As Julie mentioned, I have lucked out on the ABCA1 genes (and also seemingly ABCA7) but have the GG for the one above. But not sure now whether than is good or bad!
BTW that is a very good read the link about the HDL etc.
I somehow missed this one when it was published. Rasmussen has confirmed her work demonstrating that peripheral APOE levels are protective against AD independent of E4 isoform. This nicely correlates with Goodenowe’s work. While he doesn’t specifically focus on APOE per se, he said it was an excellent proxy for his plasmalogen level. Perhaps this will be a modifiable biomarker that we can eventually track and tweak…
Abstract
INTRODUCTION:
In recent prospective studies, low plasma levels of apolipoprotein E (apoE) are associated with high risk of dementia. Whether this reflects a causal association remains to be established.
METHODS:
Using a Mendelian randomization approach, we studied 106,562 and 75,260 individuals from the general population in observational and genetic analyses, respectively.
RESULTS:
In observational analyses risk of Alzheimer's disease and all dementia increased stepwise as a function of stepwise lower apoE levels (P for trend, 2 × 10-17 and 9 × 10-21). APOE-weighted allele scores were associated with stepwise decreases in apoE (P for trend, <1 × 10-300). In instrumental variable analysis, the causal risk ratios for a 1 mg/dL genetically determined lower apoE were 1.41 (1.27-1.57) for Alzheimer's disease and 1.33 (1.25-1.43) for all dementia (F-statistics = 3821).
DISCUSSION:
Genetic and hence lifelong low apoE is associated with high risk of dementia in the general population. The concordance between observational and genetic estimates suggests a potential causal relationship.
Julie G wrote:I somehow missed this one when it was published. Rasmussen has confirmed her work demonstrating that peripheral APOE levels are protective against AD independent of E4 isoform. This nicely correlates with Goodenowe’s work. While he doesn’t specifically focus on APOE per se, he said it was an excellent proxy for his plasmalogen level. Perhaps this will be a modifiable biomarker that we can eventually track and tweak…
Yes, I hope so, going to have a detailed read now. In terms of the linkage between the different promoters and alleles, I read elsewhere that seemed to differ in different ethnicities. (the linkage I mean) May be another way APOE4 and AD link is different in different populations. Genetics is so complicated and I feel they need to study the whole area of APOE area more really, rather than just the two alleles related to 4/3/2..as well. This seems to lead more to the idea of APOE4 being a loss of function problem, then...perhaps. Maybe now they can go from here in terms of looking more at what might increase these levels and what might help that.
It is frustrating that the genetic tests do not seem to report on some of these alleles: I don't have results for (2491A>T (rs449647), or 2427T>C (rs769446), presumably this is the same for others? I'm not sure why 23andme or Promethease don't report these, on mine anyway. It would be helpful, as could then calculate the score as in the paper... It mentions in the paper about linkage being explained in a table in the supplementary info but I find it a bit difficult to interpret.
Here is another post where I did some reading about the linkage between these alleles in the past and seem to remember they all seemed to be in linkage with one another, in a pattern, but I did get a bit bogged down in it. viewtopic.php?f=16&t=3989&p=49816&hilit ... ers#p49816
Any more news on this?
rs449647(T;T)
Normal levels of ApoE
Significant Alzheimer's disease associations with were found for rs449647(A;A) and rs405509(G;G) genotypes (positive), and rs449647(A;T) and rs405509(T;T)
more info
Wow. Thanks so much for sharing this. Dense paper! Here's what I could see.
So, this is about low levels of apoe in plasma being associated with AD in a general population.
Wow, these Danes were really healthy overall. Low incidences of diabetes and only 9% were on any cholesterol-modifying therapy.
25% of the population was 3/4. ~3% was 4/4.
They noticed that plasma E levels generally increase with age - about 25% from age 20 to age 80. And tended to be higher in women.
apoe genotype really had a big impact on plasma apoe levels. 2/2s had an average apoe plasma concentration of 10 units compared to 4 units for 3/3s and only 3 units for 4/4s.
At this point I started to wonder, when they say that those with lower plasma apoe levels were more at risk for AD weren't they just says that older e4's were at a higher risk (which we already know)? In other words, is low apoe plasma levels just a proxy for E4 status?
Figure 5 really seems to support this notion, that it is mostly apoe4 genotype that is driving risk.
They said: In the present cohorts, interactions between apoE levels and ε2/ε3/ε4 APOE genotype on risk of Alzheimer disease and all dementia were nonsignificant, reflecting that there is no differential risk of plasma apoE levels by ε2/ε3/ε4 APOE genotype or no differential risk of genotype by plasma level.
meaning genotype and plasma E4 levels could basically be the same signal.
but then they say this, which seems, in my mind, to imply the opposite: Furthermore, it does not seem likely that the ε4 risk‐increasing effect is explained by its association with lower plasma apoE levels, because ε44 versus ε33 is associated with an 8‐fold risk of Alzheimer disease but only a ∼1mg/dL lower apoE level, whereas lowest versus highest apoE tertile is associated with a 3‐fold risk and a ∼3mg/dL lower apoE level. Collectively, these data provide the strongest evidence to date that low plasma levels of apoE are associated with dementia independently of ε2/ε3/ε4 APOE genotype, and that both low levels of apoE and ε2/ε3/ε4 APOE genotype contribute to risk of dementia, independently of each other.
So, I'm confused about that.
Also, there is the issue that apoE levels in plasma aren't connected to those in the brain. They are two separate pools. The brain makes it's own apoE to make it's own lipoproteins. They discuss this at the end: Whether plasma apoE levels mirror apoE levels in CSF and brain tissue remains to be determined.Previous work suggests a limited blood–brain barrier permeability to circulating lipid‐poor apoE2, apoE3, and apoE4,30 supporting that apoE in blood and brain are regulated independently.31, 32 Levels of apoE in human CSF do however display a similar genotype‐dependent pattern as in plasma,17 and recently murine interstitial fluid was observed to have similar genotype‐dependent apoE levels as in CSF.33 We therefore speculate that at least in a preclinical baseline state, as in the present large human study, plasma levels of apoE may reflect CSF and brain apoE levels, although this reflection happens in parallel, in 2 metabolically different compartments.
This is a really big question.
So they conclude that : In conclusion, low plasma levels of apoE are associated with increased risk of future Alzheimer disease and all dementia in the general population, and may be a new, easily accessible preclinical biomarker. These associations were independent of ε2/ε3/ε4 APOE genotype.
And this seems believable. It can be a biomarker, for reasons we don't understand. That's potentially useful.
But it doesn't mean raising apoE in the plasma or even the brain will fix the problem. We see this with artificially raising HDL levels with niacin - though those with naturally high HDL tend to do better, raising HDL in others does not seem to help. It's like holding a flag out against the wind and expecting the wind direction to change.
Also, I can't seem to wrap my brain around all the data indicating that apoe4 has lots of toxic effects. Why would we want more of that?
Couldn't help but notice, once again, the magnitude of the risk for 4/4 being so high.
As Julie mentioned, I have lucked out on the ABCA1 genes (and also seemingly ABCA7) but have the GG for the one above. But not sure now whether than is good or bad!
BTW that is a very good read the link about the HDL etc.
Hi Orangeblossom, here's a new 2021 paper on rs405509. I am GT. I think you're good with GG.
Functional experiments using APOE promoter fragments demonstrated that TT lowered APOE expression in human brain and serum. The modifying effect of rs405509 genotype explained much of the ethnic variability in the AD/ε4 association, and increasing APOE expression might lower AD risk among ε4 homozygotes. [Emphasis added]
I haven't dug into any of this, but on the surface I can't figure out how increasing the expression of a genetically malformed protein could be a good thing?
ApoE 3/4 > Thanks in advance for any responses made to my posts.
I haven't dug into any of this, but on the surface I can't figure out how increasing the expression of a genetically malformed protein could be a good thing?
And yet, Rasmussen's work clearly shows that high levels of peripheral APOE (despite genotype) are correlated with reduced rates of cognitive decline. This felt very similar to the plasmalogen story and Dr. Goodenowe has confirmed that the relationship between peripheral plasmalogens and APOE are strongly correlated.
I haven't dug into any of this, but on the surface I can't figure out how increasing the expression of a genetically malformed protein could be a good thing?
And yet, Rasmussen's work clearly shows that high levels of peripheral APOE (despite genotype) are correlated with reduced rates of cognitive decline. This felt very similar to the plasmalogen story and Dr. Goodenowe has confirmed that the relationship between peripheral plasmalogens and APOE are strongly correlated.
Thank you. It would seem that the protein structure is less important than epigentically turning on the gene, though there are still structure corrector studies going on too … Can they make up their minds
I have to catch up on the plasmalogen story, including your podcast, to better understand the parallel.
ApoE 3/4 > Thanks in advance for any responses made to my posts.
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