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

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NF52
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Re: Apoe4 /4 a new genetic variant of Alzheimer’s ??

Post by NF52 »

Julie G wrote: Sun May 12, 2024 6:43 am
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.
Happy Mother's Day, Julie!

I did assume that Dr. Bredesen's hope is to have more biomarker data from cognitively healthy ApoE 4/4 carriers who are aware of their status and using one or more specific interventions. Knowledge of a risk, taking steps to mitigate that risk and having specific personalized data on baseline and results of interventions, is empowering !

The results of a p-tau217 test could produce a "convenience sample" of this motivated population and data from populations with no subjective cognitive impairment, a need the authors recognized. Results in people in their 30's, 40's, 50's and 60's, or even 70's and 80's, could be evidence that healthy lifestyles and/or specific interventions are associated with less amyloid or tau accumulation or at later ages.

Yet ApoE 4/4 carriers both able and willing to learn the results of that test may be in smaller numbers, and at different ages, than the 519 people in the clinical cohorts who were ApoE 4/4 carriers at a median age of 69. The results would be important to the users, but probably not enough to support or refute the view that ApoE4 is a highly heritable form of AD, at about a 60% lifetime risk, but a risk that is not predictive for any one person-- especially not for those a generation or more younger than those studied.

Testing in younger carriers may also be less efficient. It appears from the attached chart (Fig. 3 in the article) that amyloid was rarely measurable before age 50 even in 4/4 carriers (in red), and only reached the level of 20 centiloids for most in the mid-to-late 60's, earlier than for ApoE 3/3 carriers (in green).
Changes in PET amyloid by ApoE and Age.png


Supplementary Figure 3. Tau-PET SUVr by age and CDR score encouragingly shows that many ApoE 4 carriers with elevated tau still score at the cognitively normal of CDR=O.
Tau Pet levels by ApoE and CDR.png
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Re: Apoe4 /4 a new genetic variant of Alzheimer’s ??

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Dr Kellyann Niotis is a neurologist specializing in risk reduction strategies for the prevention or slowing of neurodegenerative disorders. In this short (1+ minute) video, Dr. Kellyann Niotis - ApoE4 Alleles and Alzheimer's Dr Niotis addresses the Nature Article.

From Dr Niotis:
I know this Nature Medicine paper has gotten a lot of press, but let’s be careful with the conclusion we draw. Having two copies of the ApoE4 allele does NOT guarantee you will develop AD. According to population-based studies, the lifetime risk of mild cognitive impairment or dementia for ApoE4 homozygotes is 30-67% and this depends on multiple factors: age, sex, other genes, ethnicity, and environmental and lifestyle factors.

- We know amyloid is insufficient to cause cognitive impairment or dementia due AD
- Based on prior work, pTau217 tracks best with cognitive trajectory
- AD is a CLINICO-Pathological condition. No clinical decrement in cognitive function = NO DISEASE! It cannot be diagnosed based on the presence of biomakers alone.
-Theresa
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Re: Apoe4 /4 a new genetic variant of Alzheimer’s ??

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NF52 wrote: Sun May 12, 2024 3:27 pm ...
I did assume that Dr. Bredesen's hope is to have more biomarker data from cognitively healthy ApoE 4/4 carriers who are aware of their status and using one or more specific interventions. Knowledge of a risk, taking steps to mitigate that risk and having specific personalized data on baseline and results of interventions, is empowering !
Somewhat tangentially, I saw this study focused on healthy APOE ε4 carrier biomarkers:

APOE ε4 carrier status modifies plasma p-tau181 concentrations in cognitively healthy super-seniors
https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/alz.13804

Jennifer G. Cooper, Mohammad Ghodsi, Sophie Stukas, Stephen Leach, Angela Brooks-Wilson, Cheryl L. Wellington
First published: 16 May 2024
https://doi.org/10.1002/alz.13804

INTRODUCTION
This study investigates the effect of apolipoprotein E (APOE) genotype on neurology plasma biomarkers in cognitively healthy Super-Seniors.

METHODS
Three hundred seventy plasma specimens from Super-Senior participants ≥ 85 years old, who have never been diagnosed with dementia, cancer, diabetes, cardiovascular, or major pulmonary disease, were analyzed on the Quanterix Simoa HD-X analyzer using commercial Neurology 4-plex E and phosphorylated tau (p-tau)181 assays.

RESULTS
Eighty (22%) participants were APOE ε4 carriers and 290 (73%) were non-carriers. No significant differences were found between APOE ε4 carriers and non-carriers regarding age, sex, or Mini-Mental State Examination scores. In APOE ε4 carriers, plasma amyloid beta 42/40 was lower and p-tau181 and glial fibrillary acidic protein were higher compared to non-APOE ε4 carriers. After adjusting for demographic variables, p-tau181 was the only biomarker to remain significantly associated with APOE ε4 carrier status.

DISCUSSION
APOE ε4 genotype modifies plasma p-tau181 concentration in seniors resilient to age-related clinical disease, suggesting that some Super-Seniors may have Alzheimer's disease pathology without progressing to cognitive decline.

Highlights
  • Healthy seniors enable identification of associations that may be masked by disease.
  • Plasma phosphorylated tau (p-tau)181 concentrations associate with apolipoprotein E (APOE) ε4 carriership in healthy seniors.
  • APOE should be accounted for when interpreting p-tau181, regardless of disease.
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Re: Apoe4 /4 a new genetic variant of Alzheimer’s ??

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BrianR wrote: Sun May 19, 2024 7:39 amSomewhat tangentially, I saw this study focused on healthy APOE ε4 carrier biomarkers:

APOE ε4 carrier status modifies plasma p-tau181 concentrations in cognitively healthy super-seniors
https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/alz.13804

Jennifer G. Cooper, Mohammad Ghodsi, Sophie Stukas, Stephen Leach, Angela Brooks-Wilson, Cheryl L. Wellington
First published: 16 May 2024
https://doi.org/10.1002/alz.13804

INTRODUCTION
This study investigates the effect of apolipoprotein E (APOE) genotype on neurology plasma biomarkers in cognitively healthy Super-Seniors.

METHODS
Three hundred seventy plasma specimens from Super-Senior participants ≥ 85 years old, who have never been diagnosed with dementia, cancer, diabetes, cardiovascular, or major pulmonary disease, were analyzed on the Quanterix Simoa HD-X analyzer using commercial Neurology 4-plex E and phosphorylated tau (p-tau)181 assays.

RESULTS
Eighty (22%) participants were APOE ε4 carriers and 290 (73%) were non-carriers. No significant differences were found between APOE ε4 carriers and non-carriers regarding age, sex, or Mini-Mental State Examination scores. In APOE ε4 carriers, plasma amyloid beta 42/40 was lower and p-tau181 and glial fibrillary acidic protein were higher compared to non-APOE ε4 carriers. After adjusting for demographic variables, p-tau181 was the only biomarker to remain significantly associated with APOE ε4 carrier status.

DISCUSSION
APOE ε4 genotype modifies plasma p-tau181 concentration in seniors resilient to age-related clinical disease, suggesting that some Super-Seniors may have Alzheimer's disease pathology without progressing to cognitive decline.

Highlights
  • Healthy seniors enable identification of associations that may be masked by disease.
  • Plasma phosphorylated tau (p-tau)181 concentrations associate with apolipoprotein E (APOE) ε4 carriership in healthy seniors.
  • APOE should be accounted for when interpreting p-tau181, regardless of disease.
I'd love to be one of those Super-Seniors in 13 years, with normal cognition in spite of having AD pathology. Better yet, without AD pathology!

But I'd have to be the lucky 0.8% of this study ( 3 of 370) that were ApoE 4/4 carriers, about half of the expected 2% of the population. The lucky ApoE 2/4 carriers in this study, also about 2% of the population, had twice as many Super-Seniors: 6 instead of 3 people.

By comparison, 17% of the CLARITY study of lecanemab in MCI and mild AD were ApoE 4/4 carriers, and I believe about 15% of the people with normal cognition in my AHEAD-45 study of lecanemab are also ApoE 4/4 carriers. We do seem to accumulate AD pathology and then have to navigate lifestyle, interventions and cognitive resilience to keep our brains working!
4/4 and still an optimist!
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