377:633-643.

    CrossrefMedlineGoogle Scholar
  • 35. Poly T.N., Islam M.M., Walther B.A., et al. "Association between use of statin and risk of dementia: a meta-analysis of observational studies". Neuroepidemiology 2020;54:214-226.

    CrossrefMedlineGoogle Scholar
  • 36. 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;13:817-824.

    CrossrefMedlineGoogle Scholar
  • 37. Bernick C., Katz R., Smith N.L., et al. "Statins and cognitive function in the elderly: the Cardiovascular Health Study". Neurology 2005;65:1388-1394.

    CrossrefMedlineGoogle Scholar
  • 38. Evans D.A., Bennett D.A., Wilson R.S., et al. "Incidence of Alzheimer disease in a biracial urban community: relation to apolipoprotein E allele status". Arch Neurol 2003;60:185-189.

    CrossrefMedlineGoogle Scholar
  • 39. Adhikari A., Tripathy S., Chuzi S., Peterson J., Stone N.J. "Association between statin use and cognitive function: a systematic review of randomized clinical trials and observational studies". J Clin Lipidol 2021;15:22-32.e12.

    CrossrefMedlineGoogle Scholar
  • 40. Rea T.D., Breitner J.C., Psaty B.M., et al. "Statin use and the risk of incident dementia: the Cardiovascular Health Study". Arch Neurol 2005;62:1047-1051.

    CrossrefMedlineGoogle Scholar
  • 41. Zandi P.P., Sparks D.L., Khachaturian A.S., et al. "Do statins reduce risk of incident dementia and Alzheimer disease? The Cache County Study". Arch Gen Psychiatry 2005;62:217-224.

    CrossrefMedlineGoogle Scholar
  • 42. Winblad B., Jelic V., Kershaw P., Amatniek J. "Effects of statins on cognitive function in patients with Alzheimer’s disease in galantamine clinical trials". Drugs Aging 2007;24:57-61.

    CrossrefMedlineGoogle Scholar
  • 43. Bettermann K., Arnold A.M., Williamson J., et al. "Statins, risk of dementia, and cognitive function: secondary analysis of the ginkgo evaluation of memory study". J Stroke Cerebrovasc Dis 2012;21:436-444.

    CrossrefMedlineGoogle Scholar
  • 44. Lazris A., Roth A.R. "Overuse of statins in older adults". Am Fam Physician 2019;100:742-743.

    MedlineGoogle Scholar
  • 45. Ray K.K., Seshasai S.R., Erqou S., et al. "Statins and all-cause mortality in high-risk primary prevention: a meta-analysis of 11 randomized controlled trials involving 65,229 participants". Arch Intern Med 2010;170:1024-1031.

    CrossrefMedlineGoogle Scholar