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
- 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 1;71(10):1228-36. PubMed.