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ARTICLES: Z. Arvanitakis, J. A. Schneider, R. S. Wilson, J. L. Bienias, J. F. Kelly, D. A. Evans, and D. A. Bennett Statins, incident Alzheimer disease, change in cognitive function, and neuropathology Neurology 2008; 0: 01.wnl.0000288181.00826.63v1 [Abstract]

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Statins and Alzheimer's disease. The answers have not come of age yet.

Miguel A Pappolla, MD, PhD   (18 April 2008)

Reply from the authors to Pappolla

Zoe Arvanitakis, David A. Bennett   (18 April 2008)

Statins, incident Alzheimer disease, change in cognitive function, and neuropathology

Hadi Meeran Hussain, Manzar Zakria, Abdul Rehman Arshad   (18 April 2008)

Reply from the authors to Hussain et al

Zoe Arvanitakis, David A. Bennett   (18 April 2008)

Statins and Alzheimer's disease. The answers have not come of age yet. 18 April 2008
Miguel A Pappolla, MD, PhD, J. T. Morse Professor of Neurology-Medical University of South Carolina 173 Ashley Ave. Neurosciences 403 BSB. Charleston, SC 29425 Send Correspondence to journal: Re: Statins and Alzheimer's disease. The answers have not come of age yet. memorycenter{at}aol.com Miguel A Pappolla, MD, PhD	Arvanitakis et al. evaluated the relationship between statin use and Alzheimer disease (AD) and concluded that statins were “unrelated to incident AD”. [1] However, there are some disparities between this and other studies. [2] Concerning the purported association between hypercholesterolemia and AD, most positive studies examined cholesterol levels at midlife (cohorts’ ages ranged from 40 to 59 years) and then correlated these levels to later development of dementia. [2] Most negative reports, in contrast, included participants of much more advanced ages. [2] Additionally, gradual declines in cholesterolemia are known to precede the development of dementia by years in most affected patients, potentially obscuring abnormalities that occurred earlier in life. [3, 4] In a neuropathological study, we substantiated these findings. [5]Hypercholesterolemia strongly correlated with presence of brain amyloid but only in subjects aged 40 to 55. However, the differences in cholesterol between amyloid-bearing and amyloid-free brains disappeared as the subjects’ age increased beyond 55 years. These observations suggest that hypercholesterolemia is an early (not a late) risk factor for AD. Despite this revelation, discrepancies in statin trial outcomes are often attributed to study design (cross-sectional versus longitudinal) ignoring the age-related dynamics. It is not surprising that most studies negating a role for statins in AD prevention have been conducted in populations older than 65 years, overlooking the mentioned age-related risk relationship. These include the CRISP, the PROSPER, one community-based study, and the Cache County studies. The Honolulu study found no effect for statins but the average participants’ age was 80 years, indicating that the average age at the start was at least 54 years considering the study length. The mean age of the participants in the Arvanitakis et al’s study was 74.9 years and the follow up 12 years which may have also influenced the results. The only trial that included younger individuals was the Heart Protection Study. Unfortunately, the young individuals’ risk to develop late-onset AD could not be assessed, because the study lasted only 5 years. In order to conclude that statins can prevent AD, studies must include individuals who began therapy much earlier in life, when there is evidence that cholesterolemia may impact the disease neuropathology. References 1. Arvanitakis Z, Schneider JA, Wilson RS, et al. Statins, incident Alzheimer disease, change in cognitive function, and neuropathology. Neurology. 2008 0: 01.wnl.0000288181.00826.63v1. 2. Kivipelto M, Solomon A. Cholesterol as a risk factor for Alzheimer's disease - epidemiological evidence. Acta Neurol Scand Suppl. 2006;185:50-57. 3. Kivipelto M, Helkala EL, Laakso MP et al. Apolipoprotein E epsilon4 allele, elevated midlife total cholesterol level, and high midlife systolic blood pressure are independent risk factors for late-life Alzheimer disease. Ann Intern Med. 2002;137:149-155. 4. Notkola IL, Sulkava R, Pekkanen J et al. Serum total cholesterol, apolipoprotein E epsilon 4 allele, and Alzheimer's disease. Neuroepidemiology. 1998;17:14-20. 5. Pappolla MA, Bryant-Thomas TK, Herbert D et al. Mild Hypercholesterolemia is an early risk factor for the development of Alzheimer amyloid pathology.Neurology. 2003;61:199-205. Disclosure: The authors report no disclosures.
Reply from the authors to Pappolla 18 April 2008
Zoe Arvanitakis, Rush Alzheimer's Disease Center 600 S. Paulina, Suite 1020, Chicago, IL 60612, David A. Bennett Send Correspondence to journal: Re: Reply from the authors to Pappolla zarvanit{at}rush.edu Zoe Arvanitakis, et al.	We thank Dr. Pappolla for his interest in our article [1] and for outlining the importance of evaluating statin use earlier in life. In our analyses of data from the Religious Orders Study, participants enrolled at an average age of 75 and were followed for up to 12 years. Statin use was not related to incident AD, change in cognition, or the pathology of AD, including amyloid load or tangles density. We do not have data on statin use prior to enrollment in our study. The possibility that statin use in early or mid life is related to clinical or pathologic disease cannot be excluded in our study. We agree that the association of other cardiovascular risk factors for AD, such as cholesterol levels and hypertension, appears to have risk related to age at exposure. [6] It is reasonable to believe that this might be true for statin use as well. [7] However, another study [8] that reports statin data from earlier in life (from persons with an average age of 56 years when statin data became available) did not find a protective effect. These substantial issues may not be resolved by observational, epidemiologic studies. However, observational data are essential in determining whether a large clinical trial is warranted and the proper design of such a trial. References 6. Kivipelto M, Helkala EL, Laakso MP, et al. Midlife vascular risk factors and Alzheimer's disease in later life: longitudinal, population based study. BMJ 2001;322:1447-1451. 7. Rockwood K, Kirkland S, Hogan DB, et al. Use of lipid-lowering agents, indication bias, and the risk of dementia in community-dwelling elderly people. Arch Neurol 2002;59:223-227. 8. Li G, Higdon R, Kukull WA, et al. Statin therapy and risk of dementia in the elderly: a community-based prospective cohort study. Neurology 2004;63:1624-1628. Disclosure: The authors report no disclosures.
Statins, incident Alzheimer disease, change in cognitive function, and neuropathology 18 April 2008
Hadi Meeran Hussain, Department Of Internal Medicine, Combined Military Hospital House No 59, Street No 40, Gunj Moghal pura, Lahore, Pakistan 54000, Manzar Zakria, Abdul Rehman Arshad Send Correspondence to journal: Re: Statins, incident Alzheimer disease, change in cognitive function, and neuropathology hussain.hadi{at}yahoo.com Hadi Meeran Hussain, et al.	Arvanitakis et al. examined 929 cases from the Religious Orders Study to investigate whether statins modify the pathology associated with Alzheimer disease (AD). [1] Large numbers of patients are necessary to determine the effects of medications on disease parameters. Typically, a small fraction of patients take the medication and only a fraction of those patients exhibit the specific phenotype of interest. This study began with 929 patients of whom 119 were positive for statin use. The use of lipid-lowering medication is presumably by self-report, and there is no description of duration or dosing of medication. The authors used these cases to examine incident AD and then to examine effects on pathology. Only 199 or 231 out of the 989 cases had amyloid or tangle pathology, respectively; 16.6 percent of these cases used statins, which corresponds to 33 or 38 cases for amyloid or tangle pathology. Presumably, only about one-third (10-12 cases) used a brain penetrant statin such as simvastatin. Obtaining statistical significance with such small numbers is difficult. Regardless of the considerations of number or power, we are struck by the absence of any effect associated with the statins. There was no overall effect for any measure. In addition, the authors stratified the results by type of medication: lipophilic statin, lipophobic statin or non-statin agent as well as by ApoE genotype. These stratifications could be important because other groups have observed more significant effects in ApoE4 subjects. [2,3] The absence of any effect is striking and contrasts with the Cache County cohort in which Li et al. observed that subjects taking statins showed a significant reduction in neurofibrillary plaque formation, but no change in neuritic plaque formation. [4] Moreover, Arvanitakis et al. did not examine inflammatory markers which are known to decrease in subjects taking statins. [5] The discrepancy between the work by Arvanitakis et al. and previous data are difficult to reconcile. It is possible that in studies of pharmaco-epidemiology, medication use history and large numbers are both as important as accurate diagnostic criteria for evaluating data. Without these factors, studies might be prone to conflicting results. As the data accumulate, a meta-analysis may be informative. References 1.Arvanitakis Z, Schneider JA, Wilson RS, et al. Statins, incident Alzheimer disease, change in cognitive function, and neuropathology. Neurology 2008; 0: 01.wnl.0000288181.00826.63v1. 2.Kivipelto M, Ngandu T, Fratiglioni L, et al. Obesity and vascular risk factors at midlife and the risk of dementia and Alzheimer disease. Arch Neurol 2005;62:1556-1560. 3.Rovio S, Kåreholt I, Helkala EL et al. Leisure-time physical activity at midlife and the risk of dementia and Alzheimer's disease. Lancet Neurol 2005;4:705-711. 4.Li G, Larson EB, Sonnen JA, et al. Statin therapy is associated with reduced neuropathologic changes of Alzheimer disease. Neurology 2007;69:878-885. 5.Lee WJ, Lee WL, Tang YJ,et al. Early Improvements in insulin sensitivity and inflammatory markers are induced by pravastatin in nondiabetic subjects with hypercholesterolemia.Clin Chim Acta. 2007 Dec 23; [Epub ahead of print]. Disclosure: The authors report no disclosures.
Reply from the authors to Hussain et al 18 April 2008
Zoe Arvanitakis, Rush Alzheimer's Disease Center 600 S. Paulina, Suite 1020 Chicago IL 60612, David A. Bennett Send Correspondence to journal: Re: Reply from the authors to Hussain et al zarvanit{at}rush.edu Zoe Arvanitakis, et al.	We appreciate Dr. Hussain et al.’s interest in our article. [1] Three main points were raised: limited power; concern about assessment of the exposure; and differences with the one other clinical-pathologic study that examined the relation of statin use to AD pathology. First, we agree that larger studies allow us to detect modest effect sizes from a limited number of persons exposed to the risk factor of interest, such as statins in this study. While the Religious Orders Study--with more than 1,000 participants--is a moderately-sized clinical study, it is among the largest longitudinal, epidemiologic, clinical-pathologic studies allowing us to examine the relation of risk factors to both incident AD and neuropathology in a single cohort. Second, we agree that the accurate assessment of exposure to statins in this study is critical to study validity. We assessed statin use by direct visual inspection of all medication containers and recorded dosage. While we were able to quantify duration of use during the study period with a follow-up of up to 12 years, we do not have data on use prior to study baseline. It is possible this may have influenced our findings. Third, in the Adult Changes in Thought (ACT) Study, authors did not find that statins lowered risk of incident AD despite very detailed exposure data, including duration of exposure. [6] Thus, clinical findings in the Religious Orders Study were similar to the findings in ACT. Furthermore, our findings were internally consistent (null) across multiple clinical and neuropathologic outcomes. By contrast, the ACT study findings were inconsistent, with statins being associated with less neurofibrillary pathology [4] despite the absence of a relation to incident AD. [6] Dr. Hussain et al. also raised the possible effect of statins on inflammatory markers, which is worthy of further study. [7] Overall, the relation of statins to AD remains unclear. Observational studies, despite their limitations (e.g., indication bias), play an important role in identifying hypotheses that guide future research and clinical trials. References 6 Li G, Higdon R, Kukull WA, et al. Statin therapy and risk of dementia in the elderly: a community-based prospective cohort study. Neurology 2004;63:1624-1628. 7. Lindberg C, Crisby M, Winblad B, Schultzberg M. Effects of statins on microglia. J Neurosci Res 2005 1;82:10-19. Disclosure: The authors report no disclosures.