Skip Navigation LinksHome > Blogs > Neurology News > Patient Lacking Apolipoprotein E Found to Have Normal Cognit...
Neurology News
Follow our Neurology News blog for the most current news on neurologic diseases and research. We want your input! Leave your comments at the end of each article.
Thursday, August 14, 2014
Patient Lacking Apolipoprotein E Found to Have Normal Cognitive Function, Suggesting Target for Alzheimer’s Disease

by Rebecca Hiscott

 

A patient with a deficiency of apolipoprotein E (apoE) caused by a rare genetic mutation was found to have normal neurocognitive function, suggesting that future therapies aimed at reducing apoE4, an apoE variant associated with Alzheimer’s disease (AD), could be effective.

 

            The patient, a 40-year-old African-American man, presented to the Adult Lipid Clinic at the University of California, San Francisco, with a rare form of severe dysbetalipoproteinemia, which causes abnormally high levels of cholesterol and tryglicerides in the blood that manifest physically as xanthomas—painful, swollen pustules on the skin. Researchers performed whole-exome DNA sequencing and determined that the patient had a novel 1-bp homozygous APOE frameshift deletion leading to apoE deficiency.

 

Apolipoprotein E is believed to be important for normal brain function, but a variant of apoE, apolipoprotein E4 (apoE4), is the greatest genetic risk factor for AD. It can accelerate the accumulation of plaques in the brain and has been shown to alter connectivity patterns in regions of the brain related to AD. Consequently, researchers have been investigating treatments in animal models that reduce apoE4 in the brain, but it remains unclear whether such treatments have a positive impact on brain function.

 

            After submitting the patient to a battery of retinal and neurocognitive tests, the researchers determined that he had normal cognitive and neurological function. They published their findings in the August 11 online issue of JAMA Neurology. The patient had a normal Mini-Mental State Examination score and magnetic imaging showed normal brain volume and healthy white matter. Cerebrospinal fluid showed normal levels of beta-amyloid and tau proteins, with no evidence of neurodegeneration.

 

Since the apoE-deficient patient appeared to have normal cognitive function, the authors proposed that either “the functions of apoE in the brain and eye are not critical or … they can be fulfilled by a surrogate protein,” they wrote. “Surprisingly, with respect to central nervous system function, it appears that having no apoE is better than having the apoE4 protein. Thus, projected therapies aimed at reducing apoE4 in the brain could be of benefit in neurodegenerative disorders such as Alzheimer disease.”

 

Cases of apoE deficiency have been reported previously, but no apoE-deficient patient had undergone extensive neurocognitive and retinal testing, the authors noted.

 

Several mouse apoE knockouts have been generated to investigate the effect of apoE loss on atherosclerosis and cognition, with conflicting results.  Some groups have reported that while apoE knockout mice develop normally, they begin to lose neurons around five months of age accompanied by a reduction in working memory.

 

In a separate editorial published in the August 11 online issue of JAMA Neurology, Courtney Lane-Donovan, SB, and Joachim Herz, MD, professor at the University of Texas Southwestern Medical Center, wrote, “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.” Therefore, “interventions that reduce cerebral apoE levels may hold promise as a potential therapeutic approach to AD,” they wrote.

 

Since absence of apoE in the blood is linked with exceedingly high cholesterol, which can pose significant health risks and is an independent risk factor for AD, any therapeutic approach would need to target the brain without crossing the blood-brain barrier, they added.

 

Look for the full discussion in the September 18 issue of Neurology Today. For more coverage of apoE and Alzheimer’s disease, browse our archives here: http://bit.ly/apoE-AD.

About the Author

Neurology Today

Share