Gene editing solution not far away?

[J11]

Given the above reasoning, a total collapse of fertility should be expected.

[Verax]

https://files.eric.ed.gov/fulltext/ED023722.pdf Arthur R. Jensen: "How Much Can We Boost IQ and Scholastic Achievement?" (Oct, 1967) Intelligence (or "g") is usually considered a subset of mental ability,. Computers have mental ability and can even mimic human abilities (Turing test) but what we are talking about here is the cognitive reserve considered important to delay or prevent the particular memory component failures characteristic of Alzheimer's dementia. External memory aids such as computers or smart phones or big data can help, and gene editing might also someday, but I feel we cannot count on The Singularity or eugenic projects or a single drug cure.

[J11]

What seems so surprising is that we have already reached the Genetic Singularity and there appears to be so little popular recognition of what is currently occurring. The Nature Genetics article that will soon be published discloses over 500 points of Educational Attainment. It should be clear to all that we are now right at the edge of truly profound social change.

Once fertility collapses possibly to 0, it will no longer be possible to ignore anymore. A certain level of panic will result when parents realize that their children who were born just before the intelligence uplift will be completely unable to compete with those who were enhanced.

[floramaria]

Risky, especially at first. And expensive. And society will have to male some big decisions about it. But it'll do a lot more than diet and exercise ever will.

Since ApoE4 is just one risk factor and not a determinant, I am not convinced that editing it out will "do a lot more that diet and exercise ever will". Many people without an ApoE4 allele develop AD. For example, the AD subtype Dr Bredesen identifies as driven by toxicity is not linked to ApoE4 status.
Looking at the world from my own particular perspective, society having some big decisions to make about how this technology will be employed is not reassuring.

[LG1]

I have been absent on this forum for a long time, perhaps a year or so. J11 and I used to do a bit of back and forth with a very fascinating Alz snp list. That was very interesting. A user friendly version was never fully published by the research team unless I am unaware?

I have not had the opportunity to enjoy a discussion on what I find incredibly promising which is Dr. Huang's Gladstone study using CRISPR technology: https://gladstone.org/about-us/news/sci ... alzheimers I am sure all of you are aware of it. Has there been a lot of discussion in the forums? Could someone here point me to that discussion?

I sometimes wonder if there is a coloring of one's ideas/ideals based on one's own situation. For instance, I find the Gladstone project to be extraordinarily hopeful. Being a female with both 4/4's and in my early 50's I am thrilled. Am I overlooking the potential abuse of the technology? Well I am personally pretty secure in my values. I look at my life in light of my daughter's and other people's children, family members. Future society will make their own decisions. We cannot ignore this or dismiss as it is here and not going away.

This technology as you know is already happening with Cystic Fibrosis, Genetic Eye Diseases, many more and Alzheimer's is right around the corner. Turning my misshapen 4 to a happy 3 in my dreams.

Maybe there is a luxury looking at it from a safer place. Do those with only one 4 and male feel safer? Does that make a difference in where they come from having these discussions?

In my absence I have been on another intense project, looking into my ancestry. This is a vast and almost never ending project as both sides of my family have been in America since the very beginning, 1620's on.

I came across my father's side a few generations back of which I of course have inherited one 4 and found a pattern of dementia.

Yes I think we always strive for the best in science. Policing morality is very difficult. I have faith in humanity.

[Fiver]

Hi LG1. I also read Dr. Huang's Gladstone study using CRISPR technology with great interest. I wish society would have a reasonable debate about issues like this, but that's not how it has worked in the past. Someone, somewhere will move forward. Having said that, I think this issue is a lot less worrisome than some others. First, changing one amino acid in a naturally-occurring protein to change it from E4 to E3 is really very minor compared to engineering organisms with entirely new genes or whole pathways and releasing them into nature. It doesn't invent anything new. And it doesn't change the germ line. And the benefit, at least in the Gladstone studies, seems absolutely huge.

I think you're right: folks with lower risks probably don't have the same sense of urgency. But they might not want the healthcare system to collapse from the future costs of dementia care. In the end, there will be only two types of people in the future - those who suffer from dementia and those who pay for care, one way or another.

[LG1]

Fiver, it is comforting to know there are others with a strong interest in this specific use for CRISPR. I am fascinated.

I will be watching for Dr. Huang/Gladstone's next step. I plan on approaching these and other experts in this research via email to find more information on what is in store soon. If I hear back from them I will share here.

[J11]

LG1 welcome back to the forum!

I am so excited about what is happening now in IQ genetics!!!
I have no idea how we will be able to navigate through the next 5 years.
For many of us the extreme social disruption that is now clearly imminent will happen well before dementia sets in.

The latest and soon to be published GWAS research has found 37 SD of Educational Attainment.
37 SD of IQ would be over 500 IQ points. It is not accurate to compare Educational Attainment and IQ in this way,
though at the same time it would be equally inaccurate to suggest that the current findings have not revealed a great deal of
the genetic architecture of IQ.

It seems highly likely that once this research is more widely appreciated that there will be a range of disease communities that will champion this technology so as to create the cures and the treatments for their loved ones that we have been unable to create even after many decades of intense effort.


The research is filling in more and more of the AD genetics.

However, I continue to be surprised at how much of the genetics of Alzheimer's still remains undiscovered and how little initiative appears to be devoted to find the remaining pieces. For example, some rare Sorl1 variants have recently been found to be causative for AD. Yet, the larger scale exome/genome studies that would find all the large and intermediate risk variants for dementia still have not been done. The recently identified rare Sorl1 variants represent 2% of AD. Why is it not recognized that such discoveries have large social relevance? The payback for this discovery will be enormous. Why is it not more of a priority to identify yet more of them?

I also find it quite odd that the below url notes that it is difficult to fill in AD genetics because some family members do not want to participate etc. I certainly understand this problem. However, I am not sure why they did then not go to GEDmatch. They could find relatives on the known DNA stretch and then contact them. It would be somewhat awkward in terms of privacy, some people would not want to know, though I would think that there could be a reasonable why to accommodate such viewpoints.

Having the intermediate and high risk AD genes would be a great help to me. Even with the below url, I was able to consult our exome file and find variants of interest for 2 of the 4 genes noted in the research. When you have 60,000 variants to choose from almost any gene could produce a plausible variant. For the latest 4 genes, SORL1 gave a rarish variant within 150 bp of one of those mentioned, GRID2IP gave 2 rare variants none of which had rs numbers, though they were both of low quality while Mutation Taster called them both as disease causing. With this information I could go onto GEDmatch and find relatives who shared these stretches. It is a very easy process. If I could be told the 20-50 or so genes that substantially increase AD risk, I would probably be able to rapidly figure out the cause of our dementia.

https://www.alzforum.org/news/research- ... mers-genes

It is also disappointing that the HEX database only has 500 people sequenced. This is very difficult for me to understand. It would not be only the lobbying voice of the dementia community; Every single genetic diseases community would benefit from an online database of healthy people variants. A database of perhaps 200-300,000 people would give everyone valuable information about their genetic risks by eliminating the very large number of variants that have no obvious role in illness. Typical exomes VCF files have between 50-100,000 variants. This makes actually finding even a causative AD variant through individual efforts almost impossible. I would guess that nearly all of the variants (perhaps 98%) that are in a typical exome/genome could be easily identified as non-causal if a large scale Healthy exomes database were available. It is possible that this resource does already exist, though I am not aware of it.

https://www.alzforum.org/exomes/hex

Notwithstanding my above comments, there is a concern that we are moving to the time in which genetics will be highly predictive.
Up till this point the simple-minded conception of genetic technology being able to predict many of the common illnesses (including Alzheimer's) has largely been unrealized. Most illnesses (including AD) are highly polygenic and even a single epsilon 4 only adds risk; it is not causative. In fact, epsilon 4 is one of the intermediate risk variants that is common. Yet, in my family a single epsilon 4 did not seem to contribute to AD risk.

What happens when AD risk can be accurately predicted with a polygenic score? How will our society respond to such knowledge?
It should be obvious to all of us that these are no longer hypothetical questions. Human genome sequencing now costs about $700. At a price point of $100, genome sequencing will be wide spread. It is not entirely unreasonable to expect that the $100 genome is not that far off in the distance.

LG1, I am not sure whether you are aware, though Right to Try is now the law of the land. This could be of considerable help for the AD community because typically CRISPR and almost any other new technology that might be of help to those at risk for dementia probably would be on a time line of decades (possibly a few). All of us have watched the years recede and potential treatments appear to remain stationary. The years become decades and still there is often little or no progress; at most there might need to be yet more clinical studies. Right to Try does offer some hope, though with CRISPR one might perhaps like to be more cautious than is allowed by the law ( especially if one had a time cushion).

Aside from CRISPR there is also the anti-oligos that are moving ahead.
https://www.alzforum.org/news/research- ... -av-spigot

This is interesting LG1, how you found e4 dementia in your father's line. The expression of e4 dementia through generations is probably different from what my family has experienced. I am not completely sure, though I would guess that typical e4 dementia families would not have a clearly observable dominant style transmission pattern. In most instances within families, most would only have a single e4 and for males this might not result in a great deal of dementia risk. Of course, as happened in my family, there does seem to be AD assortative mating. For those who want to make informed genetic choices, this will no longer need to be a haphazard random process.

What is very very odd is how unaware most people appear to be about their family histories much beyond 2 or 3 generations. Most of the relatives who I contacted that did not have direct experience with demented family members had no awareness that in a broader context such dementia was clearly present. When I moved out to the level of 4-5 generations, the pattern became self-apparent.

[SusanJ]

What is very very odd is how unaware most people appear to be about their much beyond 2 or 3 generations. Most of the relatives who I contacted that did not have direct experience with demented family members had no awareness that in a broader context such dementia was clearly present. When I moved out to the level of 4-5 generations, the pattern became self-apparent.

When you looked out into further generations, were you looking at heart disease, too? Some of my dad's relatives never made it out of their 50s because of heart attacks. Those folks might well have gone on to AD had they lived.

[J11]

Very good point SusanJ!

It was not so much heart disease on our main non-e4 line as some sort of a mystery illness. My best guess is some form of epilepsy.
Many of these relatives might then have gone on to dementia. It is still surprising how even close family seem to be largely unaware of the genetic pattern. Given today's smaller family sizes people might need to look back even further.

Once the AD genome unlocks, I suspect there will be a substantial number of people who will be surprised at their actual level of dementia risk. There should be a doubling in the number from our current e4 subpopulation. It is very scary to realize that in today's technology environment people will bring children into this world without being fully informed of the genetic medical risks involved.
We really need to begin the conversation and provide the resources and guidance so that the next generation can make fully informed genetic choices of the children that they will bear.

One major distinction that perhaps has not been emphasized enough on the forum is that non-e4 dementia likely acts more of a genetic attractor for a range of unrelated phenotypes. My guess is that with e4 dementia it is not as prominent. So, in one generation there might be an e44, then in the next generation there might be males with a single e4. It would be very interesting to have research that looked into this lived experience of dementia. Dementia from outer space occurs much more commonly than one might typically imagine. The polygenic nature of AD could entirely obscure the risk. For these families, they have no reference points for what an appropriate care-giving approach might be.