Tuesday, 12 August 2014

Man walks into hospital with no ApoE. Stupidity ensues.

A 40 year old American man sought treatment for sky-high cholesterol (760mg/dL or 19.7) and triglycerides (534 mg/dL). The xanthomas covering his body were so extreme, it was painful to walk. I could have put in some photos, but they're not very nice, so you can see for yourself in the complete paper here.

The docs eventually found out the man was a bit of a genetic freak and had a complete absence of apoliprotein E due to several genetic mutations. "
ablative APOE frameshift mutation" is the cool name they gave it. I understand this is not exactly unheard of, but the lab geeks got a bit excited because they usually have to mess around with mice to 'make' an animal with fucked up or non-existent ApoE. Having a human to prod and test is probably a novelty. 
Malloy et al 2014
They tested his eyes, heart, cerebrospinal fluid and cognitive ability and according to them he was fairly normal. He didn't do so well in a memory test and appeared to have a learning impairment (didn't speak until age 3) but that was brushed off as possible dyslexia

There are many things you could probably take away from this fascinating man, but the one thing that they appear to be shouting with a megaphone is:

Your brain doesn't need ApoE, and in fact probably hates the stuff, so lets find a way to get rid of it so you don't get Alzheimer's.

I'm paraphrasing, but that's the gist of the comments in the paper and also in the quotes attributed to the authors in the press.

A few examples:
  • "having no apoE is better than having the apoE4 protein"
  • “it is unlikely that APOE is key for normal brain development or function, as there are other proteins that can compensate in its absence.”
  • “Minimizing APOE4 levels in the brain may provide us with a new venue for intervention with Alzheimer’s disease and other cognitive disorders,”
  • "This opens the door to explore such possibilities more rigorously because we have the proof of concept that reducing APOE isn’t harmful to patients,”
  • “This particular case tells us you can actually live without any APOE in the brain,” said Dr. Joachim Herz, a neuroscientist and molecular geneticist, who was not involved in the research. “So if they were to develop anti-APOE therapies for Alzheimer’s, we would not have to worry about serious neurological side effects.”
  • Several experts are working on ways to reduce APOE4 or increase APOE2 in the brain, and the results have been promising.
  • Dr. Herz said, “based on what we know now, I would say this patient will most likely never accumulate amyloid.” 
That's all rather exciting but I have a few issues with their conclusions, such as:
  • This is one man and he's 40 years old. 
  • Did someone dispose of the lipid hypothesis and not tell me? 
  • ApoE is something scientists only have a partial clue as to what it actually does and they just want to start pulling it out of people's heads. 
  • The ApoE variant that is claimed to have the least risk for Alzheimer's is E2 and E2 people have shitloads of ApoE.  
  • ApoE E4 is purported to be the 'ancestral allele', but the geeks continue with this mindset that our ancestors must have all had dementia. 
  • This is one man and he's 40 years old.
This quote made me laugh - "Dr. Malloy is working to treat the man’s cholesterol problem, which has barely improved despite medication and a healthy diet."

They tested his heart thoroughly and didn't find much wrong with it so it seems they're just giving him statins for the hell of it. You can, of course, imagine what a 'healthy diet' involves.

"The main potential side effect of reducing apoE would be the effect on cholesterol and triglyceride levels. This patient had extremely high levels of both -- something we would have to avoid when treating patients. It would obviously not be beneficial to reduce the risk for Alzheimer's disease if in the process we increase the risk for cardiovascular disease."

The paper is an interesting read, mainly because of the subject, but the conclusion is quite odd - "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."

I'll be stuffed if I let anyone target my ApoE for knockdown. 

irrelevant pictures, I have them