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Lipid lowering agents to delay cognitive decline in Alzheimer’s disease?
  1. F-E de Leeuw
  1. Correspondence to:
 Dr F-E de Leeuw
 Department of Neurology (HP326), University Medical Centre St Radboud, PO Box 9101, 6500HB Nijmegen, Netherlands; h.deleeuwneuro.umcn.nl

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More work to be done before concluding that lipid lowering agents are useful in Alzheimer’s disease

There is conflicting evidence for a causal relation between cholesterol, its treatment, and the incidence of Alzheimer’s disease.1,2 Merely the finding of a reduced incidence of Alzheimer’s disease among statin users does not necessarily imply any beneficial clinical effect of cholesterol lowering in patients with Alzheimer’s disease.

This gap in our understanding of the interplay between cholesterol and Alzheimer’s disease prompted Masse and colleagues3 to carry out the study on which they report in this months’ issue of the journal (see p 1624 of this issue).

Previous reports on the effect of statins on the incidence of Alzheimer’s disease have always been criticised for possible weaknesses in study design—especially confounding by indication and cessation bias. The authors of the present study have proven to have learned these lessons well by choosing a study design that only included patients with Alzheimer’s disease, among whom the majority had already been prescribed lipid lowering agents before the Alzheimer diagnosis was made, a proportion that only increased during follow up. As the investigators mention correctly, this may, at least in part, have avoided indication bias. Other factors that are often associated with indication bias—such as education, severity of the disease, and age—were also equally distributed among the treated and the non-treated groups. The increase in the use of lipid lowering agents along the course of Alzheimer’s disease also warrants a good control for another important source of biasthat is, “cessation bias”, a phenomenon that may occur if physicians decide not to prescribe relatively expensive drugs any more the moment a patient has become demented. Because of cessation bias the use of lipid lowering agents will be much less among demented patients, consequently leading to spurious associations between lipid lowering agent use and Alzheimer’s disease. Perhaps because they rigorously excluded all these biases the investigators succeeded in finding a delay in cognitive decline during the course of Alzheimer’s disease among lipid lowering drug users.

Limitations of the study were that the cholesterol lowering effects of the lipid lowering drugs could not be disentangled from other putative effects that these drugs may have had, and that there was no distinction between the various classes of lipid lowering agents (mainly statins and fibrates in their study) with respect to the delay in cognitive decline. Support for at least an important role of statins in this matter comes from a another recent small double blind randomised trial which showed delayed cognitive decline in atorvastatin users compared with a placebo group in patients with Alzheimer’s disease.4

There are many hypotheses on how lipid lowering agents may work in delaying progression of Alzheimer’s disease, and both in vitro and in vivo studies suggest a reduction of cerebral Aß1-40 and Aß1-42 by statins.5 Another theory, which is not unlikely when dealing with a drug that prevents future vascular events, is a reduction in the cerebrovascular ischaemic events that are known to play a role in Alzheimer’s disease.6 As Alzheimer’s disease has in common with stroke its relatively weak association with cholesterol, a modest beneficial effect of cholesterol lowering on the progression of the two diseases is also a common factor.4,7 Unfortunately the current study does not provide us with detailed longitudinal neuroimaging data that could shed more light on this potential (vascular) underlying mechanism.

As there seem to be so many similarities between Alzheimer’s disease and stroke with respect to the “cholesterol” issue, would it not be sensible to include dementia as a primary outcome measure in future cardiovascular trials in order to sort this matter out?

More work to be done before concluding that lipid lowering agents are useful in Alzheimer’s disease

REFERENCES

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Footnotes

  • Competing interests: none declared

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