Stavia,
Here's the relevant quote from the PLOS study: (embedded in the longer quote at the end of this post.
The Generation Study elected to disclose the following “lifetime” risks of MCI or dementia to its potential participants: 30%–55% for individuals with APOE-e4/e4; 20%–25% for individuals with APOE-e3/e4 and -e2/e4 (with a note that risk might be lower for those with APOE-e2/e4); and 10%–15% for individuals with APOE-e3/e3, -e3/e2, and -e2/e2 (with a note that risk might be lower for those with APOE-e2/e3 and -e2/e2).
I've referenced this PLOS article often, because I think it does a terrific job of explaining in fairly understandable terms the difference between a
model of Alzheimer's and the
prospective studies of actual groups. The authors go into fascinating descriptions of the similarities as well as limitations of the 4 studies they used for meta-analysis, which included the Framingham Study and Rotterdam study. They are open about the goal of the Generations Study as well as the need for ALL prevention studies to have cohort groups which are statistically and clinically justifiable: the need to determine what is the necessary length of time for a longitudinal study of a currently "healthy" cohort in order to determine risk of progression to either MCI or AD.
More importantly, the authors spend a significant section of the "Discussion" on the need to provide potential study participants with accurate data and an understanding of the variability in "relative risk" of groups and "absolute risk" of any one individual. They note on multiple occasions that the ability to provide personalized risk analysis, gender-based risk analysis etc. is not where individuals or researchers would like it to be.
As an example of how data can be confounding, they note that early sign-ups for Gene Match were overwhelmingly white (about 90%) female (about 80%) and had a first degree relative with AD or dementia (about 70%) and that therefore recruitment efforts should try to reach populations not well-represented. They noted than on one earlier study (not theirs), men showed a higher rate of progression to AD and MCI--an entirely unexpected result given incidence rates for AD in women versus men. Rather than assume this means the study proved that ApoE 4 men do have the same risk as women based on this one sample, these authors speculate that men who volunteered for the study self-selected on the basis of subjective memory complaints. That would be consistent with many studies showing that subjective memory complaints and lower cognitive scores at baseline are associated with progression to MCI.
So the Generations Study added questions about subjective memory complaints at screening and at every Generations visit, to be able to do that level of analysis in the future. I appreciate that, especially since every week the media trumpets another "discovery" from one mouse study or another.
I think it's absolutely necessary to be able to offer people reassurance that the best estimates are that 1) there's wide variation among people with ApoE 4/4, so no one can say what any one's individual risk of AD is for the next 5 years or over the lifetime and 2) it appears that unlike OLD studies saying diagnosis is likely to be at age 68, the 5-year risk at ages 65-69 is highly variable, but still relatively small, and that the lifetime risk to 85 (current life expectancy) is somewhere between 40-60% but probably not over 60%.
As for recruiting people to the Generations Study, as a participant I can safely say that I know of two people who elected NOT to participate when they were reassured about their risk (both men!) Given the requirements for screening over a period of up to 90 days, no one goes into this study because it's easy and reassuring. We do it so the questions around prevention of MCI and AD using amyloid immunotherapy and/or BACE-1 inhibition of amyloid precursor protein can be answered once and for all
APOE-related risk of mild cognitive impairment and dementia for prevention trials: An analysis of four cohorts
In the genetic counseling setting, any risk information would need to give a broad range of estimates to reflect uncertainty within cohorts and variation across cohorts. Because risk for disease is ongoing, and the lifetime risks were more stable than the 5-y risks in our analyses, we thought the lifetime risks were more informative for genetic disclosure. However, such risks may be less salient to some of those considering enrollment in trials at younger ages. The Generation Study elected to disclose the following “lifetime” risks of MCI or dementia to its potential participants: 30%–55% for individuals with APOE-e4/e4; 20%–25% for individuals with APOE-e3/e4 and -e2/e4 (with a note that risk might be lower for those with APOE-e2/e4); and 10%–15% for individuals with APOE-e3/e3, -e3/e2, and -e2/e2 (with a note that risk might be lower for those with APOE-e2/e3 and -e2/e2). These values are consistent with our findings, but use round numbers for intelligibility, and broader ranges to reflect statistical and other sources of uncertainty. The regression models are insufficiently precise for “personalized medicine” incidence estimates based on sex, education, or other factors, but they do allow for qualitative adjustments to overall stratified risk estimates. Relative risks by APOE genotype or APOE-e4 dose have limited relevance in the setting of the prevention trial, but may provide context. If these are provided, risk should be compared to the general population (based on a weighted average across the three possible APOE-e4 doses rather than the typical “no APOE-e4” base category used in regression models), which would more fairly allow a participant to put his or her own risk in the context of friends and acquaintances of unknown genotype. On the basis of our regression findings (S1 Appendix Table E), for APOE-e4/e4 homozygotes, the adjusted relative risk for MCI/dementia is 2.7 for NACC, 3.4 for the Framingham Heart Study, and 2.4 for the Rotterdam Study, so disclosing a relative risk of about 3-fold compared to the general population would make sense
Who would agree to be tested if the news were dire? I hate to be cynical, but we all know that statistics can be manipulated to make a point. That said, epigenetics rule and E4 is not deterministic, even for 4/4s!
