When geneticists think of Alzheimer’s, the first gene that comes to mind is APOe. Can its effect be stopped or at least dampened? The recent discovery of a man without the gene may hold the key to a sizable breakthrough.
A 40-year-old California man exhibits normal cognitive function although he has no apolipoprotein E (apoE), which is believed to be important for brain function but a mutation of which is also a known risk factor for Alzheimer disease (AD). Researchers suggest this could mean that therapies to reduce apoE in the central nervous system may one day help treat neurodegenerative disorders such as AD.
The study was authored by Angel C. Y. Mak, Ph.D., of the University of California, San Francisco, and colleagues.
The patient was referred to UCSF with severe high cholesterol that was relatively unresponsive to treatment. He has a rare form of severe dysbetalipoproteinemia (abnormally high levels of cholesterol and triglycerides in the blood) and the authors identified a mutation leading to his apoE deficiency.
Extensive studies of the patient’s retinal (eye) and neurocognitive function were performed because apoE is found in the central nervous system and the retinal pigment epithelium of the eye.
Results: Despite lacking apoE, the patient had normal vision and exhibited normal cognitive, neurological and eye function. The patient also had normal brain imaging findings and normal cerebrospinal fluid levels of other proteins.
“Failure of detailed neurocognitive and retinal studies to demonstrate defects in our patient suggests either that the functions of apoE in the brain and eye are not critical or that they can be fulfilled by a surrogate protein. 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.”
In a related editorial, Courtney Lane-Donovan, S.B., and Joachim Herz, M.D., of the University of Texas Southwestern Medical Center, Dallas, write: “More than 20 years ago, a polymorphism in the apolipoprotein E (apoE) gene was identified as the primary risk factor for late-onset Alzheimer disease (AD). Individuals carrying the Ɛ4 isoform of apoE (apoE4) are at significantly greater risk for AD compared with apoE3 carriers, whereas the apoE2 allele is associated with reduced AD risk.”
“Despite two decades of research into the mechanisms by which apoE4 contributes to disease pathogenesis, a seemingly simple question remains unresolved: is apoE good or bad for brain health? The answer to this question is essential for the future development of apoE-directed therapeutics. … 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,” they continue.
“Overall, the patient’s normal cognitive function together with the earlier mouse work suggest that interventions that reduce cerebral apoE levels may hold promise as a potential therapeutic approach to AD,” they conclude.
- 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. Kane, Pui-Yan Kwok, Mary J. Malloy. Effects of the Absence of Apolipoprotein E on Lipoproteins, Neurocognitive Function, and Retinal Function. JAMA Neurology, 2014; DOI: 10.1001/jamaneurol.2014.2011
This is a CASE REPORT, a single incidence, not scientific research. It poses an intriguing question for possible research. Good luck getting an NIH grant based on a case report. Good media though!
Call me crazy, but claiming that this single case study supports the use of targeted knockdown of CNS apoE to treat neurodegenerative disorders makes absolutely no sense whatsoever.
In the first place, it's the apoE4 allele that is a risk factor, not the presence of the apoE gene itself. As the editorial notes, apoE3 is "neutral" with regard to the risk of AD and apoE2 is *protective*.
A risk factor is one that has not been shown to have a causative relationship. People can carry two copies of apoE4 and never develop AD. People can develop AD without carrying apoE4 at all. And treating a progressive disease that's already been triggered is a far cry from doing something to reduce risk. We have no idea what role, if any, apoE4 plays in the emergence *or progression* of AD.
And even apoE4 is not the "primary risk factor for late-onset AD" as this article states — *age* is far and away the biggest risk factor.
Which leads us to the fact that the patient in this study is only 40. Who's to say whether or when he'll develop a neurodegenerative disorder? It is extremely rare to develop sporadic AD that young — the fact that he apparently doesn't already have clinical AD is meaningless. In fact, who's to say whether he would have had much better neurocognitive function at his current age had he not carried this severe mutation? After all, he did show signs of dysfunction from a very young age, such as his failure to start talking until he was 3 years old, and his performance in school was less than stellar.
And dysbetalipoproteinemia causes all sorts of other health problems. Patients with familial dysbetalipoproteinemia develop xanthomas (as this patient already has over much of his body); are at high risk of developing atherosclerosis early in life, often accompanied by angina and TIAs; and are at high risk of heart attack, stroke, peripheral vascular disease, intermittent claudication, and/or gangrene of the feet or legs.
Even if it were possible to selectively knock out a gene in the brain without affecting that same gene anywhere else in the body, are we sure we understand the routes whereby dysbetalipoproteinemia causes so many problems?
So. We knock out this gene to *possibly* reduce the risk of AD (we have no idea what having no apoE genes at all might do to the risk of developing AD or to the progression of subclinical or clinical AD), while at the same time possibly greatly increasing the risk of vascular dementia, stroke, and heart attacks, among other serious problems. Do I have that right?