Apolipoprotein E and Alzheimer disease: risk, mechanisms, and therapy

[Julie G]

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

I continue to be humbled by your personal service to our cause, NF52. I suspect I speak on behalf of many others when I extend my deep gratitude.

[NF52]

Thanks Julie,
I am also humbled by the depth of knowledge of you and many others on this site, and the commitment to sharing stories, support and strategies. Lots of paths to plugging those holes in the roof--even it some of us have steeper roofs and more holes!

[Stavia]

thanks team for your analysis of this evidence. I had no idea it existed.

Sent from my SM-G930F using Tapatalk

[DesertRaven]

thanks team for your analysis of this evidence. I had no idea it existed.

Sent from my SM-G930F using Tapatalk

Thanks to the others for providing the details for my reference while I was out. As noted, these data aren't definitive yet, but they are so much better than anything else that we have on this that they will be the standard for the foreseeable future. It is also clear that any individual's risk may vary widely from another's, despite the genotype similarities, but we can be reassured that the variance appears to be centered around a lower number than had been assumed previously.

As someone who plans and conducts clinical studies, I suspect that these results were a bit disconcerting to those responsible for conducting the blinded studies of asymptomatic people with A4/A4 (Generations, etc). For a tested intervention to be positive, it in this case needs to show that fewer individuals would develop MCI/dementia with the intervention than would be the case with standard care. If 60-65% of the subjects aren't fated to deteriorate anyway, as these data suggest, the study needs to be much larger or longer than maybe had been estimated initially, as the intervention has to show meaningful improvement in the remaining 35ish%.


Sent from my iPad using Tapatalk

[Dontworry]

Hi Orangeblossom!
In case you (or anyone else) is looking for the actual study showing your old study was debunked, as others have stated in posts, here it is. Hope this helps!
I've been following aapoe4/4 for many years now and keep my eyes open for any research. I hope that this is helpful and causes less stress and more hope to all of you like It did me!
here's the link but below is the cut and paste I did for everybody to read. http://journals.plos.org/plosmedicine/a ... ed.1002254
PLOS
RESEARCH ARTICLE 2017
APOE-related risk of mild cognitive impairment and dementia for prevention trials: An analysis of four cohorts
Jing Qian, Frank J. Wolters, Alexa Beiser, Mary Haan, M. Arfan Ikram, Jason Karlawish, [...view 8 more...], Deborah Blacker
Abstract
Background
With the onset of prevention trials for individuals at high risk for Alzheimer disease, there is increasing need for accurate risk prediction to inform study design and enrollment, but available risk estimates are limited. We developed risk estimates for the incidence of mild cognitive impairment (MCI) or dementia among cognitively unimpaired individuals by APOE-e4 dose for the genetic disclosure process of the Alzheimer’s Prevention Initiative Generation Study, a prevention trial in cognitively unimpaired APOE-e4/e4 homozygote individuals.

Methods and findings
We included cognitively unimpaired individuals aged 60–75 y, consistent with Generation Study eligibility criteria, from the National Alzheimer’s Coordinating Center (NACC) (n = 5,073, 158 APOE-e4/e4), the Rotterdam Study (n = 6,399, 156 APOE-e4/e4), the Framingham Heart Study (n = 4,078, 67 APOE-e4/e4), and the Sacramento Area Latino Study on Aging (SALSA) (n = 1,294, 11 APOE-e4/e4). We computed stratified cumulative incidence curves by age (60–64, 65–69, 70–75 y) and APOE-e4 dose, adjusting for the competing risk of mortality, and determined risk of MCI and/or dementia by genotype and baseline age. We also used subdistribution hazard regression to model relative hazard based on age, APOE genotype, sex, education, family history of dementia, vascular risk, subjective memory concerns, and baseline cognitive performance. The four cohorts varied considerably in age, education, ethnicity/race, and APOE-e4 allele frequency. Overall, cumulative incidence was uniformly higher in NACC than in the population-based cohorts. Among APOE-e4/e4 individuals, 5-y cumulative incidence was as follows: in the 60–64-y age stratum, it ranged from 0% to 5.88% in the three population-based cohorts versus 23.06% in NACC; in the 65–69-y age stratum, from 9.42% to 10.39% versus 34.62%; and in the 70–75-y age stratum, from 18.64% to 33.33% versus 38.34%. Five-year incidence of dementia was negligible except for APOE-e4/e4 individuals and those over 70 y. Lifetime incidence (to age 80–85 y) of MCI or dementia for the APOE-e4/e4 individuals in the long-term Framingham and Rotterdam cohorts was 34.69%–38.45% at age 60–64 y, 30.76%–40.26% at 65–69 y, and 33.3%–35.17% at 70–75 y. Confidence limits for these estimates are often wide, particularly for APOE-e4/e4 individuals and for the dementia outcome at 5 y. In regression models, APOE-e4 dose and age both consistently increased risk, as did lower education, subjective memory concerns, poorer baseline cognitive performance, and family history of dementia. We discuss several limitations of the study, including the small numbers of APOE-e4/e4 individuals, missing data and differential dropout, limited ethnic and racial diversity, and differences in definitions of exposure and outcome variables.

Conclusions
Estimates of the absolute risk of MCI or dementia, particularly over short time intervals, are sensitive to sampling and a variety of methodological factors. Nonetheless, such estimates were fairly consistent across the population-based cohorts, and lower than those from a convenience cohort and those estimated in prior studies—with implications for informed consent and design for clinical trials targeting high-risk individuals.

Author summary
Why was this study done?
Having one copy of the e4 variant of the APOE gene (APOE-e4) is associated with increased risk and earlier onset age of Alzheimer disease dementia, and the 1%–2% of the population who carry two copies of this variant (APOE-e4/e4) are at especially increased risk.
For this reason, individuals with APOE-e4/e4 are being targeted for special prevention strategies.
Accurate risk estimates allow potential participants in prevention trials to compare the risk of developing Alzheimer disease dementia to any risk associated with the preventive intervention itself.
Such estimates also help those planning trials decide how many participants they need.
The risk that an individual with APOE-e4/e4 will develop Alzheimer disease dementia has been reported to be as high as 50%–67%, but these estimates come from statistical modeling, not direct observation.
Our study was designed to develop risk estimates for potential participants in the Generation Study, a prevention trial in individuals with APOE-e4/e4, as well as estimates for those with one or no copies of APOE-e4. The non-APOE-e4/e4 individuals are not eligible for the Generation Study, but participate in genetic counseling as part of the recruiting process, and might be eligible for future trials.
What did the researchers do and find?
We examined data from 16,844 individuals, 292 with APOE-e4/e4, from four different samples of cognitively normal older individuals aged 60–75 years (consistent with the eligibility criteria for the Generation Study). These individuals have been followed for an average of 4 to 18 years and assessed for the development of dementia or a less serious condition called mild cognitive impairment that sometimes leads to dementia.
We divided each sample into six groups based on the number of copies of APOE-e4 (none, one, and two, i.e., APOE-e4/e4) and age (60–64, 65–69, and 70–75 years), and developed estimates of the risk of developing mild cognitive impairment or dementia in each group during the five years planned for the trial as well as “lifetime” risk through age 80–85 years.
Five-year risk was highly variable across the four samples within each group; for APOE-e4/e4 individuals, it ranged from 0% to 23% in those entering the study at age 60–64 years, 9% to 35% in those entering at 65–69 years, and 19% to 38% in those entering at 70–75 years.
Lifetime risk was more consistent across the two samples in which it could be estimated, and did not vary as much with age, ranging from 31% to 40% for those with APOE-e4/e4.
We developed statistical models to understand the differences across the four samples. These analyses showed that, beyond age and APOE-e4, the following variables were associated with increased risk: less education, memory concerns or poorer cognitive screening test scores at the beginning of follow-up, and having a family history of dementia.
Differences in these characteristics, differences in methods of recruiting and evaluating participants, and statistical fluctuation probably account for a large share of the variety in risk estimates across the samples.
What do these findings mean?
The risk of dementia in those with APOE-e4/e4 is somewhat lower than previously estimated.
Short-term risk is more subject to variability due to details of how a particular study is conducted than longer-term risk.
This information is valuable to those considering joining a prevention trial, as well as those designing such trials.
Citation: Qian J, Wolters FJ, Beiser A, Haan M, Ikram MA, Karlawish J, et al. (2017) APOE-related risk of mild cognitive impairment and dementia for prevention trials: An analysis of four cohorts. PLoS Med 14(3): e1002254. doi:10.1371/journal.pmed.1002254

Academic Editor: Bruce L. Miller, University of California San Francisco Memory and Aging Center, UNITED STATES

Received: November 13, 2016; Accepted: February 3, 2017; Published: March 21, 2017

[cflegal]

MAJOR FACTORS INFLUENCING PREVENTION
-“. . . Alzheimer’s Disease pathogenesis starts 2-3 decades before the onset of symptoms.”
-There exist a number of genetic risk factors for AD. However the major risk factor is age. The age of onset is about 70 years, and disease prevalence increases exponentially with age.
-Inherited or “familial” cases of Alzheimer's account for less than 5% of all cases,
-PARTNERS of those with dementia are 600% more likely to develop Alzheimer’s than the general population. Shared lifestyles are a major risk factor in health outcomes of long-term couples including cognitive impairment.
-In Sonoma County, CA Alzheimer’s is now the third leading cause of death.
-Observational studies have identified a range of potentially modifiable lifestyle risk factors for Alzheimer’s and dementia, including cardiovascular risk factors (e.g., hypertension, diabetes, obesity), psychosocial factors (e.g., depression) and health behaviors (e.g., low level of physical or mental activity, smoking) and a low quality diet. The projected life expectancy at age 50 years is on average 14.0 years longer among female Americans with five low risk lifestyle factors compared with those with zero low risk lifestyle factors; for men, the difference was 12.2 years.