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Re: Statin therapy is associated with reduced neuropathologic changes of Alzheimer disease

Li et al. referred to direct evidence of statin effects on the brain reducing Alzheimer disease (AD). [1] What they show are neither “direct” nor “effects,” but associations. This study failed to heed critiques of previous AD statin links. [2]

Patients who took statins have had lower rates of AD or associated autopsy changes [1] but this means little. Similarly, people who took hormone replacement therapy (HRT) also had sharply lower AD rates [3] (and mechanisms supported potential benefit) [4] but with randomization providing a comparable control group, HRT significantly increased dementia. [5]

Better educated people—who have greatly lowered rates of AD irrespective of medications [6]—are more likely to receive preventive medicines like HRT and statins, creating the appearance of a protective connection. Moreover, in the case of statins, low LDL and low cholesterol have been linked to more neurodegeneration [7] and preclude statin use. This again could explain lower rates of AD in statin users. (Statin users have higher LDL before and often despite statin therapy).

In theory, statins could even be harmful, since studies have repeatedly shown that more potent statins, which may better combat the high LDL that motivated their use, lose the beneficial link to AD. One possible reason is that LDL transports vital antioxidants including coenzyme Q10, which have been shown to defend against neurodegeneration.

Statins may prove to benefit or harm AD or both (via effect modification) or neither. This study by Li et al. does little to advance our understanding. Worse, it may cause harm. The sole large randomized trial of statins in the elderly (age >70, ~5800 subjects) showed no trend toward statin benefit to either mortality or combined serious morbidity. It also showed no trend to stroke benefit, no hint of cognitive benefit, and a significant increase in cancer.[8]

Moreover, the elderly are at heightened risk of statin adverse effects, which can be disabling. The older elderly rarely recover once disabled for any reason, even if the triggering cause is removed. [9] It would be tragic if extravagant inferences beyond the evidence—implying that statins cause benefits to AD—led to unwarranted statin use and perhaps needless suffering in the elderly.

References

1. Li G, Larson EB, Sonnen JA, et al. Statin therapy is associated with reduced neuropathologic changes of Alzheimer disease. Neurology 2007;69:878-885.

2. Golomb BA, Jaworski BA. Statins and dementia. Archives of Neurology 2001;58:1169-1170.

3. Zandi PP, Carlson MC, Plassman BL, et al. Hormone replacement therapy and incidence of Alzheimer disease in older women: the Cache County Study. Jama 2002;288:2123-2129.

4. Cholerton B, Gleason CE, Baker LD, Asthana S. Estrogen and Alzheimer's disease: the story so far. Drugs Aging 2002;19:405-427.

5. Shumaker SA, Legault C, Rapp SR, et al. Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women: the Women's Health Initiative Memory Study: a randomized controlled trial. Jama 2003;289:2651-2662.

6. Evans DA, Hebert LE, Beckett LA, et al. Education and other measures of socioeconomic status and risk of incident Alzheimer disease in a defined population of older persons. Arch Neurol 1997;54:1399-1405.

7. Huang X, Chen H, Miller WC, et al. Lower low-density lipoprotein cholesterol levels are associated with Parkinson's disease. Mov Disord 2007;22:377-381

8. Shepherd J, Blauw GJ, Murphy MB, et al. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial. Lancet 2002;360:1623-1630.

9. Gill TM, Robison JT, Tinetti ME. Predictors of recovery in activities of daily living among disabled older persons living in the community. J Gen Intern Med 1997;12:757-762.

Send Correspondence to journal:
Re: Reply from the authors.

We thank Dr. Golomb et al. for their interest in our article. However, we must note that we did not refer to our findings as “direct evidence” of a “statin effect” on neurofibrillary tangle burden at autopsy. [1]

Our study was not a clinical trial, but an observational study in which some potential for bias was inevitable. We note, however, that a well conducted observational study with careful control of potential biases can provide important clues about the long term consequences of statin use on the risk of AD. We also note that it would be extremely difficult, if not logistically impossible, to establish a causal basis for neuropathologic consequences of statin therapy on the basis of a randomized controlled trial.

Golomb et al. correctly state that “healthier behavior” in highly educated persons could potentially confound the association between statin use and risk of AD. The potential for this confounding effect is less in our study than in some others, however, since all participants were members of the Group Health Cooperative, a Health Maintenance Organization with relatively uniform prescribing practices.

Also, the educational attainment of our statin users and non-users was comparable (14.3 ± 2.4 vs. 14.1 ± 3.5 years). These facts reduce the likelihood that our findings result principally from confounding by education, socioeconomic status, or health service availability.

Golomb et al. also suggest that “in theory, statins could even be harmful, since studies have repeatedly shown that more potent statins which may better combat the high LDL that motivated their use lose the beneficial link to Alzheimer’s”. The sources for this statement are unclear. Our group has recently reported that 14 weeks of treatment with simvastatin, a drug with high central nerves system (CNS) penetration, reduced cerebrospinal fluid levels of phosphorylated tau protein in cognitively normal hypercholesterolemic subjects, while treatment with pravastatin (with low CNS penetration) showed no such effect. [10] There was no evident increase in adverse effects in the simvastatin-treated group.

Another recent one-year clinical trial of the potent compound atorvastatin for treatment of mild to moderate AD showed no adverse effects on memory and cognition with treatment. Instead, atorvastatin-treated subjects may have shown some clinical benefit in cognition, mood and behavior. [11] Finally, the National Lipid Association Statin Safety Task Force’s Neurology Expert Panel recently concluded that statins do not impair memory or cognitive function. [12]

References

10. Riekse RG, Li G, Petrie EC, et al. Effect of statins on Alzheimer's disease biomarkers in cerebrospinal fluid. Journal of Alzheimer's disease 2006;10:399-406.

11. Sparks DL, Sabbagh MN, Connor DJ, et al. Atorvastatin for the treatment of mild to moderate Alzheimer disease: preliminary results. Archives of neurology 2005;62:753-757.

12. Brass LM, Alberts MJ, Sparks L. An assessment of statin safety by neurologists. Am J Cardiol 2006;97:86C-88C.

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Re: Statin therapy is associated with reduced neuropathologic changes of Alzheimer disease

We are interested in the report by Li et al concerning autopsy findings in brains with Alzheimer disease (AD) pathology from patients who had been users of statins compared to brains with AD pathology from nonusers of statins. [1]

The statin users were defined as those who had received at least three prescriptions (>15 pills per prescription) for simvastatin, lovastatin, pravastatin, or atorvastatin during the period of the study. They report that statin users exhibited a lower burden of both neurofibrillary tangles and neuritic plaques compared with nonusers. However, they also observed that the "association between statin use and CERAD plaque scores did not reach statistical significance."

This apparent lack of effect on plaques seems to mitigate the significance of earlier transgenic mouse in vivo studies that showed a statin oral dose-dependent correlation with reduction in brain amyloid peptides and plaques for both lovastatin and pravastatin. [2] The doses of 1 mg/kg/d in the 3-month old mice for 1 month correspond to about 80 mg/d in humans—the maximum recommended for lovastatin and pravastatin—which produced 37% and 21% reductions, respectively, in amyloid content. [2] Linear reductions in amyloid to 69% and 52% at 10mg/kg/d with lovastatin and pravastatin, respectively, were observed.

Possible explanations for the lack of statin effect on amyloid plaques seen in the human AD brains are that the human doses in this retrospective study were not controlled and they were too low. In addition, the statins were not started early enough to prevent amyloid formation and amyloid plaques are less readily reversible than abnormal tau phosphorylation.

It appears that to be effective in human AD, the statins need to be started at earlier ages before amyloid formation and at larger doses. [2]

References

1. Li G, Larson EB, Sonnen JA, et al., Statin therapy is associated with reduced neuropathologic changes of Alzheimer disease, Neurology 2007;69:878-885.

2. Chauhan NB, Siegel GJ, Feinstein DL. Effects of lovastatin and pravastatin on amyloid processing and inflammatory response in TgCRND8 brain, Neurochem. Res. 2005;29:1897-1911.

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Re: Reply from the authors

We thank Dr. Siegel et al for their interest in our work. We would add two further possibilities: neuritic plaque score may be a poor measure of disease progression [1]; or transgenic mice with cerebral A-beta amyloidosis may not sufficiently model the pathogenesis of Alzheimer disease (AD).

Further investigation and more accurate models are needed to discover the ensemble of effective and accessible targets for prevention of the dementias of aging including AD.