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Aug 12, 2014

Delete ApoE Gene, Set Back Alzheimer’s, and Preserve Brain Health?

  • Although a mutated form of the gene for apolipoprotein E (apoE) is a risk factor for Alzheimer’s disease, it is not known whether apoE, in general, is important for brain health. And so, it was not known whether completely abrogating apoE, in all its forms, would be safe. While many may have been tempted to somehow clear the central nervous system of apoE, few were willing to say, in effect, fire at will.

    An unusual opportunity to revisit the question of apoE’s role in brain health recently presented itself in the form of a 40-year-old California man. Although he had a rare form of severe dysbetalipoproteinemia—and a complete absence of apoE—he exhibited normal cognitive function.

    The man was examined at the University of California, San Francisco (UCSF). There, he was examined by a clinical and scientific team led by Mary Malloy, M.D., who codirects UCSF’s Adult Lipid Clinic.

    Because apoE is found in the central nervous system and the retinal pigment epithelium of the eye, Dr. Malloy’s team closely examined the man’s retinal and neurocognitive function. In addition, whole-exome sequencing was performed on the patient’s DNA, revealing that that the patient carried a mutation that accounted for his apoE deficiency.

    The results of all the testing appeared August 11 in JAMA, in an article entitled, “Effects of the Absence of Apolipoprotein E on Lipoproteins, Neurocognitive Function, and Retinal Function.”

    “The patient was homozygous for an ablative APOE frameshift mutation (c.291del, p.E97fs). No other mutations likely to contribute to the phenotype were discovered, with the possible exception of two, in ABCC2 (p.I670T) and LIPC (p.G137R),” wrote the authors. “Despite complete absence of apoE, he had normal vision, exhibited normal cognitive, neurological, and retinal function, had normal findings on brain magnetic resonance imaging, and had normal cerebrospinal fluid levels of β-amyloid and tau proteins.”

    “Failure of detailed neurocognitive and retinal studies to demonstrate defects in our patient suggests either that the functions of apoE in the brain and eye are not critical or that they can be fulfilled by a surrogate protein,” they continued. “Surprisingly, with respect to central nervous system function, it appears that having no apoE is better than having the apoE4 protein.”

    The authors concluded that targeted knockdown of apoE in the central nervous system might be a therapeutic modality in neurodegenerative disorders.

    A JAMA editorial that accompanied the UCSF research paper took up the central point, the role of apoE in brain health: “Despite two decades of research into the mechanisms by which apoE4 contributes to disease pathogenesis, a seemingly simple question remains unresolved: Is apoE good or bad for brain health? The answer to this question is essential for the future development of apoE-directed therapeutics.... In light of apoE as the primary risk factor for AD, the lack of neurological findings in this patient would appear to answer the question of whether apoE is necessary for brain function with a resounding no.”

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