Statins and Alzheimer's: Moving the Field Forward

Megan Brooks

November 30, 2011

November 30, 2011 — The time has come for more rigorous studies that look into the potential of lipid-lowering statins in the prevention and/or treatment of Alzheimer's disease (AD), authors of a new review of the literature conclude.

For a variety of reasons, studies to date have "precluded a clear answer to the overarching question of whether statins, such widely prescribed and generally safe drugs in our society, represent viable therapeutic or preventive agents for the most common cause of progressive cognitive failure in older humans," they note.

The authors are Dennis J. Selkoe, MD, and Nina E. Shepardson, MS, both from the Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, and Ganesh M. Shankar, MD, PhD, who is also from the Center for Neurologic Diseases, as well as the Department of Neurological Surgery, Massachusetts General Hospital, Boston.

The review is published in the November issue of the Archives of Neurology.

Jury Still Out

A substantial amount of evidence supports the hypothesis that high cholesterol levels increase the risk of developing AD by promoting the formation of amyloid beta and its accumulation in the brain, the authors note. This has fueled numerous studies of whether statins and other lipid-lowering agents act as preventive or therapeutic agents in AD.

However, clinical studies of statins to date have shown "highly variable outcomes, making it difficult to draw firm conclusions," the researchers point out.

Dr. Selkoe and colleagues believe several factors are behind the divergent outcomes seen in studies to date; chiefly, the different biochemical properties of the statins and other lipid-lowering agents used in the studies; differing blood–brain barrier permeabilities among statins; the drugs' pleiotropic metabolic effects; the stage in AD at which statins were tested; and the inconsistent use of biomarker and cognitive endpoints.

The authors suggest that in the future, studies that investigate the potential link between statin use and AD risk or progression take into account the blood–brain permeabilities of statins when analyzing results.

Going Forward

John Ringman, MD, associate professor of neurology at the University of California, Los Angeles, School of Medicine, who was not involved in the review, agrees. "It is important the blood–brain barrier permeability be taken into consideration" in future studies, he told Medscape Medical News.

Dr. Selkoe and colleagues also recommend that future epidemiological studies and clinical trials uniformly apply an agreed-on set of biomarkers in serum and cerebrospinal fluid, particularly amyloid beta42, tau, and phospho-tau levels; that they employ brain imaging, including amyloid imaging by positron-emission tomography; and that they use cognitive measures such as the cognitive subscale of the AD Assessment Scale and, preferably, more sophisticated and specific tests of verbal and episodic memory.

Dr. Ringman said he "wouldn't bother with more epidemiological studies. What we need now is randomized, blinded, placebo-controlled studies."

It is also "most important," say Dr. Selkoe and colleagues, to conduct statin treatment trials "solely in patients with mild AD, who have the best chance for disease modification."

Dr. Ringman agrees. This patient population "is becoming the standard for testing interventions that are thought to have disease-modifying effects," he said. Future studies "should be prospective studies that include participants with early- and presymptomatic-stage disease and have sensitive cognitive and biomarker endpoints," he added.

The study was supported by a grant from the National Institutes of Health. Dr. Selkoe is a founding scientist and consultant of Elan PLC. The other authors and Dr. Ringman have disclosed no relevant financial relationships.

Arch Neurol. 2011;68:1385-1392. Abstract

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