It Began With a Phantom Menace
A mysterious gene. A disease with no cure, rapidly affecting more and more people. It sounds like the makings of a great science-fiction thriller, but this is the reality of Alzheimer’s.
Back in 1992, Dr. Allen Roses was working with a team at Duke University when he discovered a connection between a gene responsible for transporting fatty acids, and Alzheimer’s disease (AD).
This gene, apolipoprotein-E (APOE), can take on three different forms. One form (APOE-4) appears to increase your risk of developing Alzheimer’s disease; another (APOE-2) seems to protect you from it. And the other form, APOE-3, doesn’t seem to affect your risk in either direction.
Just like you can’t choose your parents, you can’t choose which form of the APOE gene you get from them. You may inherit two of the “bad guy” APOE-4 types from your mom and dad, or one “good” APOE-2 type from dad and neutral APOE-3 from mom, and so forth.
But in the most oversimplified sense, what you need to know about APOE is this: the more APOE-4 someone has in their genetic makeup, the higher the risk of developing late-onset Alzheimer’s – and in the 25 years since this link was discovered, no one has quite figured out why.
Battle of the Alzheimer’s Theories
When Roses found the connection between APOE and Alzheimer’s risk, he believed he’d found a game changer for a disease that had consistently baffled researchers. But as he was publishing his findings, interest was brewing within the scientific community over another radical discovery in the field involving the proteins beta amyloid and tau.
The “amyloid hypothesis” took center stage, gaining favor and grants; the APOE theory, on the other hand, was brushed off as being unlikely (why would a gene involved in cholesterol transport impact a neurological disease?) and technically hard to approach.
Frustrated (he told a reporter in 2015 that he felt “ignored” by his peers) but determined, Roses continued to explore his APOE theory in various capacities, at times even using his own money to fund the work.
“We know the excitement and amount of work that's gone into BRCA-1 and the susceptibility of developing 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 with BRCA-1.”
A Force Awakens
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?”
A New Hope
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.