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neurolove: I had a great question from floating-point that I started to answer earlier this week.  Let’s get back to ApoE e4.  Depending on the number of alleles (you can have up to two, one from each parent), there is an increasing risk of developing Alzheimer’s. People with no ApoE e4 alleles have a 9% risk of getting Alzheimer’s.  Compare that to a 27% risk with one ApoE e4 allele and 55% risk with two ApoE e4 alleles.  Overall, this mutation accounts for about 40% of all Alzheimer’s cases.  The only other genes that are related to Alzheimer’s are causal, which means if you have that mutation, you WILL get Alzheimer’s, but they only account for about .5% of all Alzheimer’s cases.  A few of these genes are AP1 and Presenilin 1 and 2, for example.  The interesting thing is that most of these genes affect APP (Amyloid-Beta Precursor Protein), which is cleaved (cut into a smaller piece) to become amyloid-beta.  It is important to note that amyloid-beta is a normal protein and even with normal aging, there are some amyloid-beta plaques that form.  This makes it extra complicated.  It seems that it might have to do with how amyloid-beta is cleaved (the lengths of the protein once it has been cut normally) and how well it is broken down that might lead to this normal process becoming Alzheimer’s.  There is some evidence that ApoE might help breakdown amyloid-beta and that the e4 allele might not do it as efficiently as the other variants of ApoE, which leads to pathological build up and widespread amyloid-beta plaques.  It isn’t entirely clear at this point, however. I’ve also added a picture to help show the Alzheimer’s brain and degeneration that occurs in the disease progression (above).  It’s pretty marked post-mortem (after death), as you can see. [Image Source] This is a pretty good explanation of ApoE4 as a risk factor for Alzheimer’s Disease. I’d only add that although amyloid is a “normal protein,” in the sense that our brains make it and degrade it, the oligimerization (when a bunch of amyloid gets together) of amyloid and the formation of plaques are NOT a normal part of getting older - they just show up 10-15 YEARS (!) before symptoms begin, so there’s still lots of time to die from other things before Alzheimer’s starts making you forget stuff. Also, that paper about ApoE helping to degrade amyloid they cited is from my lab! There’s so much more to the story about apoE being a risk factor for the disease and it’s SUPER INTERESTING and it mostly boils down to a story about CHOLESTEROL and how ApoE4 is worse at carrying it around than the other forms of ApoE.

neurolove:

I had a great question from floating-point that I started to answer earlier this week.  Let’s get back to ApoE e4.  Depending on the number of alleles (you can have up to two, one from each parent), there is an increasing risk of developing Alzheimer’s.

People with no ApoE e4 alleles have a 9% risk of getting Alzheimer’s.  Compare that to a 27% risk with one ApoE e4 allele and 55% risk with two ApoE e4 alleles.  Overall, this mutation accounts for about 40% of all Alzheimer’s cases.  The only other genes that are related to Alzheimer’s are causal, which means if you have that mutation, you WILL get Alzheimer’s, but they only account for about .5% of all Alzheimer’s cases.  A few of these genes are AP1 and Presenilin 1 and 2, for example.  The interesting thing is that most of these genes affect APP (Amyloid-Beta Precursor Protein), which is cleaved (cut into a smaller piece) to become amyloid-beta. 

It is important to note that amyloid-beta is a normal protein and even with normal aging, there are some amyloid-beta plaques that form.  This makes it extra complicated.  It seems that it might have to do with how amyloid-beta is cleaved (the lengths of the protein once it has been cut normally) and how well it is broken down that might lead to this normal process becoming Alzheimer’s.  There is some evidence that ApoE might help breakdown amyloid-beta and that the e4 allele might not do it as efficiently as the other variants of ApoE, which leads to pathological build up and widespread amyloid-beta plaques.  It isn’t entirely clear at this point, however.

I’ve also added a picture to help show the Alzheimer’s brain and degeneration that occurs in the disease progression (above).  It’s pretty marked post-mortem (after death), as you can see.

[Image Source]

This is a pretty good explanation of ApoE4 as a risk factor for Alzheimer’s Disease. I’d only add that although amyloid is a “normal protein,” in the sense that our brains make it and degrade it, the oligimerization (when a bunch of amyloid gets together) of amyloid and the formation of plaques are NOT a normal part of getting older - they just show up 10-15 YEARS (!) before symptoms begin, so there’s still lots of time to die from other things before Alzheimer’s starts making you forget stuff.

Also, that paper about ApoE helping to degrade amyloid they cited is from my lab! There’s so much more to the story about apoE being a risk factor for the disease and it’s SUPER INTERESTING and it mostly boils down to a story about CHOLESTEROL and how ApoE4 is worse at carrying it around than the other forms of ApoE.

4 months ago

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    feel smarticle re-bloging...^^ —I’ll read...later though..i...
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    pretty good explanation...although amyloid is a “normal protein,” in the sense
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