HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

Correspondence to:

ARTICLES: C. Cramer, M. N. Haan, S. Galea, K. M. Langa, and J. D. Kalbfleisch Use of statins and incidence of dementia and cognitive impairment without dementia in a cohort study Neurology 2008; 71: 344-350 [Abstract] [Full text] [PDF]

Correspondence: Submit a response to this article

Correspondence published:

Use of statins and incidence of dementia and cognitive impairment without dementia in a cohort study

Eddie Vos, Herbert H. Nehrlich   (14 December 2008)

Reply from the authors

Mary N. Haan, C. Cramer, S. Galea, K.M. Langa, J. D. Kalbfleisch   (14 December 2008)

Use of statins and incidence of dementia and cognitive impairment without dementia in a cohort study

Mark R. Goldstein, MD, Luca Mascitelli, MD, Medical Service, Comando Brigata alpina "Julia", Udine, Italy; Francesca Pezzetta, MD, Cardiology Service, Ospedale di Tolmezzo, Tolmezzo, Italy   (11 September 2008)

Reply from the authors

Mary N Haan, Caryn Cramer, Jack Kalbfleisch, Ken Langa, Sandro Galea   (11 September 2008)

Use of statins and incidence of dementia and cognitive impairment without dementia in a cohort study 14 December 2008
Eddie Vos, www.health-heart.org 127 Courser Rd, Sutton, Quebec, Canada J0E 2K0, Herbert H. Nehrlich Send Correspondence to journal: Re: Use of statins and incidence of dementia and cognitive impairment without dementia in a cohort study vos{at}health-heart.org Eddie Vos, et al.	Cramer et al. reported less dementia and cognitive decline among statin users in the SALSA study participants. [1] This study implied that less cognitive decline may be a statin benefit yet the authors did not attribute the finding to the selection and prescribing bias. The only on-label prescribing rationale for statin is elevated cholesterol, thereby unselecting those with lower levels of cholesterol. This was recently confirmed by a study asserting that, "Overall, the mean baseline cholesterol measurement of the statin-treated population is higher than that of the general population." [2] The Framingham Heart study found that those with high cholesterol—defined as 240-380 mg/dL [6.1-9.7 mmol/L]—had significantly better cognition scores than those with lower levels of 150-199 mg/dL (3.85-5.1 mmol/L; P <0.01 for group test scores). [3] Statin prescriptions naturally select a higher cholesterol population where cognitive status tends to be better. Cramer et al. should have conducted a simple cholesterol test as was done in the Framingham study. In the abstract, Cramer et al.’s conclusion suggests a protective effect of statin use on cognitive outcomes. However, this is not supported by other data and cannot be concluded from this patient selection study where baseline cholesterol pre-statin use is the one factor for which there was not adjustment. The authors, later in the article, mention that no randomized study to date has reported a cognitive benefit from statin use. This contradicts the assertion made in the abstract. Cholesterol is vital to memory and the aging brain [4] and the message the authors convey may promote non evidence-based drug use. At an age where cognitive decline, low cholesterol, and heart failure become major health issues, a recent observational study found 2.6 times the in-hospital mortality from heart failure in those with lowest cholesterol, an effect that became highly significant among statin users. [5] References 1. Cramer C, Haan MN, Galea S, Langa KM, Kalbfleisch JD. Use of statins and incidence of cognitive impairment without dementia in a cohort study. Neurology 2008;71:344-350. 2. Thompson R, O’Regan C, Morant A, Phillips B, Ong S. Measurement of baseline total cholesterol: new data from The Health Improvement Network (THIN) database. Prim Care Cardiovasc J 2008;1:107-111. 3. Elias PK, Elias MF, D'Agostino RB, Sullivan LM, Wolf PA. Serum cholesterol and cognitive performance in the Framingham Heart Study. Psychosom Med 2005;67:24-30. 4. West R, Beeri MS, Schmeidler J, et al. Better memory functioning associated with higher total and low-density lipoprotein cholesterol levels in very elderly subjects without the apolipoprotein e4 allele. Am J Geriatr Psychiatry 2008;16:781-785. 5. Horwich TB, Hernandez AF, Dai D, Yancy CW, Fonarow GC. Cholesterol levels and in-hospital mortality in patients with acute decompensated heart failure. Am Heart J 2008:0:1-7 (in press). Disclosure: The authors report no disclosures.
Reply from the authors 14 December 2008
Mary N. Haan, University of Michigan 109 S. Observatory St, Ann Arbor, MI 48109, C. Cramer, S. Galea, K.M. Langa, J. D. Kalbfleisch Send Correspondence to journal: Re: Reply from the authors mnhaan{at}umich.edu Mary N. Haan, et al.	We thank Dr. Vos for his comments. We accounted for indication bias by including only cases that occurred after baseline, only statin use that occurred at a visit prior to the diagnosis, and by adjusting for access to health care. We went beyond a simple cholesterol test and obtained lipids six times during study follow-up. LDL-C was lower in statin users at study baseline and declined over time more rapidly than among non-users. In additional analyses, adjustment for LDL-C as a time dependent co-variate does not influence the association between dementia/CIND and statin use over time. [6] Dr. Vos compared our study to that of elderly hospitalized patients with heart failure. [7] Our study was population based and included healthy and young people. Horwich et al. showed that sick, elderly people with low cholesterol are more likely to die. [5] The lower LDL reported by Horwich et al. was probably due to underlying pathology, declining weight and/or frailty. The association of lower LDL with higher mortality is expected in this sample and it does not follow that community dwelling elderly would be at similar risk. Elias et al. [3] averaged change over time in total cholesterol rather than modeling decline and evaluated means or odds ratios for cognition rather than incidence of dementia. [4] Neither study addressed the role of statins. In a statin-free sample, Curb found a quadratic (u-shaped) association between LDL and CHD, attributed the effects of low LDL-C to aging-related metabolic/physiologic changes, and concluded statin treatment as appropriate in healthy elderly. [8] Decline in LDL-C due to underlying disease is not the same as lowering LDL-C by statins or another intervention in relatively healthy, non-frail individuals. It is inappropriate to compare our study to randomized clinical trials of statin treatment in demented patients with established disease. These trials may have failed because statins cannot slow decline or reverse pathology. The mechanistic roles of statins in neurodegeneration are unclear; our results may be due to the effect statins have on subclinical cerebrovascular disease. For example, the SPARCL trial recently reported that aggressive treatment with atorvastatin reduced stroke risk by 16%. [9] Cerebrovascular disease is a major contributor to cognitive impairment and dementia so we adjusted for stroke. Cognitive decline and dementia in statin users appear to be less than in non-users. However, this is not a recommendation for treatment for the purpose of preventing dementia. Only a randomized trial in people with normal cognition can determine whether statin treatment will prevent cognitive decline and dementia. References 6. Haan MN. Use of statins, LDL-C and incidence of cognitive impairment or dementia in a seven year cohort study of older Mexican Americans. Presentation at the International Congress on Alzheimer's disease, August 2008. 7. Vos E. Available at: (http://www.health-heart.org/) 8. Curb JD, Abbott RD, Rodriguez BL, et al. Prospective association between low and high total and low-density lipoprotein cholesterol and coronary heart disease in elderly men. J Am Geriatr Soc 2004;52:1975-1980. 9. Fitchett DH, Goodman SG, Langer A. Ischemic stroke: a cardiovascular risk equivalent? Lessons learned from the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial. Can J Cardiol 2008;24:705-708. Disclosure: Caryn Cramer was employed by Pfizer Corporation during completion of her doctoral degree during which time this study was conducted. Pfizer did not provide any material support for this study, and did not participate in the design, conduct, management, analysis, interpretation, review, or approval of the study or the manuscript. The other authors have reported no conflicts of interest.
Use of statins and incidence of dementia and cognitive impairment without dementia in a cohort study 11 September 2008
Mark R. Goldstein, MD, Fountain Medical Court 9410 Fountain Medical Court, Suite A-200, Bonita Springs, FL, 34135, Luca Mascitelli, MD, Medical Service, Comando Brigata alpina "Julia", Udine, Italy; Francesca Pezzetta, MD, Cardiology Service, Ospedale di Tolmezzo, Tolmezzo, Italy Send Correspondence to journal: Re: Use of statins and incidence of dementia and cognitive impairment without dementia in a cohort study markrgoldstein{at}comcast.net Mark R. Goldstein, MD, et al.	We read the interesting observational study of Cramer et al. regarding statin therapy and the incidence of cognitive impairment without dementia and dementia in an elderly Mexican-American population. [1] The authors conclude that statin users are half as likely to develop cognitive impairment or dementia over the five years of observation. However, the study suggests that higher cholesterol levels actually protect subjects from cognitive impairment and dementia. Baseline total cholesterol levels of statin-treated populations are higher than those of the general population. [2] Presumably, the cholesterol levels of the statin-treated patients in this study were higher than those of the non-statin treated patients. In the Framingham Heart Study cohort, subjects with total cholesterol levels more than 200 mg/dL, compared to those with levels less than 200 mg/dL, performed significantly better in cognitive measures including word fluency, attention, and concentration. The observation period in that study pre-dated the widespread use of statins. [3] Moreover, an eight-year observational trial involving middle-aged women revealed that women with higher, low-density lipoprotein (LDL) cholesterol levels had a significantly better memory. [4] Interestingly, Cramer et al. found that baseline Modified Mini-Mental State Examination scores were significantly higher in statin users compared to statin non-users, suggesting a benefit from higher cholesterol levels. Both lipophilic and hydrophilic statins promote oligodendrocyte lineage commitment by parenchymal glial progenitor cells in vitro. [5] If statins are taken for decades, it is possible that the homeostatic self-renewal of glial progenitor cells may be impaired resulting in cognitive decline. Therefore, statins may be detrimental over the long term by both lowering cholesterol levels and diminishing the glial progenitor cell pool. Finally, we need long-term randomized prospective trials specifically designed to settle this important dispute. Regarding cholesterol and cognitive decline, perhaps more is better. References 1. Cramer C, Haan MN, Galea S, et al. Use of statins and incidence of dementia and cognitive impairment without dementia in a cohort study. Neurology 2008;71:344-350. 2. Thompson R, O’Regan C, Morant S, et al. Measurement of baseline total cholesterol: new data from The Health Improvement Network (THIN) database. Prim Care Cardiovasc J 2008;1:107-111. 3. Elias PK, Elias MF, D’Agostino RB, et al. Serum cholesterol and cognitive performance in the Framingham Heart Study. Psychosomatic Med 2005;67:24-30. 4. Henderson VW, Guthrie JR, Dennerstein L. Serum lipids and memory in a population based cohort of middle aged women. J Neurol Neurosurg Psychiatry 2003; 74: 1530-1535. 5. Sim FJ, Lang JK, Ali TA, et al. Statin treatment of adult human glial progenitors induces PPAR gamma-mediated oligodendrocytic differentiation. GLIA 2008;56:954-962. Disclosure: The authors report no disclosures.
Reply from the authors 11 September 2008
Mary N Haan, University of Michigan Epidemiology, 109 S Observatory St, rm 5174, Caryn Cramer, Jack Kalbfleisch, Ken Langa, Sandro Galea Send Correspondence to journal: Re: Reply from the authors mnhaan{at}umich.edu Mary N Haan, et al.	The Goldstein et al. letter highlights the importance of considering adverse effects from overly effective lipid lowering drugs. Some studies have found a decline in cholesterol levels in older populations associated with adverse outcomes. Interpretation of decline is not straightforward. Curb et al. [6] found a u-shaped association between coronary heart disease outcomes and concluded that LDL-lowering drugs could still be used in older populations with the caveat that statins have the potential to lower LDL-C too far. Reasons for declines of cholesterol in old age may be multivariate (e.g., weight loss, reduction in muscle mass) and may be unrelated to statin use. LDL declines may be markers of prodromal changes accompanied by cognitive decline. Baseline LDL-C levels in our population were higher in non-statin vs. statin users: 123 vs. 112 mg/dl respectively (p=0.0002). Total cholesterol was 212 vs. 204, p=0.016). LDL in statin users declined over time more rapidly than in non-statin users. We found that higher LDL-C over time is associated with higher mortality rates (Cox model =HR: 1.89 for a LDL-C SD of 34.5, p=0.02) which may indicate a direct effect of LDL-C or the residual association of LDL with heart disease. Change in LDL-C over time is not associated with dementia/CIND incidence. LDL-C does modify the effect of statin use on dementia/CIND. A one SD decrease in LDL-C (34.5 mg/dl) is associated with an approximately 54% increase in the benefit associated with statin use. (HR for statin use: 0.29, p=0.04 for interaction between LDL and statins). Our results confirm that those who are taking statins over time may experience lower rates of cognitive impairment and dementia related to the reduction in LDL-C. This result does not support a treatment recommendation. We would enthusiastically support a primary prevention trial that could examine the effects of lowering lipids on the development of incident dementia and AD. However, a primary prevention trial should be preceded by a better understanding of the mechanisms by which statins may confer this benefit and should include arms for both behavioral and various drug treatments. Reference 6. Curb JD, Abbott RD, Rodriguez BL et al. Prospective association between low and high total and low-density lipoprotein cholesterol and coronary heart disease in elderly men. J Am Geriatr Soc 2004;52:1975-1980. Disclosure: Caryn Cramer was employed by Pfizer Corporation during completion of her doctoral degree during which time this study was conducted. Pfizer did not provide any material support for this study, and did not participate in the design, conduct, management, analysis, interpretation, review, or approval of the study or the manuscript. The other authors have reported no disclosures.