Statins and Cognitive Decline in Older Adults With Normal Cognition or Mild Cognitive Impairment

Kyle Steenland PhD; Liping Zhao MS; Felicia C. Goldstein PhD; Allan I. Levey MD, PhD

Disclosures

J Am Geriatr Soc. 2013;61(9):1449-1455. 

In This Article

Abstract and Introduction

Abstract

Objectives To determine the effect of statins on cognitive decline in healthy elderly adults.

Design Longitudinal.

Setting National Institute of Aging network of Alzheimer's Disease Centers.

Participants Research volunteers with normal cognition at baseline evaluated an average 4.1 times over 3.4 years (1,244 statin users, 2,363 nonusers) and with mild cognitive impairment (MCI) at baseline evaluated an average 3.9 times over 2.8 years (763 users, 917 nonusers).

Measurements Cognitive performance was assessed according to 10 neuropsychological indices and the Clinical Dementia Rating Sum of Boxes (CDR-SOB). Repeated-measures analyses adjusted for age, sex, education, comorbidities, and family history of dementia were conducted.

Results Of participants with normal cognition at baseline, statin users performed significantly better across all visits in attention (Trails A) and had significantly slower annual worsening in CDR-SOB scores (P = .006) and slower worsening in Mini-Mental State Examination scores than nonusers (which was not significant after adjusting for multiple comparisons, P = .05). For participants with MCI, statin users performed significantly better across all visits on attention measures (Trail-Making Test Part A), verbal skills (Category Fluency), and executive functioning (Trail-Making Test Part B, Digit Symbol, and Digits Backward), but there were no differences in cognitive decline between users and nonusers.

Conclusion Elderly adults with normal cognition at baseline who used statins had a slower rate of annual worsening in CDR-SOB than nonusers.

Introduction

There is controversy regarding the effects of statins on cognition and cognitive decline in aging. Epidemiological findings have been mixed regarding statin use and cognition.[1–3] Prospective observational studies have mostly found a significantly lower risk of dementia or incident Alzheimer's disease (AD) in statin users;[4–13] some studies have found no association between statins and dementia risk.[14,15] Two previous studies analyzed data according to age and found a strong beneficial effect for subjects younger than 80 at baseline, but not in those aged 80 and older.[8,9]

Two other studies found less cognitive decline in individuals with AD taking statins.[16,17] The potential for a neuroprotective effect of statins has led to two recent multicenter clinical trials for treatment of AD, both of which showed no benefit over time,[18,19] although it may be unlikely that disease-modifying therapies will be successful if initiated at the mild to moderate stages of the disease because there is already extensive AD pathology and irreversible degeneration at those stages.

In support of a possible early benefit of statins, four studies have shown that, in older adults without dementia, statin users have better cognition.[4,13,20,21] One was a secondary analysis of a clinical trial of the effect of ginkgo biloba in 3,069 elderly adults (≥75) in which dementia and cognition were the primary endpoints.[4] A significantly slower rate of decline was found on the Modified Mini-Mental State Examination (3MSE) and the Alzheimer's Disease Assessment Scale—Cognitive Subscale (ADAS-Cog) for current statin users than for nonusers who had normal cognition at baseline, although no effect on rate of decline was found in those who had mild cognitive impairment (MCI) at baseline.

Against this background of many studies showing that statin users have better cognition, other longitudinal studies of cognition (randomized trials and observational studies) in individuals without dementia have yielded negative results.[14,22–25] Cognition was assessed as a secondary endpoint in a population with cardiovascular disease or strong risk factors for cardiovascular disease in two clinical trials of statins (pravastatin and simvastatin) (see also [25]). One had an evaluation of cognition only at follow-up and not at baseline,[23] and approximately one-third of the subjects were nonadherent to statin use or nonuse, which was not taken into account in the intention-to-treat analysis. One of the observational studies studied cognitive decline in 6,830 community residents followed for 7 years, 16% of whom were taking statins.[14] No significant protective effects were found on visual memory (Benton Visual Retention Test), attention (Trail-Making Test Part (Trails A)), or set shifting speed (Trails B). A limitation of this study is that trends in cognition over time were not evaluated using continuous scores but instead were dichotomized into decliners and nondecliners. Another study followed 548 community residents aged 65 and older in Spain for a median of 2 years.[25] No differences in cognition were observed between statin users and nonusers at baseline, as measured using a comprehensive battery of cognitive tests at the end of 2 years of follow-up. This study was limited by small numbers of subjects and short follow-up.

In 2012, the Food and Drug Administration required warnings on statin prescriptions indicating that rare instances of memory loss have occurred in association with statin use.[26] These warnings, along with informal communications on the Web, have alarmed some individuals and families regarding the adverse risks of statin use in those concerned with memory loss and cognitive decline. Given the mixed results of studies and public messaging, additional studies of statins and cognition are warranted.

The current investigation further explored the effects of statin use on cognitive functioning and change over time in a sample of more than 5,000 research participants in National Institutes of Health (NIH), National Institute on Aging (NIA)-supported Alzheimer's Disease Centers (ADCs). Whether statins affect cognitive decline in subjects with normal cognition at baseline and subjects with MCI at baseline was investigated separately. These participants had repeated evaluations of cognitive performance and information about statin use at each annual follow-up as part of the Uniform Data Set (UDS), a standardized assessment and data protocol that the National Alzheimer's Coordinating Center maintains. Repeated observations enabled a population taking statins to be characterized consistently throughout follow-up, an advantage over a number of prior studies that queried statin use only at baseline. A standardized battery of neuropsychological measures that examined a wide range of cognitive areas, as opposed to using an index of overall cognitive status such as the 3MSE, was also available. This rich dataset allowed whether certain areas such as executive functioning are more vulnerable to the effects of statins to be determined. The minimum requirement of at least three annual visits, resulting in an average follow-up of 3 years, provided a strong test of whether statins are associated with longitudinal cognitive changes.

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