New research on other Genes in AD- ABCA7, FERMT2

[Orangeblossom]

Thought this may be of interest, https://www.medscape.com/viewarticle/891630

"A comprehensive genetic study has shed new light, not only on the role of the apolipoprotein ε4 (APOE 4) allele in brain amyloid deposition but also on the importance of other genes in this process as it relates to Alzheimer's disease (AD).
Investigators found that the adenosine triphosphate–binding cassette subfamily A member 7 (ABCA7) gene has the strongest association with amyloid deposition after APOE4 and that the fermitin family homologue 2 (FERMT2) gene is linked to amyloidosis, but only in early stages of AD."

Unfortunately it isn't possible to access the full text and see the snps involved though.

[NF52]

It does seem like the level of research is increasing to discover other genetic factors which may explain some of the wide variability in both relative risk of MCI and AD in ApoE 4 carriers and the variability in age of onset and progression from Mild Cognitive Impairment to diagnosed AD. All of that seems like good news for both intervention targets and for better understanding of personalized risk assessments coming in the future for people on this site.

Here's a link to a free article I came across a few days ago from research done on several cohorts in Canada and the U.S: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4318698/
HMGCR is a genetic modifier for risk, age of onset and MCI conversion to Alzheimer’s disease in a three cohorts study

Mapping of the introns, on the other hand, turned out to be more interesting as the rs3846662 SNP in intron 13 of the HMGCR gene (A or G allele) was found to significantly associate with sporadic AD.
Interestingly, conversion rate among APOE4/HMGCR’s Gnegative subjects was markedly reduced [from 76% to 26.97% conversion to AD] to levels similar to APOE4 non-carriers [27.14% conversion to AD] at three years’ post-MCI diagnosis. This suggests that the HMGCR gene variant can markedly attenuate APOE4 risk, especially in the pre-dementia stages of the disease.
This HMGCR protective genotype exerted a strong impact in women [Wilcoxon Survival test: X2 1, 188= 6.09; P = .017] who exhibited a delayed age of onset of about 3.6 years. This age effect in G negative subjects was not found in men [Wilcoxon Survival test: X2 1, 100= 1.88; P = .170]. Analysis of the “A” variant dose effect on age of onset reveals a significant association (p <0.03) in women; particularly between the age of 60 and 80
...our eastern Canadian population isolate reveals that the reported apoE4-mediated increases in hippocampal and cortical plaques and tangles density in AD is actually prevented in G negative carriers as opposed to G positive subjects.

[Emphasis added]

I don't claim to comprehend the science, but what the basic translation seems to be is that people with have the SNP rs3846662 AA along with an APOE4 allele showed reduced plaques and tangles in the hippocampus and cortex, and a longer time in the MCI or pre-clinical stage of AD. Accompanying charts seem to show that the risk of "conversion" from MCI to AD is about the same for the first 20 months after MCI diagnosis in both AA and A/G or G/G populations, but then the lines diverge, with almost 80% of APOE 4 people with rs3846662 AA were still in MCI 50 months after diagnosis. At Stavia says, we all have to die of something. If my 4/4 status makes it likely that I will at some point be diagnosed with MCI, it's helpful to know that the odds are it will not progress for up to 3 or more years. Lots of time for Mother Nature to find other things wrong with me during that time!
By the way, I came across articles finding the same linkage in Swedish and Han Chinese populations, but couldn't access the full articles.
What's way above my knowledge level is that this is linked to response to statins, and the authors suggest that this polymorphism may explain why studies have shown mixed results on the benefits of statins for Apoe 4 carriers.

[Orangeblossom]

It does seem like the level of research is increasing to discover other genetic factors which may explain some of the wide variability in both relative risk of MCI and AD in ApoE 4 carriers and the variability in age of onset and progression from Mild Cognitive Impairment to diagnosed AD. All of that seems like good news for both intervention targets and for better understanding of personalized risk assessments coming in the future for people on this site.

Here's a link to a free article I came across a few days ago from research done on several cohorts in Canada and the U.S: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4318698/
HMGCR is a genetic modifier for risk, age of onset and MCI conversion to Alzheimer’s disease in a three cohorts study

Mapping of the introns, on the other hand, turned out to be more interesting as the rs3846662 SNP in intron 13 of the HMGCR gene (A or G allele) was found to significantly associate with sporadic AD.
Interestingly, conversion rate among APOE4/HMGCR’s Gnegative subjects was markedly reduced [from 76% to 26.97% conversion to AD] to levels similar to APOE4 non-carriers [27.14% conversion to AD] at three years’ post-MCI diagnosis. This suggests that the HMGCR gene variant can markedly attenuate APOE4 risk, especially in the pre-dementia stages of the disease.
This HMGCR protective genotype exerted a strong impact in women [Wilcoxon Survival test: X2 1, 188= 6.09; P = .017] who exhibited a delayed age of onset of about 3.6 years. This age effect in G negative subjects was not found in men [Wilcoxon Survival test: X2 1, 100= 1.88; P = .170]. Analysis of the “A” variant dose effect on age of onset reveals a significant association (p <0.03) in women; particularly between the age of 60 and 80
...our eastern Canadian population isolate reveals that the reported apoE4-mediated increases in hippocampal and cortical plaques and tangles density in AD is actually prevented in G negative carriers as opposed to G positive subjects.

[Emphasis added]

I don't claim to comprehend the science, but what the basic translation seems to be is that people with have the SNP rs3846662 AA along with an APOE4 allele showed reduced plaques and tangles in the hippocampus and cortex, and a longer time in the MCI or pre-clinical stage of AD. Accompanying charts seem to show that the risk of "conversion" from MCI to AD is about the same for the first 20 months after MCI diagnosis in both AA and A/G or G/G populations, but then the lines diverge, with almost 80% of APOE 4 people with rs3846662 AA were still in MCI 50 months after diagnosis. At Stavia says, we all have to die of something. If my 4/4 status makes it likely that I will at some point be diagnosed with MCI, it's helpful to know that the odds are it will not progress for up to 3 or more years. Lots of time for Mother Nature to find other things wrong with me during that time!
By the way, I came across articles finding the same linkage in Swedish and Han Chinese populations, but couldn't access the full articles.
What's way above my knowledge level is that this is linked to response to statins, and the authors suggest that this polymorphism may explain why studies have shown mixed results on the benefits of statins for Apoe 4 carriers.

I checked this one out in my report and it says the alleles are C or T. So it's a bit confusing. Mine was CT...so whatever it is, it's not a double anything

[SusanJ]

Orange, CT = GA.

It just depends which side of the DNA strand the test measured. For more, see viewtopic.php?f=33&t=1418#p15616

[Orangeblossom]

Orange, CT = GA.

It just depends which side of the DNA strand the test measured. For more, see viewtopic.php?f=33&t=1418#p15616

Ah, I see! Thanks, that makes sense. I wondered why sometimes the alleles came up differently in my reports to in some research studies

[NF52]

Hi, orangeblossom!
I sometimes want to say "can we just agree on what to call these things so I don't have to figure out how to translate to my results!" As for this specific study, I think it's probably just the tip of the iceberg of finding SNPs and other associations that serve as protective factors. In the article they mention that these could serve as targets for intervention, or even could help in cardiac treatment to determine who would need, or respond, to what type of statin. So while I'm sorry you didn't find that you have the A/A profile, your thorough reporting of research pretty clearly tells me that you'v got some serious neuro-protection working!

[KatieS]

This protective SNP was noted a few years ago so I emailed him last year as to any further updates, since I could not find more recent studies confirming this association. I might try again. Also, as an AA, I do seem to be statin resistant as to the cholesterol lowering.
Orangeblossom, both my mom (almost 100) & brother (70) are CT (GA), so in my family, it's not just one protective SNP, which I may or may not have.

[Orangeblossom]

This protective SNP was noted a few years ago so I emailed him last year as to any further updates, since I could not find more recent studies confirming this association. I might try again. Also, as an AA, I do seem to be statin resistant as to the cholesterol lowering.
Orangeblossom, both my mom (almost 100) & brother (70) are CT (GA), so in my family, it's not just one protective SNP, which I may or may not have.

Interesting. Thanks Katie

[Orangeblossom]

I wondered if anyone else might be interested in, or could throw some light on these two...

https://www.snpedia.com/index.php/Rs2075650

rs2075650

Geno Mag Summary
(A;A) 0 normal; some association with greater longevity
(A;G) 2 possibly 2x higher Alzheimer's risk
(G;G) 2 possibly 4x higher Alzheimer's risk
Reference GRCh38 38.1/141
Chromosome 19
Position 44892362
Gene TOMM40

Located close to ApoE4, yet may independently (also) influence risk of Alzheimer's disease.

A case-control study of 381 patients found a 2x higher risk for Alzheimer's disease associated with the rarer rs2075650(G) allele. 10.1371/journal.pone.0006501

This allele is associated with earlier onset of Alzheimer's disease, by ~7 years. (news) [PMID 19668339OA-icon.png] The data from this study are available online at [1]. The association of this SNP with late-onset Alzheimer's disease was confirmed by a study reported in PLoS Genetics.

The A allele of this SNP is one of 150 identified as relevant to exceptional longevity in 10.1126/science.1190532

Recent work suggests, however, that the linkage disequilibrium between rs2075650 and the ApoE ε4 defining SNP rs429358 means that there may be little, if any, independent effect of rs2075650 on Alzheimer's risk. [2]"

I have A,G for that one so wonder if is linked with my 3,4 for APOE.

Also this one is a bit confusing.

https://www.snpedia.com/index.php/rs4420638

rs4420638
Orientation plus
Stabilized plus
Geno Mag Summary
(A;A) 0 Normal/Average risk for Alzheimer's
(A;G) 2 ~3x increased Alzheimer's risk; 1.4x increased heart disease risk ; increased LDL cholesterol
(G;G) 3 2x+ increased Alzheimer's risk, further genotyping suggested ; increased LDL cholesterol
Reference GRCh38 38.1/141
Chromosome 19
Position 44919689
Gene APOC1
is a snp

"Apolipoprotein E ApoE status is technically defined by two different SNPs, rs429358 and rs7412. This SNP, rs4420638, is situated about 14kb away in the adjacent ApoC1 gene and is co-inherited with ApoE and thus associated with late-onset Alzheimer's disease.[PMID 17192785]

rs4420638 (the proxy SNP) is not independent of rs429358. These two SNPs are correlated with each other and it's believed that most of the association with AD at rs4420638 is due to its proximity to rs429358. That said, rs4420638 is not a perfect proxy for rs429358 either -- rs4420638 correlates better for certain genotypes and for certain ethnicities. For example, if you have the genotype at rs4420638 that is more correlated with the e4 allele of APOE, you still only have a 50% chance of actually having the e4 allele. And rs4420638 is not very predictive for any genotype in African populations.

The (G;G) form of this SNP indicates increased risk of Alzheimer's disease, however the probability and amount of increased risk is subject to some disagreement. The initial report concerning this SNP indicated a high likelihood that rs4420638(G;G) homozygotes were predictably ApoE4/ApoE4 homozygotes and thus at significantly (15 fold or higher) risk for Alzheimer's. However, one testing service has estimated [pers. communication] that 25% to 50% of people with the (G;G) are *not* actually ApoE4 homozygotes, and are more likely to be at ~2-3x increased risk based on being ApoE3/ApoE4 heterozygotes.

If you were tested on deCODEme or 23andMe v3 platform, ignore this proxy and just check your status at rs429358 and rs7412. 23andme added rs429358 for people who tested on the v3 platform on 04/14/2011, so you should re-download your data if you haven't."

Again I have A,G for this one so seems to be linked with 3,4, again.

[Orangeblossom]

Hi, orangeblossom!
I sometimes want to say "can we just agree on what to call these things so I don't have to figure out how to translate to my results!" As for this specific study, I think it's probably just the tip of the iceberg of finding SNPs and other associations that serve as protective factors. In the article they mention that these could serve as targets for intervention, or even could help in cardiac treatment to determine who would need, or respond, to what type of statin. So while I'm sorry you didn't find that you have the A/A profile, your thorough reporting of research pretty clearly tells me that you'v got some serious neuro-protection working!

Thanks, that is sweet of you! Thing is I did some genetics at university as part of a science degree so i should know these things...I don;t seem to be that lucky with the AD specific genes but do have the good ones for a couple of others, things like BDNF and some cholesterol ones and FOX03, so maybe they will keep me going!