Mak AC, Pullinger CR, Tang LF, Wong JS, Deo RC, Schwarz JM, Gugliucci A, Movsesyan I, Ishida BY, Chu C, Poon A, Kim P, Stock EO, Schaefer EJ, Asztalos BF, Castellano JM, Wyss-Coray T, Duncan JL, Miller BL, Kane JP, Kwok PY, Malloy MJ. Effects of the absence of apolipoprotein e on lipoproteins, neurocognitive function, and retinal function. JAMA Neurol. 2014 Oct;71(10):1228-36. PubMed.

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Comments

  1. The suggestion by researchers in the field echoed by multiple news outlets, including The New York Times, CBSNEWS, and Medical Daily, that this case study demonstrates lowering ApoE is a safe therapeutic approach for Alzheimer’s disease is potentially an over- or misinterpretation of the data. Of particular concern are the findings that:

    1.    The patient is characterized as cognitively normal by his MMSE score, an admittedly “blunt measure,” while “sub-domain” tests indicate deficits in memory, language, visual-spatial abilities and executive function, in addition to signs of dyslexia. Therefore, the subject is already displaying significant signs of cognitive stress.

    2.    Physical correlates of cognition, specifically hippocampal volume and levels of traditional CSF AD biomarkers (Ab42, ptau), are normal. This is not surprising as the individual is only 40 years old and these AD-related changes are not detectable even in early disease (>60).

    3.    Lack of ApoE exerts detrimental effects in the periphery, as described by the authors: “Given the severity of his dyslipidemia, extensive xanthomas, and high potential for premature CVD, strategies aimed at reducing the generation of chylomicrons and VLDL should be aggressively perused.” Thus, the indiscriminant knock-down of ApoE in the whole body is unlikely a beneficial strategy for the periphery.

    4.    In terms of compensation for the lack of ApoE:

    a.    It does not appear that a surrogate protein replaces the function of ApoE in the periphery. Indeed, although there are alterations in the profiles of non-ApoE plasma lipoproteins (increased ApoA-1/4 and decreased ApoC-3/4 levels), plasma cholesterol levels, cholesterol/triglyceride ratio in VLDL particles, and levels of pre-HDL are exceptionally high.  

    b.    Thus, we would predict major disruptions of CNS lipoprotein biogenesis and function, unless blood-to-brain transport of apolipoproteins occurs (e.g., via ApoA1) or there is compensatory  glial cell secretion of ApoJ (a non-lipoprotein competent apolipoprotein that is not a ligand for the LDL receptors expressed by neurons and glia). However, because a CSF lipoprotein profile was not included, this is difficult to ascertain.

    Although the APOE4 allele represents the primary genetic risk factor for late-onset Alzheimer’s disease, exactly how the apolipoprotein E4 isoform promotes AD is still unclear, and the literature conflicts on such basic questions as to whether APOE4 represents a loss of positive or gain of negative function. However, studies that include a comparison of APOE-KO mice to transgenic mice expressing human APOE3 and APOE4 support the former. Accordingly, therapeutics that correct the loss of function associated with APOE4, such as increasing the lipidation of ApoE4-containing lipoproteins in the CNS, may reduce the APOE4-induced risk of AD, while lowering cerebral ApoE levels will likely adversely affect cognition in at-risk patients.

    View all comments by Mary Jo LaDu

  2. The recent report by Mak et al. is a thorough examination of an individual lacking ApoE. This case report is remarkable for its examination of neurological function and cognition, which appears entirely normal. The dyslipidemia observed in this individual is in line with previous reports of the effect of inactivation of APOE genes.

    While the report has elicited considerable attention, it is generally consistent with phenotypes observed in ApoE knockout mice. The ApoE null mice do not exhibit cognitive or other behavioral deficits. In the brain, ApoE is the principal apolipoprotein and is responsible for trafficking cholesterol and phospholipids throughout the brain. However, other apolipoproteins are found in the CSF of normal and diseased men and mice, most prominently ApoA1. The origin of the CSF ApoA1 remains controversial, but could functionally compensate for ApoE. It would be of interest to examine CSF to determine the abundance and lipidation status of other apoplipoproteins in this individual. While much has been made about the relevance of this case report to AD risk, it is not clear to me that it provides much additional insight into disease pathogenesis. 

    View all comments by Gary Landreth

  3. This recent paper by Mak et al., describes the effects of ApoE deficiency in a 40-year-old human patient. The results revealed that, despite complete absence of ApoE, the patient had normal vision, exhibited normal cognitive neurological and retinal function, and had normal magnetic resonance in the brain and normal CSF tau and Aβ42 levels. In contrast, ApoE deficiency had a profound effect on the levels and composition of serum lipoproteins. In their concluding remarks the authors suggest that “functions of apoE in the brain and eye are not essential … and that targeted knockdown of ApoE might be a therapeutic modality.”

    Animal model studies revealed that the pathological effects of ApoE deficiency are accentuated following brain insults such as head trauma (Chen et al., 1997). Accordingly, as the patient studied was in his 40s, it is likely that under challenging conditions, such as AD or aging, lack of ApoE will have pronounced effects that are not observed at a relatively young age.

    There is a growing body of evidence based on animal models that the pathological effects of ApoE4 may be due to both loss-of-function and gain-of-toxic-function mechanisms (for review, see Michaelson 2014). Examples of the loss-of-function effect are the findings that ApoE4 is hypolipidated in targeted replacement mice and that correction of this impairment reverses key pathological effects in ApoE4 mice (Boehm-Cagan and Michaelson, 2014). A counterexample of a gain-of-toxicity mechanism is the finding that ApoE4 stimulates the accumulation of Aβ into hippocampal neurons following activation of the amyloid cascade and that this effect is significantly more pronounced than in either apoE3 mice or ApoE deficient mice (Zepa et al., 2011). 

    In view of this, we believe that it is important that the therapeutic focus remain on apoE4 versus apoE3 and not shift to targeted knockdown of ApoE.

    References:

    Chen Y, Lomnitski L, Michaelson DM, Shohami E. Motor and cognitive deficits in apolipoprotein E-deficient mice after closed head injury. Neuroscience. 1997 Oct;80(4):1255-62. PubMed.

    Boehm-Cagan A, Michaelson DM. Reversal of apoE4-driven brain pathology and behavioral deficits by bexarotene. J Neurosci. 2014 May 21;34(21):7293-301. PubMed.

    Zepa L, Frenkel M, Belinson H, Kariv-Inbal Z, Kayed R, Masliah E, Michaelson DM. ApoE4-Driven Accumulation of Intraneuronal Oligomerized Aβ42 following Activation of the Amyloid Cascade In Vivo Is Mediated by a Gain of Function. Int J Alzheimers Dis. 2011 Feb 15;2011:792070. PubMed.

    Michaelson DM. APOE ε4: the most prevalent yet understudied risk factor for Alzheimer's disease. Alzheimers Dement. 2014 Nov;10(6):861-8. Epub 2014 Sep 10 PubMed.

    View all comments by Daniel Michaelson

  4. Drs. Mary Malloy and John Kane reply to comments:

    The essential observation on the patient with total absence of any apolipoprotein E protein, resulting from homozygosity for massive deletions in the ApoE gene locus, is the absence of significant neurocognitive deficits.  His cumulative scores on extensive testing, though minimally variable, are not significantly different from the average patient.  Indeed, this is consistent with the findings on ApoE knockout mice.  However, the mouse is a limited model in terms of neurocognitive function.  The finding of essentially normal neurocognitve function when ApoE was absent from zygote to maturity is impressive in that many defects attributable to gene knockouts have their most important effects during early development. This finding suggests that, indeed, there may be surrogate proteins that can sustain the role of cholesterol transport in the absence of any apolipoprotein E.  Finding these proteins will be highly informative in terms of alternative pathways of sterol transport in the CNS.

    Two lines of investigation suggest that ApoE, and in particular, ApoE4, contribute to processes central to Alzheimer’s disease.  ApoE4 supports the polymerization of amyloid precursor protein in a dose-dependent fashion (Potter and Wisniewsk, 2012) and increases the synaptic location of amyloid beta oligomers (Jones et al., 2011). 

    A contrasting view has been put forward that ApoE has a protective effect, and that ApoE4 exerts less of this effect than the other isomers, accounting for its association with progressive Alzheimer’s disease (Potter and Wisniewsk, 2012).  If this were true, then we would expect significant defects to appear in the absence of the E apolipoproteins. Our data indicate the contrary. Thus, therapeutic strategies directed at reduction of ApoE4 in the brain may offer new approaches for treatment of a variety of neurodegenerative disorders.  If this is accomplished within the CNS, it would not be expected to have a significant impact on lipoprotein transport in the blood and peripheral tissues.  If ApoE4 levels are reduced throughout the body, it is likely that the resulting dyslipidemia would respond to lipid lowering therapy, as does typical dysbetalipoproteinemia, assuming that some ApoE is present.

    References:

    Potter H, Wisniewski T. Apolipoprotein e: essential catalyst of the Alzheimer amyloid cascade. Int J Alzheimers Dis. 2012;2012:489428. PubMed.

    Jones PB, Adams KW, Rozkalne A, Spires-Jones TL, Hshieh TT, Hashimoto T, von Armin CA, Mielke M, Bacskai BJ, Hyman BT. Apolipoprotein E: isoform specific differences in tertiary structure and interaction with amyloid-β in human Alzheimer brain. PLoS One. 2011;6(1):e14586. PubMed.

    View all comments by Mary Malloy

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News

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