ApoE 2/4

Alzheimer's, cardiovascular, and other chronic diseases; biomarkers, lifestyle, supplements, drugs, and health care.
Jlhughette
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ApoE 2/4

Post by Jlhughette »

We just found out my sister has ApoE 4/2 which was surprising as she has had diagnosis of AD since age 57, probably started around age 47. ( now age 59) I always assumed E2 was neuro protective but a risk factor for heart disease and diabetes. Her current numbers are all very good except high cholesterol HDL which we were not too concerned about. She has not gotten worse since being on the Bredesen protocol and her numbers have all improved. But when we stopped hyperbaric treatments for 2months she had a noticeable ( to me) decline, especially with knowing where to place her limbs or get up off the floor, yoga, or get money out of her wallet, as examples. She was diagnosed with type 2 AD . ( I have written about this before). So we are back doing hyperbaric treatments, though it is not part of her protocol.

Her decline into AD was surprising to us all as she was one who always ate carefully with mainly veg and olive oil for years, very little carbs and small amounts of protein, and is very fit and slim.

I’m wondering what else to explore genetically to explain her difficult case? Any info at all appreciated.
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Harrison
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Re: ApoE 2/4

Post by Harrison »

57 years old is quite young for an Alzheimer's diagnosis, and the science around the impact of apoE on AD (either E2 or E4) before the age of 60 is a mixed bag. With a strong family history of Alzheimer's disease, particularly if the cases are before age 65, I would look at some of the familial AD genes, such as APP, Presenilin 1, and Presenilin 2. I believe 23andMe tests for most of these.
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Re: ApoE 2/4

Post by slacker »

My understanding is that younger people are more likely to have "toxic" type 3 AD per Dr Bredesen's categorizations. Has your sister been tested for CIRS and heavy metals? (I apologize if you have already mentioned this in a prior post)
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Jlhughette
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Re: ApoE 2/4

Post by Jlhughette »

Hi Slacker and Harrison,

She has been tested for CIRS and heavy metals extensively and that does not seem to be an issue. I don’t know about presenilin 1 or 2 or APP. I await 23 and me results. The ApoE status was taken by a neurologist by blood. There is a pattern of AD in the family, but she is the first under 65. The others started having signs in their early 80s. Her tests revealed extremely low thyroid and lots of other important hormones, which is resolving well. But she still has definite amnestic memory loss, and limited executive function. She was an excellent musician and flutist and now cannot play, which is different from other musicians I have known with late stage AD but could still play their instruments.

Can anyone recommend a good genetic analyst?

Many many thanks for your replies!
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NF52
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Re: ApoE 2/4

Post by NF52 »

Jlhughette wrote: There is a pattern of AD in the family, but she is the first under 65. The others started having signs in their early 80s. Her tests revealed extremely low thyroid and lots of other important hormones, which is resolving well. But she still has definite amnestic memory loss, and limited executive function. She was an excellent musician and flutist and now cannot play, which is different from other musicians I have known with late stage AD but could still play their instruments.
Hello, jlhughette,

Like others here, I am so sorry for your sister's recent diagnosis of Alzheimer's disease at age 59. As someone with a sister who also has struggled with mental health issues for decades, I know that it has been linked to an increased risk of cognitive changes, and earlier onset of dementia. It sounds like your sister's language skills are still strong, but her executive functioning (planning, following through on steps needed to achieve stated goals, organization, time management, self-monitoring and task-monitoring) are all strongly affected. Those are also areas often affected in depression, and it may be that your sister compensated for some executive function difficulty for much longer than anyone realized. If so, it may be helpful to think of her as running a marathon with ankle weights and all uphill for the last several decades. As frustrating as my own sister has been at times (okay-most of the time) I realize she has often had far greater headwinds that I have.

It's possible that once you get your sister's 23&me results (with her permission, I hope) that you can run them through Promethease and see if there are additional genetic risks identified. It's also possible that the science to answer your question is still evolving, although at a faster pace than even 5 years ago. Here's an excerpt from a free article that I found fairly reabable, as a non-scientist, that explains the growing recognition that "sporadic" Alzheimer's doesn't just occur after age 65, and all cases of early-onset Alzheimer's disease (EOAD) before age 65 are not from autosomal dominant genes. In other words, your sister may have a unique combination of genes, combined with other factors, that caused her to have this diagnosis so early. Knowing that won't make it easier, but it might help to realize that it likely wasn't her fault in the choices she made in life.

By the way, many of these genes are either not specified or not analyzed by 23&me. Rather than pay a geneticist for a whole-genome sequencing, have you considered getting a university memory center clinic to do a thorough baseline evaluation of gross and fine motor skills, cognitive skills, daily living skills, language skills and behavioral functioning, along with an MRI, which might identify whether she shows white matter disease (below the level of the cortex, and so not part of AD) or microbleeds? Either of those might lead to different thoughts on progression and/or management.

[Emphasis added by me in the quote below.]
The proportion of cases of autosomal dominant AD explained by mutations in these genes is high but vary widely from 12% to 77% [16, 17], suggesting that there are additional genetic factors involved in the pathogenesis of EOAD.

Another study [19] identified mutations in the Sortilin related receptor 1 (SORL1) gene in EOAD. This gene encodes a neuronal sorting protein able to bind APP, driving it toward the endosome-recycling pathways [19]. Other studies involving EOAD found association between the Triggering Receptor Expressed on Myeloid cells 2 (TREM2) gene and the risk of develop the disease. TREM2 is an immune phagocytic receptor expressed in brain microglia, able to modulate microglial phagocytosis and inflammatory pathway [20].

By using a NGS WES based approach, an association between TREM2 variants in exon 2 and EOAD in Caucasian subjects of French origin was identified. In particular, an association between rs75932628T allele (R47H) and the risk of developing the disease was described [21]. The same variant was further confirmed to be a risk factor for EOAD in a recent study [22], which showed that individuals with the R47H variant had significantly earlier symptom onset than individuals without TREM2 variants [22]. TREM2 genetic variability has been investigated also with regard of LOAD susceptibility by different groups. Jonsson et al. [23] found that the rs7593628T in TREM2 confers a significant threefold increased risk for AD in a cohort of Icelanders.
Role of Genetics and Epigenetics in the Pathogenesis of Alzheimer’s Disease and Frontotemporal Dementia

I hope that you, your sister and your extended family reach out for supports within the community as you travel this unexpected path. Hugs from Virginia.
4/4 and still an optimist!
Jlhughette
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Re: ApoE 2/4

Post by Jlhughette »

NF52 wrote:
Jlhughette wrote:
Hi NF52

I am thrilled to have received your thoughtful reply. It is not the first time you have done so. Thank you.

In response, I do have my sister’s permission to receive her 23&me results. I also have POA status which I needed to obtain for legal matters. I am prepared to run her raw data through Promethease but other than the identification of SNPs and other genes I am not sure then what to do with the information, which leads me to want to talk with someone with experience in interpretation. When I read the study you sited, I had only the most general broad brush understanding of the concepts. Much of the terminology is over my head.

My sister did have her diagnosis at a university memory care clinic. She had cognitive tests and MRIs in 2011 and 2016 and 2017. In 2011 they attributed her troubles to depression, she did not have cell loss in the brain and she passed all the tests. By 2016 there was a big change, and a further decline in 2017. I am hoping she has at least stabilized since being on the Bredesen protocol and we will find out this fall.

I so apppreciate your sharing of your experiences with your family members and sister. I hope you continue to write down your stories and knowledge, and share when you can!

Hugs




“ It's possible that once you get your sister's 23&me results (with her permission, I hope) that you can run them through Promethease and see if there are additional genetic risks identified. It's also possible that the science to answer your question is still evolving, although at a faster pace than even 5 years ago. Here's an excerpt from a free article that I found fairly reabable, as a non-scientist, that explains the growing recognition that "sporadic" Alzheimer's doesn't just occur after age 65, and all cases of early-onset Alzheimer's disease (EOAD) before age 65 are not from autosomal dominant genes. In other words, your sister may have a unique combination of genes, combined with other factors, that caused her to have this diagnosis so early. Knowing that won't make it easier, but it might help to realize that it likely wasn't her fault in the choices she made in life.

By the way, many of these genes are either not specified or not analyzed by 23&me. Rather than pay a geneticist for a whole-genome sequencing, have you considered getting a university memory center clinic to do a thorough baseline evaluation of gross and fine motor skills, cognitive skills, daily living skills, language skills and behavioral functioning, along with an MRI, which might identify whether she shows white matter disease (below the level of the cortex, and so not part of AD) or microbleeds? Either of those might lead to different thoughts on progression and/or management.

[Emphasis added by me in the quote below.]
The proportion of cases of autosomal dominant AD explained by mutations in these genes is high but vary widely from 12% to 77% [16, 17], suggesting that there are additional genetic factors involved in the pathogenesis of EOAD.

Another study [19] identified mutations in the Sortilin related receptor 1 (SORL1) gene in EOAD. This gene encodes a neuronal sorting protein able to bind APP, driving it toward the endosome-recycling pathways [19]. Other studies involving EOAD found association between the Triggering Receptor Expressed on Myeloid cells 2 (TREM2) gene and the risk of develop the disease. TREM2 is an immune phagocytic receptor expressed in brain microglia, able to modulate microglial phagocytosis and inflammatory pathway [20].

By using a NGS WES based approach, an association between TREM2 variants in exon 2 and EOAD in Caucasian subjects of French origin was identified. In particular, an association between rs75932628T allele (R47H) and the risk of developing the disease was described [21]. The same variant was further confirmed to be a risk factor for EOAD in a recent study [22], which showed that individuals with the R47H variant had significantly earlier symptom onset than individuals without TREM2 variants [22]. TREM2 genetic variability has been investigated also with regard of LOAD susceptibility by different groups. Jonsson et al. [23] found that the rs7593628T in TREM2 confers a significant threefold increased risk for AD in a cohort of Icelanders.
Role of Genetics and Epigenetics in the Pathogenesis of Alzheimer’s Disease and Frontotemporal Dementia

I hope that you, your sister and your extended family reach out for supports within the community as you travel this unexpected path. Hugs from Virginia.
Hughette
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peggiewho
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Re: ApoE 2/4

Post by peggiewho »

I am just surfing through and don't feel that genetics is as important to AD as epigenetics. I also have the APOE2/4 snips. My father had AD and was well on his way at 65. I felt I was traveling down your sisters path. I use to be great at math but no more. I have trouble going from one computer screen to another and remembering the spelling of a word. I have physically climbed out of a hole. My feeling is that out gut drives cognitive decline. I took the 'Pinner' intolerance test and stopped eating food that swelled my joints and gave me a flu sickness. I am lactose intolerant but the A1 protein is what reddens the whites of my eyes. Recently I discovered Lipopolysaccharides and realized that was the inner poison. I have taken Undecylenic Acid (Swanson Vitamins) for 6 weeks to kill everything in my gut. I am now off the herb and on a spore probiotic. I am also on a keto diet, LDL is part of our immune response and protective. I take a systemic protease to clear LPS from my blood. I did 23andme and ran it through the foundmyfitness tool. I take supplements to offset genetic short comings plus the usual minerals missing from our soil. During the process I felt like I was an Autistic adult. Now I look back and wonder, " is this what Daddy went through?" He never said anything and I wonder if he realized he was declining and went through it silently, aware and alone? I hope I am not bothering you. I just felt the panic that I felt years ago when I was losing my father. The expense, the lack of proper care and help was consuming. You are doing what I always advise, look wider. Step out of the box and brainstorm solutions.
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Re: ApoE 2/4

Post by Gillyp »

A warm welcome to the community Peggiewho.

Thank you so much for taking the time to jump in here and share your experience and insights. I agree with you about epigenetics. It sounds like you have worked hard to put in place things that have both supported and helped you. It takes time and dedication to do this and it certainly sounds like you are moving in the right direction. It is hard looking back and wondering about what loved ones may have been going through but I'm sure your Dad would be very proud of the way you have stepped up and tackled this for yourself. It's very true that we each need to "step out of the box and brainstorm solutions" and with the recognition that those solutions may be different for each one of us.

I think you'll find lots of information on this site that will be very helpful. A good place to start is the Primer (viewtopic.php?f=33&t=1418). As a community we are here to both support each other and learn together. I hope you continue to post whether it be questions, thoughts or insights. I know your post above helped inspire me to do more. Thank you for that and again welcome to the community.
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FMCA/Reversing Cognitive Decline - Pending Fall 2018
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Re: ApoE 2/4

Post by 790alison »

Hi all, I am 2/4. My mother died from AD at 83 after an initial slow decline in early to mid 70s and then a faster decline - the last two years were terrible. Dad died of a sudden heart attack at 72. I am keen to prevent both of these ends. I am trying hard with diet and retiring early from a long teaching career at almost 56 this summer will reduce my stress. I exercise and sleep relatively well. I am interested in what people think about metal teeth fillings and if that is a path i may have to take?? and is 2/4 better than 3/4?
Alison (UK)
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Re: ApoE 2/4

Post by NF52 »

790alison wrote:Hi all, I am 2/4. My mother died from AD at 83 after an initial slow decline in early to mid 70s and then a faster decline - the last two years were terrible. Dad died of a sudden heart attack at 72. I am keen to prevent both of these ends. I am trying hard with diet and retiring early from a long teaching career at almost 56 this summer will reduce my stress. I exercise and sleep relatively well. I am interested in what people think about metal teeth fillings and if that is a path i may have to take?? and is 2/4 better than 3/4?
Alison (UK)
Welcome Alison!

I'm sorry that you've lost both of your parents. Having lost my father to cardiac arrest when he was 67 and my mother also to a slow, then fast decline when she was 86, I know something of the different kinds of grief and loss a sudden death of a father and a slow loss of a mother can bring. Also like you, I retired from a long career in education at 57, and discovered that retirement does not mean an end to learning, growth, social engagement and purpose. It can be an adjustment though, and I hope you give yourself time to get used to the idea of not having every minute of the day scripted for you!

I saw from your other post that you and your ApoE 3/3 sister are both working with a doctor you trust to make use of all the amazing ways we can keep our "health-span" as long as possible. In addition to Dr. Bredesen's book, you may find the Primer a helpful guide. It was written by Stavia, an ApoE 4/4 member who is also a practicing family physician and offers valuable advice on how to prioritize any changes, and advises patience as you begin to tackle what can feel like a tsunami of information.

You and your sister are fascinating examples of how our genetics can vary greatly even among siblings. It suggests that one of your parents was ApoE 3/4 and the other one ApoE 2/3. As such, neither would have been viewed as having extremely high risk of heart disease or Alzheimer's. Here's a quote from a 2017 study that used a large meta-analysis to determine the risk of people currently ages 60-75 of either mild cognitive impairment (MCI) or dementia by age 85 with ApoE 3/3 and 2/4:
The Generation Study elected to disclose the following “lifetime” risks of MCI or dementia to its potential participants:... 20%–25% for individuals with APOE-e3/e4 and -e2/e4 (with a note that risk might be lower for those with APOE-e2/e4); and 10%–15% for individuals with APOE-e3/e3, -e3/e2, and -e2/e2 (with a note that risk might be lower for those with APOE-e2/e3 and -e2/e2)...[The] models are insufficiently precise for “personalized medicine” incidence estimates based on sex, education, or other factors...

APOE-related risk of mild cognitive impairment and dementia for prevention trials: An analysis of four cohorts

It's possible, for example, that your father had risk factors for heart disease that went unrecognized just a few decades ago, including smoking, high blood pressure, diabetes, and exposure to toxic pollution in air, water or at work. Your doctor may be able to reassure you and your sister that your own heart and coronary arteries are in great shape. Similarly, your mother may have been like my mother and my English/Irish mother-in-law and believed that white bread, cookies and ice cream were God's gifts, to be shared liberally. (And I loved them both for that, even after I recognized it probably wasn't the best eating plan.)

So I hope you look at life now as affording you the time, energy, cognitive reserve and emotional optimism (anyone with a long career in teaching is an optimist!) to make the most of your new knowledge, while not letting it become the focus of all you do.
And along the way, please share what you learn and join in on any conversations!
4/4 and still an optimist!
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