By Kendall Powell, Science
After some costly and disappointing drug trial failures, the field welcomes a funding surge, tools for tracking disease, and interdisciplinary collaborations to tackle one of science’s most stubborn puzzles.
In the last five years, as several large clinical trials testing drugs for Alzheimer’s disease failed, the field came to a stark conclusion: These approaches did nothing to slow down—let alone reverse—the course of the disease once patients already exhibited symptoms of dementia.
The failed trials, along with the dawning realization that Alzheimer’s disease often unfolds over decades, have put the entire field on a new path—to develop and test interventions that can be used much earlier, to discover new targets beyond misfolded amyloid and tau proteins, and to fund large, interdisciplinary, big data collaborations.
Advances in understanding the role of neuroinflammation, new biomarkers and research tools, and an influx of research funding mean it’s a good time to make a career move into the Alzheimer’s field. As history has shown, there won’t be any easy answers, and advances will come only through large collaborations that require a hefty dose of teamwork and heaping amounts of perseverance.
“Most people who have thought about the role of amyloid in Alzheimer’s disease know that we need to identify different ways of intervening,” says Eric McDade, cognitive neurologist at Washington University in St. Louis School of Medicine, and a co-investigator on an 11-year observational study of 500 patients who have inherited mutations that put them at risk for early-onset forms of Alzheimer’s disease. He also serves as associate director of the Dominantly Inherited Alzheimer Network Trials Unit, a worldwide collaboration that connects researchers studying the unique population of people at high risk for early-onset disease. “There’s never been a better time for moving into Alzheimer’s research.”
The lion’s share of Alzheimer’s disease research and drug discovery to date has focused on misfolded amyloid and tau proteins, which aggregate to form plaques (amyloid) and tangles (tau) in the brain. But the body’s attempt to clear the sticky proteins might also be contributing to or causing the neurodegeneration. Drug trials have almost exclusively sought to use antibodies targeted toward these two proteins to try to attack and clear the misfolded forms or mop up soluble forms, or to inhibit enzymes responsible for generating the miscreant peptides.
Ricardo Dolmetsch, global head of neuroscience for Novartis in Cambridge, Massachusetts, paints a rosier view of the field’s failures as representing big leaps in understanding Alzheimer’s. “We’ve learned a lot from the trials, and our capacity to measure disease progress is getting much better,” he says. “There are a lot of really exciting experiments to do now.”
Because those experiments run the gamut from nearly every imaginable corner of biomedical science, researchers with any biology or clinical background, or even training in engineering and computational science, can find a way to move into Alzheimer’s work. Expertise in neuroscience and protein folding alone are no longer ideal, or even absolutely required.
At the Alzheimer’s Drug Discovery Foundation (ADDF), a nonprofit charity based in New York City, diversity is reflected in the research projects being funded there. “We’re really seeing every type of different approach to Alzheimer’s disease and related dementias,” says Lauren Friedman, director of scientific affairs at ADDF. The areas being explored include the vascular system, epigenetics, neuroprotection, synaptic health, immunity and inflammation, and metabolic dysfunction, among others.
Neuroinflammation and proteostasis, or the management of proteins within cells, are trending areas of research in ADDF’s portfolio. Researchers investigating proteostasis would like to find ways to boost the cell’s “garbage disposal” systems, which identify misfolded, clumping proteins and chew them up for recycling.
Like other companies, Novartis is exploring targets in inflammation and the immune system. Dolmetsch notes that the field has just begun to sort through all of the activated inflammatory cells that show up in Alzheimer’s patients’ brains and to characterize their various states of activity and exhaustion. Exhausted microglia, the custodians of the brain, for example, start pumping out cytokines to call up more cells (T cells, B cells, macrophages), which leads to chronic inflammation.
Such an inflammation might be fine for a temporary response to an injury in, say, the finger. But as a chronic state, “it doesn’t work so well in your brain,” Dolmetsch says. For neuroinflammation projects, Novartis looks for scientists who have training with overlaps between neuroscience, immunology, and bioinformatics.
The George & Anne Ryan Institute for Neuroscience at the University of Rhode Island in Kingston investigates underexplored factors in brain health, including the roles of vasculature, immunology, and neuroinflammation as well as lifestyle and environment in Alzheimer’s disease and other neurodegenerative disorders. Behavioral neuroscientist John Robinson works on rodent models of how exercise might play a role in modifying or preventing Alzheimer’s disease.
Another booming area of Alzheimer’s disease research is the development of biomarkers and diagnostic tests to monitor disease presence and progression. Radioactive positron emission tomography (PET) tracers enable physicians to image and measure amyloid and tau proteins in the brains of living patients. Other biomarkers can be measured precisely from collecting spinal fluid. However, both types of tests are invasive, and PET scans are expensive.
“We need a blood test like the one that we have for cholesterol that can be done in any doctor’s office quickly and inexpensively,” says Friedman. To spur such development, ADDF has teamed up with Bill Gates and other philanthropists to fund the Diagnostics Accelerator program. Friedman says the program anticipates awarding about $10 million in the first round of funding. So far it has funded projects for blood tests and tests that detect amyloid or vascular changes in the retina, and is reviewing applications for digital tests that use a smartphone or tablet to monitor disease signs or symptoms. Read The Full Story in Science.
Gary Chandler is a prion expert. He is the CEO of Crossbow Communications, author of several books and producer of documentaries about health and environmental issues around the world. Chandler is connecting the dots to the global surge in neurodegenerative disease, including Alzheimer’s disease, Parkinson’s disease, Creutzfeldt-Jakob disease, chronic wasting disease and other forms of prion disease. The scientific name for prion disease is transmissible spongiform encephalopathy. The operative word is “transmissible.” The global surge in autism appears to be related.