What is the absolute risk?

[Starfish77]

Andru, thanks for the explanation.
Starfish

[Verax]

I see a Danish open-access study has just been published in the Canadian Medical Association Journal that may answer some of the questions. "Absolute 10-year risk of dementia by age, sex and APOE genotype: a population-based cohort study," http://www.cmaj.ca/content/190/35/E1033 Katrine L. Rasmussen, Anne Tybjærg-Hansen, Børge G. Nordestgaard and Ruth Frikke-Schmidt, CMAJ September 04, 2018 190 (35) E1033-E1041; DOI: https://doi.org/10.1503/cmaj.180066

The study aimed to determine the absolute 10-risk of dementia (including, separately and together, Alzheimer's, vascular, and unspecified), by age (60 to >80), sex, and APOE genotype. It included 104,537 participants (solely white European) from Copenhagen studies up to 2014. I won't copy the results here, as you can read the breakdowns in Figures 2 and 3 of the paper. There is no exact formula to calculate risk of factors other than genotype, as they present adjusted results. "Risk of dementia as a function of APOE genotype. Hazard ratios (HRs) were adjusted for age (time scale), sex, body mass index, hypertension, diabetes mellitus, smoking, alcohol consumption, physical inactivity, menopausal status and hormonal replacement therapy (only women), lipid-lowering therapy and education."

One rather surprising result is that e2/e4s had in this study a higher risk of vascular dementia than did e3/e4s (there is a brief explanation pertaining to lipid metabolism). The risk curves by age in Figure 2 are S-shaped rather than hyperbolic, as risk appears to taper off after a certain age (I was unable in my browser to read the legend in either the online HTML nor the downloaded PPT file, so I can't reproduce the numbers exactly).

I wonder if other readers could comment on whether this study is helpful for us to assess risk? I would like more information about the other risk factor adjustments such as physical inactivity, as the overall numbers seem a little lower than other published figures.

[Harrison]

One figure I found particularly interesting was supplemental figure 4, which lists apoE levels, total cholesterol, LDL, HDL, etc by genotype. There is a clear positive correlation between E4 load and LDL and negative correlation between E4 load and HDL, although the differences aren't huge. One measure with big differences is plasma apoE levels, which are 27% lower in E4/4 compared to E3/3. That goes along with previous work by Rasmussen, but the field is very much split on the concept of increasing brain apoE levels to combat Alzheimer's disease. In the end, however, I don't know that these studies tell us much other than to be mindful of the hand we've been dealt and to do our best with it.

[Searcher]

I have been unable to figure out or locate any info on the absolute risk. Anyone have info on this?

This presentation seems relevant (look at P1-381).

https://www.alzheimersanddementia.com/a ... 2/abstract

9703 subjects followed prospectively. Each characterized by genotype including APOE status along with other genetic variants.

An individual can carry E4/4 but be placed on a spectrum of risk score when the whole genome is considered. Depending on the genetic risk score overall, there is a spectrum of risk for E4/4 carriers.

E4/4 carriers in the highest (worst) tertile for genetic risk score had a 78% absolute cumulative lifetime risk of developing AD by age 85. Other E4/4 carriers had lower absolute risk.

Other genetic risk factors substantially modify the absolute risk of eventual AD among E4/4 carriers.

In plain English? If you carry E4/4, you cannot precisely predict your lifetime risk of AD unless you specify the rest of your whole genome. On top of that you have risk modification by the whole layer of life-enhancing practices that wise people adopt.