Celebration Thread! Biogen is going to the FDA with Aducan.

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J11
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

Postby J11 » Wed Apr 07, 2021 6:54 pm

NF52, do you know of any online AD mouse databases? It would be best to not reinvent the wheel if this can be avoided. It was only recently that I heard of research into what might be our specific family AD gene. I suppose that the lab then starts by designing some CRISPRed mice.

I actually was quite surprised how easy it was to find this suspected variant.
I took an exome file; loaded it up to the CADD site and then it reported back a few thousand variants of interest.
There might have been about 200 fairly high CADD readings, and possibly about 50 very high readings.
The big problem with the CADD software is they did not include MAF, so this made it somewhat tricky.
Though I was able to find this data.

What was interesting was that there was a frameshift mutation with a CADD over 30.
This seems to be the one. Super rare and published research linking it to AD.
I can now go online and find a whole bunch of reality with this same segment.
I am moving to full genome sequencing, so I think it would be a good time to start
pushing some relatives to also confirm that they have this variant.
It would probably be an easier sell if I could direct them to a $50 high read exome sequence, though I am unsure whether
these are on the market. The current alternative wold be ~$300 whole genome sequence which for some would be pricey.

It might be worthwhile thinking about how our forum could help enable others to go through this research. Perhaps we could give the instruction for those to follow, ask them to provide epsilon 4 gentoype, polygenic score and then post their CADD results on a thread on APOE4; if possible we could allow people to do this anonymously without recording their IP address. I find it exciting that
we might be able to help unravel the genetics of AD through such an effort. This could be even more powerful if multiplex AD families uploaded their results. The variants of interest might quickly become obvious.

The million AD snowflakes was more of a personal dread. APOE e4s have been so fortunate to have an entire political lobbying arm based upon the tens of millions of epsilon 4 carriers. There are a select few illnesses that have a bypass budget (cancer, AIDS and AD). It is a rare thing in politics to have bipartisan agreement on anything; yet there is for AD.

My concern though is that at some point this magic might run out. For all of the thousands of others of medical problems it did.
Specifically, what happens as we move away from the core shared feature of amyloid and tau? The newest GWAS that you cited, included synaptic function etc.. The problem that might arise is that there might be a whole bunch of such additional brain vulnerability pathways that branch out into endless complexity.



Thank you for the SNP!
Yes, I could be absolutely swamped when they drop that 100 gigabit file on me.
It is hard to imagine not being swamped with 100 gig.
I expect that the majority of those who receive their full genome scan after about a week curl up
into the fetal position and go on a chocolate binge. How could it possibly make any sense?
That is where the polygenic software etc. will be helpful.
Most of the variants probably will have minimal relevance.
However, when yo add them up into a PGS then an IQ estimate might emerge etc..

This is a step into the future.
It is one of those look in the mirror moments that one would rather avoid.

How smart am I?
How mentally stable?
Society will be genetically organized by these results.
Unselected school rooms might not be sustainable even over the next 5 years as full genome sequencing goes
mainstream. The future is approaching -- fast.

I have some idea from my own awareness, but what does my genome say?
It is a profound time of personal discovery that has never been possible until now.
In previous times when people tried to know themselves they were not able
to have some objective readout that gave polygenic scores on every feature of their being.

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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

Postby J11 » Thu Apr 08, 2021 8:00 pm

One of the aspects of the aducan trials that perhaps has not been emphasized enough on this thread is that 0.372 SUVR is the end of the road. 0.372 SUVR = 0! This may or may not be actually true, though as of now that is what is on the table.

We can complain all we want, but there it is. We can't extrapolate to higher levels of amyloid levels because 0.372 is considered to be 0.

How does this relate to the discussion? Well all those who might be saying "22% is not acceptable", seem somewhat silent on the fact that with 0.372 as the top (actually it's the floor; can't go below 0?) we can only go to ~0.47/1.77 = ~27%. I doubt if anyone really wants to argue with the ~100% regression line that was calculated on this thread. Over the last decade or so at least 3 anti-amyloids
are nearly exactly where the line predicts they should be. We can't be 100% sure, though ~0.47 CDR-sb at 0.372 SUVR is what the extrapolation is currently suggesting. It is very unclear to me what is supposed to magically happen if we were to hit this topline CDR-sb of ~0.47. That's the best it's going to get. Would the "it's not acceptable" crowd, still say it's not acceptable? What then? What happens when the best it can possibly be is still not good enough for them? If they did find ~0.47 acceptable, then why/how exactly could 0.39 be unacceptable?

All these pharma companies have developed a number of what could fairly be described as me-toos anti-amyloids and they are presumably quite aware of their efficacy limits. Wouldn't the concern be that the best possible result could be rejected as not good enough?

Doesn't this whole mentality speak to the assumption that problems have readily discoverable solutions? As long as you are a nice person and work hard then you deserve to pass? Yet, the "I'm entitled to pass because I'm nice" card has not been honored over the last 20 years in AD. There has been many decades of what can rightfully be described as non-success. What success there has been could reasonably be described as a labeling mistake.

All of which is to say that we should be grateful with the 22% because this is a hard problem and pretending otherwise does not change this reality. It also speaks to the idea that effectively treating AD might require a multi-step regimen (i.e., drug cocktails). We max out anti-amyloids, then it is time to move on to plan b. It is a great mystery to me what other possible strategy might be contemplated instead of this rotation to plan b. Are we supposed to protest reality until such time as we have had sufficient opportunity to lodge our objection and then... and then move on to plan b? Personally, I would find anything other than accepting reality now and moving to plan b immediately to be unacceptable.

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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

Postby floramaria » Sat Apr 10, 2021 9:52 pm

J11 wrote:Yes, I think that we now need to be aware that genetic uplift is starting.
Life will never be the same.

Natural reproduction is no longer plausible.
Might not be that long before it is illegal.
The idea of simply spinning the genetic roulette wheel is already absurd.

Human traits are polygentically determined and using embryo selection will rapidly and dramatically change the nature of humanity.
That’s for sure

“The first eugenic generation is probably already emerging and will likely be quite appalled with us unselecteds.”
Some of us “unselecteds” will quite likely be equally appalled by the eugenic generation if we live long enough to see this. You always have such an optimistic view of how this turns out for humanity. I don’t doubt that you are right that humans will find it irresistible to engineer embryos and select the characteristics they believe are best. I just don’t have your confidence that this is a good thing that turns out well.

Human being understood as genetically uniform and specified. This probably will be a tough one for people to cope with, though it is the logical expectation given economic efficiency.[/quote]. Uh...yeah. As a representative “person” I can say this is a tough idea for me to cope with. I don’t expect I’d do much better with the realty of it.
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J11
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

Postby J11 » Sat Apr 10, 2021 10:50 pm

Thank you for responding floramaria.

Yes, I am not totally sure how we will be able to cope with a whole bunch of stark raving normal types.


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