As years went on, despite intense research and increased understanding of the mechanisms of the disease, the amyloid hypothesis failed to lead to any significant clinical strides in the prevention or treatment of Alzheimer’s.
Then, scientists discovered that APOE-4 affected the ability of cells to clear amyloid beta. Some began to wonder if APOE was the missing piece of the puzzle; perhaps studying APOE would help explain why drugs targeting amyloid beta weren’t working.
“As the link between APOE-4 and amyloid pathology was strengthened, that helped APOE become a more compelling story,” says Eric G. Mohler, Ph.D., senior scientist, neuroscience discovery research, AbbVie.
As compelling as that story may be to researchers, it also provokes difficult questions. An estimated 25 percent of the population carries at least one APOE-4 (increased risk of AD) genetic type, but whether we should be screened for this gene remains both an ethical and medical quandary.
“We know the excitement and amount of work that’s gone into BRCA-1 and of its connection to the development of breast or ovarian cancer, but the probability of developing Alzheimer’s is nearly as great if you have the APOE-4 genotype as your risk of getting cancer if you have BRCA-1,” says James B. Summers, Ph.D., vice president, neuroscience discovery research, AbbVie.
But unlike with breast and ovarian cancer, knowing you have an increased risk of Alzheimer’s disease doesn’t leave you with options for prevention. For this reason, scientists and physicians worry that testing for APOE-4 will do more harm than good.
“Many people would argue that (this knowledge) helps in planning the rest of your life,” Summers says. “But it’s not 100 percent certainty either – so where does that leave you?”
The ability to test for types of APOE may be of limited use for the average person, but recent efforts to learn more about the gene may offer a new hope.
One approach consists of trying to make APOE-4 act like the neutral APOE-3 or, ideally, like the protective APOE-2.
“We like that approach because regardless of what the cause of APOE-4 risk actually is, what matters is that you can make it function like a form which lowered that risk,” Summers explains.
To solve the 25-year APOE mystery, AbbVie scientists are working with a number of external teams at academic institutions, including Mass General Hospital, Washington University St. Louis, and University of Illinois, Chicago, as well as co-leading the European Union’s Innovative Medicines Initiative ADAPTED (Alzheimer's Disease Apolipoprotein Pathology for Treatment Elucidation and Development) Project.*
“We’re basically trying to understand the biology around APOE as it relates to Alzheimer’s, so we can determine the best way to go after treatment,” Mohler says.
One might say that the little apolipoprotein-E gene is finally getting its day in the sun, something that would certainly please the man who discovered it and championed its potential.
Unfortunately, Roses passed away early in 2016, before he ever got to see the fruits of his 25-year labor.
“I don’t think there’s an obvious solution right around the corner,” Mohler says of APOE research. “But on the other hand, our level of understanding of the mechanism and the approaches being used are accelerating, so I’d expect to see some sort of breakthrough in the near future.”
That would indeed be a happy ending of science-fiction film proportions.
*APOE research is part of a multi-pronged approach to Alzheimer’s discovery, which includes AbbVie’s partnership with the tau SILK™ consortium at Washington University School of Medicine.