Amyloid: Path of Resistance
A number of reasons explain why the amyloid pathway has proven resistant to a successful drug, according to Howard Fillit, M.D., executive director and CSO of the Alzheimer’s Drug Discovery Foundation (ADDF). He said the thinking that amyloid plays a critical role in the disease process is still a hypothesis based primarily on preclinical data.
“It may just be that amyloid production in the brain is a response to injury, a mechanism of cells to repair, and it’s basically similar to the formation of a scar, but not necessarily a primary driver. Indeed, there are many other proteins in the plaques besides amyloid," Dr. Fillit said.
He cited evidence in recent years of amyloid plaques being present in people who die of head trauma. These plaques, he said, can occur acutely after injury, so they cannot be said to cause injury. Other reasons, he added, may include clinical trial models and robustness of drugs.
ADDF has invested nearly $60 million to fund 400 Alzheimer’s drug discovery programs and clinical trials at academic centers and biotech companies in 18 countries, including some 60 mission-related investments to biotech companies.
“We’ve seen upwards of 3,000 new ideas for new drugs for Alzheimer’s disease since 1998, so just the depth and the breadth of innovation that is going on in the field right now is incredible,” Dr. Fillit said.
Alzheimer’s, Dr. Fillit said, requires a focus on several risk factors, key among them aging. “As we age, we have multiple medical co-morbidities, like hypertension and diabetes, that in themselves are risk factors for Alzheimer’s disease, and have their own mechanisms that include insulin resistance in the brain, insulin resistance of the mitochondria in the brain, advanced glycation endproducts in the brain, the effects of hypertension on blood vessels in the brain, and hypoxia."
That thinking is shared by Salk Institute for Biological Studies researchers developing J147, a preclinical synthetic drug that reversed memory loss, reduced amyloid levels and slowed disease progression in mice, according to a study published May 14 in Alzheimer’s Research and Therapy. The researchers showed that J147 protected neurons by increasing supply of brain-derived neurotrophic factor, rather than attacking amyloid or tau.
“I think it’s very realistic that in the next five years, and certainly outside in the next 10 years, we’ll have some disease-modifying drugs approved for Alzheimer’s,” Dr. Fillit said. “I doubt that they’ll be cures. I think they will be drugs that will have an impact on the illness in demonstrating a slowing of the progression. Then, the next step will be employing those agents earlier and earlier in disease prevention.”
Last year, the U.S. Department of Health and Human Services committed the nation to “prevent and effectively treat Alzheimer’s disease by 2025” in its “National Plan” for the disorder. If Washington truly wants to fulfill that goal, the Obama administration will need to increase NIH basic-research spending well beyond the $503 million of FY ’12, projected to drop to $484 million this fiscal year.
Obama’s proposals for an extra $50 million for Alzheimer’s research in FY 2013 and $80 million in FY ’14 are steps in the right direction, though not much more—not when NIH spends $3 billion a year on AIDS and $5.6 billion on cancer. Given today’s tight budgets, however, any more money the agency spends on Alzheimer’s will likely come at the expense of some other equally worthy disease or program.