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New Data on Risk Gene for Alzheimer Disease Suggests Different Therapeutic Targets

Valeo, Tom

doi: 10.1097/01.NT.0000403763.91117.f3
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A new study finds that apolipoprotein alleles contribute to Alzheimer disease (AD) risk by differentially regulating clearance of amyloid beta (Abeta) from the brain, suggesting that Abeta clearance pathways may be useful therapeutic targets for AD prevention.

The strongest genetic risk factor for Alzheimer disease (AD), the apolipoprotein E4 (APOE4) allele, promotes neurodegeneration by failing to clear amyloid beta (Abeta) from the brain efficiently rather than by causing over-production of the substance, according to a team led by David Holtzman, MD, of the Washington University School of Medicine in St. Louis.

However, therapies designed to inhibit the production of Abeta will still play a role in the treatment of the disease, according to neurologists, including the researchers themselves.

“It was shown many years ago that some forms of premature atherosclerosis are caused by a deficiency in the LDL receptor, which results in inadequate clearance and elevated LDL cholesterol,” said Dr. Holtzman, the Andrew B. and Gretchen P. Jones Professor and chair of neurology at Washington University in St. Louis, MO. “But you can very effectively treat atherosclerosis by reducing the production of cholesterol. Whether you have too much synthesis or too little clearance, treating either side could potentially work.”

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A multipronged approach to treatment also remains the best strategy in the opinion of Paul Aisen, MD, director of the Alzheimer's Disease Cooperative Study, a consortium funded by the National Institutes on Aging devoted to developing AD treatments.

“I think one can view amyloid as a balance between production and clearance, so altering either one should influence accumulation,” said Dr. Aisen, professor of neurosciences at the University of California-San Diego. “Even if Dr. Holtzman is correct, and sporadic AD is a disorder of reduced amyloid clearance, it still might be addressed by reducing production.”

Robert Vassar, PhD, who has devoted much of his career to investigating mechanisms that would slow the production of Abeta in the brain, said he remains “bullish” on that strategy even though secretase inhibitors have been shown to produce seizures, hypomyelination, skin cancer, and other side-effects in mice. He noted that Eli Lilly last year halted development of semagacestat, a gamma secretase inhibitor, because the drug not only failed to slow disease progression, but actually produced a worsening of some measures of cognition and the ability to perform activities of daily living. Nevertheless, Dr. Vassar considers Dr. Holtzman's paper a “seminal” contribution for demonstrating the importance of clearance.



“Clearance is an intervention we should pursue vigorously, but at the same time we will need a broad spectrum of anti-Abeta drugs, including antibodies and secretase inhibitors, to supplement treatment,” said Dr. Vassar, professor of cell and molecular biology at the Northwestern Feinberg School of Medicine. “I believe secretase inhibitors will be important therapies in the tool bag that physicians will need to create combination therapies tailored for particular patients.”

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The Holtzman study, labeled a “tour de force” by the editors of Science Translational Medicine, where the study appeared June 29, begins by demonstrating a correlation between the three common isoforms of APOE — E2, E3, and E4 — and the amount of Abeta in the CSF of nearly 283 cognitively normal people under the age of 70. The study was supported in large part by several grants from the NIH.

A drop in CSF Abeta correlates tightly with a build-up of Abeta in the brain, providing a useful biomarker of impending AD pathology, and those carrying two alleles of APOE4 showed the lowest CSF levels of Abeta. The levels of the peptide in CSF increased progressively in those carrying alleles E3/E4, E3/E3, and E3/E2. The APOE2 allele is considered protective against amyloid accumulation.



The researchers then verified this finding by imaging the study participants after administering the dye, Pittsburgh compound B (PIB), which binds to amyloid. The imaging revealed that those carrying two APOE4 alleles carried the largest burden of brain amyloid, with descending amounts again found in those with E3/E4, E3/E3, and E3/E2.

Mouse models expressing combinations of human APOE2, APOE3, or APOE4 displayed the same pattern of amyloid accumulation in the brain interstitial fluid, as well as in stained cortical and hippocampal sections. The pattern appeared in young as well as in old mice, indicating that increased levels of Abeta are present before the appearance of amyloid plaques. Using a microdialysis technique, the researchers showed that young mice carrying the human apoE4 isoform were less able to clear Abeta from the brain.

Finally, the researchers demonstrated that the processing of amyloid precursor protein (APP), and the subsequent generation of Abeta, did not vary according to genotype, supporting the hypothesis that APOE4 affects clearance of Abeta but not its production.

The paper follows up on findings reported in Science last December by one of the co-authors, Randy Bateman, MD, also of the Washington University School of Medicine. Dr. Bateman and his colleagues compared 12 patients with early AD to 12 age-matched normal controls. Both produced Abeta at the same rate, but using a process they developed called stable isotope-linked kinetics (SILK) — also used by Dr. Holtzman's team — Dr. Bateman and his colleagues determined that the clearance rate of Abeta was an average of 30 percent lower among the AD patients, suggesting that Abeta clearance mechanisms “may be critically important in the development of AD,” the authors wrote.



Although the clearance mechanism is not well understood, Dennis Selkoe, MD, whose research over decades has pursued ways to clear the brain of Abeta, believes clearance is modulated by APOE, with APOE4 the least vigorous of the three alleles.

“My opinion is that APOE somehow binds to Abeta,” said Dr. Selkoe, Vincent and Stella Coates Professor of Neurologic Diseases at the Harvard Institutes of Medicine. “Once Abeta is bound to APOE it can be taken up by astrocytes and other cells that can clear Abeta complexes. What I think is left unsaid by the Holtzman paper is that we need to redouble our efforts to find which receptor is clearing Abeta, and why it is that the APOE4 protein doesn't clear Abeta as effectively as E2 or E3.”

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Dennis Selkoe, MD, Vincent and Stella Coates Professor of Neurologic Diseases at the Harvard Institutes of Medicine sees two other possible ways of clearing amyloid beta (Abeta) from the brain. One, proposed by Berislav V. Zlokovic, MD, PhD, of the University of Rochester, in a 2008 article in The Journal of Clinical Investigation, involves Abeta exiting the brain through the blood-brain barrier. Another involves degradation of Abeta by proteases.

Recent work led by Gary Landreth, PhD, of Case Western Reserve School of Medicine, suggests that Abeta is degraded within microglia and in the interstitial fluid, and chaperoned through the proteolytic process by apolipoprotein (APOE), with APOE2 displaying the strongest effect and APOE4, the weakest. In a 2008 article in Neuron, Dr. Landreth and his colleagues stated that this process is stimulated by activation of liver X receptors (LXRs). Mice treated with an LXR agonist displayed a 67 percent reduction in brain plaque load in the hippocampus, and an improvement in memory deficits. “These data demonstrate a novel mechanism through which APOE facilitates the clearance of Abeta from the brain and suggest that LXR agonists may represent a novel therapy for AD,” the authors stated.

At the 2011 AAN annual meeting, Dr. Landreth presented more recent research in which elevating brain APOE levels in mice by administering an agonist for the retinoid X receptor (RXR) suppressed brain Abeta and improved cognition within hours. The treatment reduced the brain plaque burden in aged mice by 30 percent within 72 hours, and by 65 percent within seven days. The treatment also appeared to reverse cognition and memory impairment.

Researchers in Bonn reported in the May 2011 issue of the Journal of Neuroscience that administering an LXR agonist called TO901317 to amyloid plaque-bearing APP23 mice reduced insoluble and soluble Abeta levels by 80 percent and 40 percent respectively, without significantly affecting APP processing, which suggests that the clearance was mediated by Abeta disposal. However, the mice displayed only slight improvement in spatial learning in the Morris water maze.

“If we could raise APOE levels in the brain, we should be able to clear amyloid from brain,” Dr. Landreth told Neurology Today. “APOE facilitates the degradation. The more you have, the faster you can clear.”

However, Dr. Vassar fears that boosting APOE, while it might help carriers of APOE2 and APOE3, could prove disastrous for carriers of APOE4.

“Dr. Holtzman found more Abeta accumulating in E4 mice due to lack of clearance,” Dr. Vassar said. “I'm concerned that if you increase APOE in those who carry one or two alleles of APOE4, who account for about half of those with sporadic Alzheimer's, you may make matters worse. We still don't know how APOE4 promotes Abeta aggregation in the brain, so if you increase APOE4 you may promote amyloid plaque formation.”

He would like to see an experiment in which LXR agonists were administered to APOE4 and APOE3 target replacement mice. “That's a critical experiment that needs to be done to validate LXR agonists for Abeta clearance from brain,” he said.

Tom Valeo

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          ©2011 American Academy of Neurology