Schemes are in the works to treat Alzheimer’s disease by targeting its most potent genetic risk factor, ApoE4, but could depleting ApoE from the brain cause serious side effects? Not if a 40-year-old Californian man is any guide. Researchers led by Mary Malloy at the University of California, San Francisco, reported in the August 11 JAMA Neurology that this father of three has lost both copies of the ApoE gene and is completely devoid of the protein. However, he appears largely normal neurologically and cognitively, although he does have high cholesterol and related issues. Some commentators were uncertain how this finding relates to AD, while others debated whether it supports attempts to reduce ApoE therapeutically.

“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,” wrote Courtney Lane-Donovan and Joachim Herz of the University of Texas Southwestern Medical Center, Dallas, in an editorial that accompanied the paper. The findings suggest that “therapeutics that reduce cerebral ApoE levels will likely not adversely affect cognition in at-risk patients.” 

ApoE is an apolipoprotein that binds to lipids and cholesterol and regulates their metabolism. It is the only apolipoprotein expressed in the brain. The ApoE4 allele elevates AD risk and brings on disease earlier. Some evidence suggests that boosting ApoE4’s ability to bind lipids is a promising treatment strategy, while other work concludes that removing the protein is the best approach (see May 2014 news story). However, the potential danger of reducing ApoE expression in the human brain remained unknown.

Enter a patient with a condition called severe dysbetalipoproteinemia. The disorder is characterized by sky-high concentrations of plasma cholesterol and triglycerides, a consequence of their poor clearance from the blood. ApoE helps remove these lipids by handing them off to the liver. Lipidated ApoE binds to low-density lipoprotein (LDL) receptors on liver cells, which then ferry the lipids inside. Most people with dysbetalipoproteinemia harbor two copies of the ApoE2 allele. While that isoform binds to the LDL receptor with lower affinity than ApoE3 or E4, a combination of other genetic mutations and/or environmental factors are required to trigger the disease. In searching for such mutations in this patient, Malloy and colleagues were surprised to find that both copies of his APOE gene harbored a frameshift mutation that wiped out expression of the gene.

As is typical of dysbetalipoproteinemia, the man had exceedingly high plasma cholesterol and triglycerides. He also had cholesterol-rich deposits called xanthomas underneath his skin. Because of ApoE’s role in AD, first author Angel Mak and colleagues conducted extensive neurological tests. The patient, whom researchers described as a person with excellent social skills, scored 28/30 points on the Mini-Mental State Examination (MMSE), and within normal range on tests of visuospatial skills, verbal fluency, working memory, and executive functions, but scored slightly below average on measures of verbal memory and language. Medical history suggests he did not start talking until the age of 3, a delay that may have been caused by dyslexia, the authors said. 

While most commentators agreed the patient appeared cognitively normal, others were skeptical. “The patient is characterized as cognitively normal by his MMSE score, an admittedly ‘blunt measure,’ while ‘sub-domain’ tests indicate deficits,” wrote Leon Tai, Manel Ben Aissa, and Mary Jo LaDu of the University of Illinois in Chicago in a joint comment to Alzforum. “Therefore, the subject is already displaying significant signs of cognitive stress.” Tai and colleagues expressed other concerns about the interpretation of the study’s results, as well (see full comment below).

John Kane, a coauthor on the paper, said he felt the test scores reflected normal variability. “There was nothing striking about his performance—everyone does better in some areas than others,” he said. “It’s typical of what you see in the average person.” Kane, also at UCSF, added that the researchers plan to track the man’s cognitive and neurological status.

MRI scans of the patient’s brain revealed normal brain volume, with no signs of the atrophy in the hippocampus, or elsewhere, that characterizes advancing AD, and no white-matter lesions. Levels of Aβ42, total tau, and phospho-tau in his cerebrospinal fluid were also normal.

“This case report is remarkable for its examination of neurological function and cognition, which appears entirely normal,” commented Gary Landreth of Case Western Reserve University in Cleveland. He added that the results do not necessarily shed light on the role of ApoE in the context of AD. “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,” he wrote.

Daniel Michaelson of Tel Aviv University in Israel commented that the patient was quite young, and it is possible that neurological consequences of his ApoE deficiency could emerge with age. The mechanism by which ApoE4 hastens AD is still under intense study, he added, and evidence exists for both toxic gain-of-function and loss-of-function mechanisms. “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 in general.”—Jessica Shugart


  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.

  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.


    . Motor and cognitive deficits in apolipoprotein E-deficient mice after closed head injury. Neuroscience. 1997 Oct;80(4):1255-62. PubMed.

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

    . 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.

    . 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.


    . Apolipoprotein e: essential catalyst of the Alzheimer amyloid cascade. Int J Alzheimers Dis. 2012;2012:489428. PubMed.

    . Apolipoprotein E: isoform specific differences in tertiary structure and interaction with amyloid-β in human Alzheimer brain. PLoS One. 2011;6(1):e14586. PubMed.

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Alzpedia Citations

  1. APOE

News Citations

  1. Has ApoE’s Time Come as a Therapeutic Target?

Further Reading

Primary Papers

  1. . Effects of the absence of apolipoprotein e on lipoproteins, neurocognitive function, and retinal function. JAMA Neurol. 2014 Oct;71(10):1228-36. PubMed.