Apoe4 /4 a new genetic variant of Alzheimer’s ??

Insights and discussion from the cutting edge with reference to journal articles and other research papers.
Fiver
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Re: Apoe4 /4 a new genetic variant of Alzheimer’s ??

Post by Fiver »

Hi Glampers. Nice to “meet” you. 🙂. Thanks for the positive thinking!

I’m hopeful about the Lexeo trial. Just the fact it targets apoe4 directly is exciting.

I think about ALZ-801 in a slightly different category. Exciting but different because, as you know of course, it works by attacking AB and/or via GABA signaling. Even though the benefits were observed in apoe4s it doesn’t directly impact the apoe4 protein or gene.

It’s actually good to have drugs working in different places and ways, of course, because in theory we could use them together.

I just feel like there should be more trials, more companies, involved. Like with the -mabs. Or before that with statins. Every big company wanted one. Sure, it’s selfish in part. And I’m not as young as I was, so I don’t have all the time I did. But also not all of the trials will work and competition speeds things up.
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Re: Apoe4 /4 a new genetic variant of Alzheimer’s ??

Post by Glampers »

>I just feel like there should be more trials, more companies, involved. Like with the -mabs. Or before that with statins.

Couldn't agree more. And not a selfish opinion at all, when you think about how much AD robs from individual people and their families, and how much it costs the healthcare system.
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Re: Apoe4 /4 a new genetic variant of Alzheimer’s ??

Post by TLS »

As the daughter of a Mom who is 4/4 and who has Alzheimer's starting at age 68, I found the article to be both distressing and hopeful. Distressing because it describes what I am experiencing with my mother.

Hopeful because we can't fix what isn't measured. We can't address a specific risk when APOE 4/4 is lumped in with APOE 3/4 because it impacts the statistics. If we want progress then it is important to start to pinpoint treatments and lifestyle factors geared toward the 4/4 which may need to be different from the rest of the population.

Also hopeful because in my loved one's case there are so many additional cofactors that led to the disease. It is not just the 4/4 gene (in my opinion). Multiple genetic SNPS impacting choline, thyroid, liver function, etc. They also worked in a factory. Dental issues, high blood pressure, bad thyroid, and so on.

I am also following the ALZ-801 trials with hope. There are interesting developments in the immunity area too. I feel we are on the cusp of meaningful developments in science and lifestyle. We can do things to improve our lives and chances of not getting the disease.

Finally, I appreciate everyone's posts. I found it helped me work through the sadness the article made me feel initially. Nancy's posts are always measured and pragmatic!
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SusanJ
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Re: Apoe4 /4 a new genetic variant of Alzheimer’s ??

Post by SusanJ »

In addition to the explanations so far on this thread, I thought this was a well-written summary of the process and findings, along with comments from other researchers to put it into perspective.

And here's a quote I wanted to highlight, because we already know that merely having amyloid and tau does not mean you will have symptoms.
"Gaël Nicolas and Camille Charbonnier of Normandie University in Rouen, France, believe the findings convincingly demonstrate that APOE4 homozygosity leads to AD biology with near-full penetrance. However, they emphasized that about half of these will not develop dementia by age 85. “That is very important to keep in mind when dealing with such a concept in the clinic, especially with asymptomatic individuals,” they wrote. “In other words, penetrance of AD biology is not penetrance of AD dementia
https://www.alzforum.org/news/research- ... alzheimers
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Re: Apoe4 /4 a new genetic variant of Alzheimer’s ??

Post by seltzaman »

LondonGirl wrote: Mon May 06, 2024 10:44 am https://www.nature.com/articles/s41591-024-02931-w


This article claims that apoe4 homozygosity repreeenrs a distinct form of the disease. It also claims that onset averages at age 65 and almost all homozygotes will suffer from it.

Does anyone have any response ?
Almost everyone in my paternal family had lost their ADL capabilities by the time they were between 70 and 75. My dad, his brother, their mother, her sister (my great aunt) and further back as well. Those two generations were diagnosed with Alzheimer's, while the prior generations were simply "dementia" for lack of enough knowledge in those days. Of all of them, I am the only one who got my genetic profile, and it's probably not just a coincidence that I indeed have two copies of APOE4. The claimed 95% figure at age 65 comes as no surprise to me having watched everyone in my family fade away at the same time of life. While in excellent physical health, I had to quit my job a few years ago as I could no longer keep track of all the details, and maintain the needed conversations with clients. I can still write well because I can take the time to find the words and recompose, but conversing in real time is frustrating at age 67. There's an "N=1" response for you.
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Re: Apoe4 /4 a new genetic variant of Alzheimer’s ??

Post by Lyre Taylor »

seltzaman wrote: Fri May 10, 2024 8:59 pm Almost everyone in my paternal family had lost their ADL capabilities by the time they were between 70 and 75. My dad, his brother, their mother, her sister (my great aunt) and further back as well. Those two generations were diagnosed with Alzheimer's, while the prior generations were simply "dementia" for lack of enough knowledge in those days. Of all of them, I am the only one who got my genetic profile, and it's probably not just a coincidence that I indeed have two copies of APOE4. The claimed 95% figure at age 65 comes as no surprise to me having watched everyone in my family fade away at the same time of life. While in excellent physical health, I had to quit my job a few years ago as I could no longer keep track of all the details, and maintain the needed conversations with clients. I can still write well because I can take the time to find the words and recompose, but conversing in real time is frustrating at age 67. There's an "N=1" response for you
Hello! Welcome to this site. I truly understand that you’ve faced serious challenges, especially with so many family members affected by cognitive decline. I’m genuinely sorry for what you’ve been through. Your input here on this platform is greatly appreciated. You’ve found a supportive community, and I want to assure you that you are not alone. This is a place where we learn from each other and strive to grow together. Your commitment to writing and taking the time to find the right words is commendable.If you haven't already checked out apoe4.info, as a Support Team Intern I'm happy to share several tools & resources to help you get the most out of your experience here. The Primer is a detailed and informative resource written by a practicing M.D. with ApoE4/4. It includes information about the biochemistry of the ApoE4 gene and offers a variety of research-based prevention strategies.

Some helpful tips to navigate the site include the How-To Guide. It includes topics such as navigating the forum, private messaging, and searching. One great tip is using the quote (") button when replying to a post. Using the button will automatically alert the member of your response.

Wiki Main Page contains a wealth of information.

If you are interested in learning more about other members check out Our Stories.

Again, Thank you for connecting with us. We are always here for you. Please feel free to reach out anytime.

Warmly,
Lyre
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Re: Apoe4 /4 a new genetic variant of Alzheimer’s ??

Post by TheresaB »

FYI, this paper was shared on May 8th on our sister Facebook website, https://www.facebook.com/apoe4.info, which should be accessible to all whether or not they have a facebook account.

Needless to say, this post attracted a number of comments, here is what Dr Dale Bredesen wrote about this paper in his comment to the facebook post,
Dale Bredesen, MD
I think it is important to remember that this study did not include people who were on active prevention, or who had utilized a precision medicine protocol to reverse their cognitive decline. So this study is a "natural history" study for the many on standard diets and lifestyles. We have seen, and published, repeatedly that many with ApoE 4/4 can avoid dementia and improve cognition sustainably. It would be of great interest for ApoE4.Info to survey the many members with ApoE 4/4: how many are asymptomatic, how many have SCI, how many with MCI, and how many with dementia? The new p-tau 217 tests should help to support the notion that dementia is NOT inevitable with ApoE 4/4, and ApoE4.Info could go a long way toward showing that this new study does not apply to those who are doing optimal prevention or treatment.
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Re: Apoe4 /4 a new genetic variant of Alzheimer’s ??

Post by NF52 »

TheresaB wrote: Sat May 11, 2024 6:37 am FYI, this paper was shared on May 8th on our sister Facebook website, https://www.facebook.com/apoe4.info, which should be accessible to all whether or not they have a facebook account.

Needless to say, this post attracted a number of comments, here is what Dr Dale Bredesen wrote about this paper in his comment to the facebook post,
Dale Bredesen, MD
I think it is important to remember that this study did not include people who were on active prevention, or who had utilized a precision medicine protocol to reverse their cognitive decline. So this study is a "natural history" study for the many on standard diets and lifestyles. We have seen, and published, repeatedly that many with ApoE 4/4 can avoid dementia and improve cognition sustainably. It would be of great interest for ApoE4.Info to survey the many members with ApoE 4/4: how many are asymptomatic, how many have SCI, how many with MCI, and how many with dementia? The new p-tau 217 tests should help to support the notion that dementia is NOT inevitable with ApoE 4/4, and ApoE4.Info could go a long way toward showing that this new study does not apply to those who are doing optimal prevention or treatment.
I actually know some people who were in the ADNI study and A4 Study, although possibly not this iteration, since ADNI has had three prospectively-followed cohorts and is now enrolling a fourth, with an emphasis on enrollment of under-represented groups. They take prevention seriously--auditing college classes, eating a Mediterranean diet, learning a new musical instrument, relearning a HS language.

I've also listened to people connected to the WRAP (Wisconsin Registry for Alzheimer's Prevention) Study, another cohort, with the word "Prevention" a key focus of efforts in diverse communities. Of note, their results do suggest that even without a "precision medical approach", these people are changing the story of the people in the NACC cohort. At an average age of 69 for ApoE 4/4 carriers, with a 7-year standard deviation (i.e. 62-76 years of age) 57% were "healthy controls", 22% had MCI and 21% had AD upon initial enrollment.

What was really lost in the news articles was that this study looked at "biological penetrance" in these clinical cohorts--using amyloid, tau and hippocampal volume to look for evidence of a process happening years or decades before symptoms of MCI or AD--or before death occurred.

This finding is important, I think:
By age 65, nearly all APOE4 homozygote participants show abnormal levels of CSF Aβ1–42 and 75% had positive amyloid scans. The biological penetrance of AD increased with age for the other biomarkers, reaching 88% for all amyloid and tau biomarkers at age 80, despite the selection bias in this population toward cognitively unimpaired individuals
A survey of apoe4.info user would be neither random nor imply that we are all following the same protocols, nor have the same demographics. It especially wouldn't show how many of us have elevated amyloid or tau. And having those would not predict at what age we might show cognitive symptoms.

I think it may be beneficial to agree that "no one size fits all" and that biomarkers for ApoE 4/4 carriers are meaningful and that lifestyle and interventions are also very important.. https://www.nature.com/articles/s41591- ... ardian.com
4/4 and still an optimist!
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Re: Apoe4 /4 a new genetic variant of Alzheimer’s ??

Post by Fiver »

Well said NF52

I don’t think we need many more studies measuring the risks of apoe4.

We all agree the risks are high enough to warrant more attention.

Whatever risk numbers one plugs into the equation, the development of apoe4-specific medical interventions would help tens of millions.
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Re: Apoe4 /4 a new genetic variant of Alzheimer’s ??

Post by Julie G »

A survey of apoe4.info user would be neither random nor imply that we are all following the same protocols, nor have the same demographics. It especially wouldn't show how many of us have elevated amyloid or tau. And having those would not predict at what age we might show cognitive symptoms.
Great post, NF52. However, I think you may have misunderstood the gist of what Dr. Bredesen was suggesting. My guess is that he was interested in surveying a group of people who were aware of their ApoE4 status and chose to intervene in some way as opposed to those who engaged in longitudinal observational studies without formalized intervention. He mentions the new p-tau217 test as a way of helping to gather this information. IF enough of us 4/4s were to engage, we could either help to confirm or rebut this new hypothesis.
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