Effects of the absence of apolipoprotein E on lipoproteins, neurocognitive function, and retinal function

Angel C.Y. Mak, Clive R. Pullinger, Ling Fung Tang, Jinny S. Wong, Rahul C. Deo, Jean Marc Schwarz, Alejandro Gugliucci, Irina Movsesyan, Brian Y. Ishida, Catherine Chu, Annie Poon, Phillip Kim, Eveline O. Stock, Ernst J. Schaefer, Bela F. Asztalos, Joseph M. Castellano, Tony Wyss-Coray, Jacque L. Duncan, Bruce L. Miller, John P. KanePui Yan Kwok, Mary J. Malloy

Research output: Contribution to journalArticlepeer-review

73 Scopus citations


Objectives To discover the molecular basis of this rare disorder and to determine the effects of complete absence of apoE on neurocognitive and visual function and on lipoprotein metabolism.

Design, Setting, and Participants Whole-exome sequencingwas performed on the patient's DNA. He underwent detailed neurological and visual function testing and lipoprotein analysis. Lipoprotein analysis was also performed in the Cardiovascular Research Institute, University of California, San Francisco, on blood samples from the proband's mother, wife, 2 daughters, and normolipidemic control participants.

IMPORTANCE The identification of a patient with a rare form of severe dysbetalipoproteinemia allowed the study of the consequences of total absence of apolipoprotein E (apoE).

Main Outcome Measures Whole-exome sequencing, lipoprotein analysis, and neurocognitive function.

Results 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). 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. He had no significant symptoms of cardiovascular disease except a suggestion ofmyocardial ischemia on treadmill testing and mild atherosclerosis noted on carotid ultrasonography. He had exceptionally high cholesterol content (760mg/dL; to convert to millimoles per liter, multiply by 0.0259) and a high cholesterol to triglycerides ratio (1.52) in very low-density lipoproteins with elevated levels of small-diameter high-density lipoproteins, including high levels of prebeta-1 high-density lipoprotein. Intermediate-density lipoproteins, low-density lipoproteins, and very low-density lipoproteins contained elevated apoA-I and apoA-IV levels. The patient's apoC-III and apoC-IV levels were decreased in very low-density lipoproteins. Electron microscopy revealed large lamellar particles having electron-opaque cores attached to electron-lucent zones in intermediate-density and low-density lipoproteins. Low-density lipoprotein particle diameters were distributed bimodally.

Conclusions and Relevance Despite a profound effect on lipoprotein metabolism, detailed neurocognitive and retinal studies failed to demonstrate any defects. This suggests that functions of apoE in the brain and eye are not essential or that redundant mechanisms exist whereby its role can be fulfilled. Targeted knockdown of apoE in the central nervous system might be a therapeutic modality in neurodegenerative disorders.

Original languageEnglish
Pages (from-to)1228-1236
Number of pages9
JournalJAMA Neurology
Issue number10
StatePublished - 1 Oct 2014
Externally publishedYes


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