Research ArticleAlzheimer’s Disease

Human apoE Isoforms Differentially Regulate Brain Amyloid-β Peptide Clearance

Science Translational Medicine  29 Jun 2011:
Vol. 3, Issue 89, pp. 89ra57
DOI: 10.1126/scitranslmed.3002156

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Clearing the Debris in Alzheimer’s Disease

The strongest risk factor for developing the common sporadic form of Alzheimer’s disease (AD) that occurs in old age is the ε4 allele encoding apolipoprotein E4 (apoE4). Two ε4 alleles can lower the age of onset of AD by 10 to 15 years. In contrast, the ε2 allele decreases the risk of developing this neurodegenerative disorder. APOE is important for lipoprotein metabolism, but how it might be involved in AD has remained unclear. It has been suggested that the apoE4 isoform might somehow help to drive accumulation of the peptide amyloid-β (Aβ), which forms amyloid plaques in the brain that contribute to neuronal death and are the characteristic hallmark of AD. In a tour de force study in humans and mice, Holtzman and his team at Washington University in St. Louis now show that apoE4 contributes to Aβ accumulation in the brain not by affecting Aβ synthesis but by affecting its clearance.

First, the authors looked at the Aβ concentration in the cerebrospinal fluid (CSF) of cognitively normal individuals under age 70 carrying different APOE genotypes. They found that those with the ε4/ε4 genotype had a much lower CSF Aβ concentration than did those with the protective ε2/ε3 genotype. A CSF Aβ concentration of less than 500 pg/ml is an indication that Aβ peptide is accumulating in the brain and thus is not moving into the CSF. Next, the researchers analyzed imaging data using a dye called Pittsburgh compound B that binds to amyloid plaques in the brain and showed that those individuals with the ε4/ε4 genotype bound more dye than did those with the other APOE genotypes. They then moved to a mouse model of AD in which the mice expressed one of the three human apoE isoforms. They measured Aβ concentrations in the interstitial fluid of these mice using in vivo microdialysis and then looked at stained hippocampal sections from these mice. They found greater Aβ concentrations in both interstitial fluid and the hippocampus in mice expressing the human apoE4 isoform than in animals expressing either the E3 or E2 isoforms. They discovered that this difference in Aβ concentration between the mice carrying different APOE genotypes was present in young as well as aged mice, suggesting that it predates the appearance of amyloid plaques. They then measured clearance of Aβ from the interstitial fluid of young mice and showed that those with the human apoE4 isoform were less able to clear Aβ than those with the apoE2 or apoE3 isoforms. The researchers showed that processing of the amyloid precursor protein and generation of the Aβ peptide did not vary according to genotype, lending credence to the hypothesis that apoE4 affects clearance of Aβ but not its synthesis. This thorough study sheds new light on how apoE4 is implicated in AD and highlights the Aβ clearance pathway as a new target for developing drugs to slow or even halt the accumulation of amyloid plaques in patients with AD.


  • * These authors contributed equally to this work.

  • Citation: J. M. Castellano, J. Kim, F. R. Stewart, H. Jiang, R. B. DeMattos, B. W. Patterson, A. M. Fagan, J. C. Morris, K. G. Mawuenyega, C. Cruchaga, A. M. Goate, K. R. Bales, S. M. Paul, R. J. Bateman, D. M. Holtzman, Human apoE Isoforms Differentially Regulate Brain Amyloid-β Peptide Clearance. Sci. Transl. Med. 3, 89ra57 (2011).

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