What does a 2x risk of AD mean?

[Nick]

Update: I got a reply from the Alzheimer's Association about risks and multipliers. I posed the issue to them that risk times multiplier numbers presented in their document give nonsensical results in some cases and also asked ... to what can the multiplier be applied. The reply focused on why we cannot apply the multipliers (2x, 3x, 8x, etc) against the risk number for a group. And yes, the answer is as inferred by Juliegee above and here is the reply I got:

"Regarding the risk calculation you made, the math doesn't work exactly that way. Essentially, this is because the risk shown in Figure 3 include people with all different combinations of APOE. In other words, it includes people with APOE4, but also with the protective variant of APOE2. So the people with elevated risk due to being E4/E4 are already included in the overall lifetime risk shown in the figure."

That answer does not answer the question "to what can one apply the multiplier?". I re-asked the question and I'm awaiting a reply.

Based on how the E2 and E4 multipliers are presented (E2 being a reduction & E4 being an increase) I'm 99.99% confident the multipliers are used against the E3/E3 population risk. Since that E3/E3 risk is not presented in the document (best I can tell), the multipliers are of no value to the reader. They are virtually useless. It is also risky to use the E3/E3 population risk as presented by others (if available) since the multipliers shown may not calculate the same for the other's analysis.

Personally, I believe giving a multiplier without the base to which it can be applied is bad form! So, in bad form, to all the readers out there I wish you have a 23.4x better day. I'll leave it to you to figure out 23.4x better than who or what or when or whatever

[Julie G]

LOL, Nick

That answer does not answer the question "to what can one apply the multiplier?". I re-asked the question and I'm awaiting a reply.

I eagerly await their response and have wondered the same.

[SusanJ]

So, in bad form, to all the readers out there I wish you have a 23.4x better day. I'll leave it to you to figure out 23.4x better than who or what or when or whatever

But, given my day, I'd take 3x better. (Ever try to figure out EPA and state standards on disposal of PCB, yeh, me neither, until today. That's what I get for volunteering!)

[Nords]

Nice link, Susan. So, the 11% risk by age 65 is an absolute risk and the genotype specific risks (like 2x, 3x 4x, etc.) are relative risks. I would assume that inclusive in the absolute risk is all APOE genotypes whereas the relative risk would be specific to that APOE genotype.

With that understanding, look how this blurb from the Alzheimer's Organization (link above) is worded:

Having the e4 form increases one’s risk compared with having the e3 form, while having the e2 form may decrease one’s risk compared with the e3 form. Those who inherit one copy of the e4 form have a three-fold higher risk of developing Alzheimer’s than those without the e4 form, while those who inherit two copies of the e4 form have an 8- to 12-fold higher risk.25-26 In addition, those with the e4 form are more likely to develop Alzheimer’s at a younger age than those with the e2 or e3 forms of the APOE gene.27 Researchers estimate that between 40 and 65 percent of people diagnosed with Alzheimer’s have one or two copies of the APOE-e4 gene.23,28-29

For those with a singular E4 allele, the risk is compared to those with zero E4 alleles thereby raising the risk to 3x whereas E4 homozygotes are purported to have an 8-12 fold higher risk using the same comparison.

And I'm still having troubles with relative numbers that when applied to x of y populations yield more than the y population.

My guess is that in that case the y population is being defined with zero E4 alleles which is not a true absolute risk artificially raising the relative risk to be higher than the true absolute risk. Make sense?

With some of the numbers quoted so far (which may or may not be accurate), the math of 100 85-year-olds would break down very roughly to:
33 with Alzheimer's
A couple of the 33 are E3 homozygote
6-7 of the 33 are E3/E4
24-25 of the 33 E4 homozygote.

But this is way higher than the 40%-65% of the 33 having at least one E4, so it's tough to squeeze all the numbers into the right slots. My math may be off by one or two people in each group, but that's about as precise as we can get considering the statistics.

Now I'd rather focus on the cognition of the other 67 people. How many of them are E4/E4, and why is their cognition still good?

[Nick]

I think that the 33% number presented by the AD org is misleading if you apply it to an 85YO.

Per page 16
• One in nine people age 65 and older (11 percent) has Alzheimer’s disease.
• About one-third of people age 85 and older (32 percent) have Alzheimer’s disease.

1) What bullet one says is that 11% of people 65 - 120 have AD
2) What bullet two says is that 32% of people 85 - 120 have AD
NOTE: 120 is my guess but you get my point

Neither of the statistics can be used to estimate disease risk for anyone 65 or 85 or any age point other than 120. These really only apply to people who are 120 (or whatever the max age in the study was).

I prefer:
- In figure 3 it says "Estimated Lifetime Risk for Alzheimer’s, by Age and Sex, from the Framingham Study" 10% men and 20% women for 85YO's

I interpret that as ... 10% of men and 20% of women who are 85YO have AD and as such, that is the 85YO risk of the population as defined by the study group.

[Nick]

BTW ... I'm hearing only crickets from the AD org relative to my question "to what can we apply the multiplier?"

If the risk that we can apply the multiplier is lower than the population as a whole, then the number may not be "67 people" (67%) or whatever the number/% is, and the at risk is starting to approach the population as a whole.

[Julie G]

Too bad. I was hoping for a response, but somehow I'm not surprised that you haven't heard back. Bear in mind that any statistic that you do receive will just be a rough estimate. Dxing Alzheimer's is a very imprecise science. Pathology begins decades before the first symptoms appear and patients typically deal with the disease for several years before seeking help. Further impeding statical record keeping is the fact that the cause of death for many Alzheimer's patients will also be misreported as pneumonia, starvation, cardiovascular disease, etc. All that being said, I recall diving into this around 5 years ago when I first learned of my 4/4 status. At that time, 23andMe provided an odds ratio chart for each of the APOE genotypes. At the time, I think they reported the risk for a 3/3 to be around 7% before age 85. (LOL, my memory could be faulty .) How does that plug into the other stats you've uncovered?

[Aurelius]

If I might chime in here (I've been thinking a lot about relative risk factors the last few days), clearly one can't take a general population percentage and naively multiply it by the risk factor, because that would indeed lead to ridiculously high numbers. I read somewhere recently the disturbing statistic that something like 45-50% of people with homozygotic APOE-4 alleles will get Alzheimer's by 80 yo, but one has to remember that that percentage represents a 10-20x greater risk over a 3/3. So if a 10-20 percent risk increase results in a 50% chance, that ought to give you some idea of the numbers being dealt with. Also this doesn't mean that any single individual who is a 4/4 has a 50% chance.

At least that's what I think this all means.

[Nick]

It is risky to disassemble any conclusion by using numbers from differing analysis. You start assuming and everyone knows what it means to "assume".

[Nick]

Aurelius, I follow your thinking but I'm not sure how to factor the weighting of the 9 combinations that make up the population and their impact on the results. In other words, I'm not sure how the overall average was created. As such, disassembly is risky.