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Around 25 years ago, Duke researchers discovered the largest known genetic risk for Alzheimer's disease in people over 65-a gene called APOE4. Researchers still are not sure what it does.
These delays are not unusual for Alzheimer's research. When the disease's namesake, Alois Alzheimer, was analyzed the patient's dementia patients in the first decade of the 1900s, he noticed a bizarre jumble of plaques and tangles in their brains. The intricacies of those plaques and tangles are still being teased apart in labs today, though
The National Institutes of Health budget for the 2019 fiscal year will raise funding for Alzheimer's disease and dementia research by $ 425 million to $ 2.34 billion total. This increase continues to be a growing trend in Alzheimer's funding, reflecting an aging population and growing Medicare expenditures for AD.
"As the population ages, this disease will become more pronounced in terms of health burden to society," said Ornit Chiba-Falek, associate professor of neurology at Duke. "I'm very happy that we're getting more funding and we can investigate and hopefully advance the field."
The Alzheimer's Association estimates that 5.7 million Americans are living with AD in 2018, 96 percent of which are older than 65. Women are disproportionately affected-making up about two-thirds of cases-and the total number of Americans suffering from the disease is expected to climb to around 13.8 million in 2050.
'More of the status quo'
Researchers are yet to arrive at a consensus on the molecular mechanisms driving the disease. As a result, treatments for Alzheimer's is currently focusing on improving the symptoms of the disease, not directly fighting AD or attempting to reverse its course.
Richard O'Brien, Chair of the Department of Neurology at the Duke University School of Medicine, said that the results of these studies are mildly encouraging at best.
"There currently are some things you can do to increase your memory to a tiny little bit," he said. "They do not do anything to the disease itself."
O'Brien, who sees Alzheimer's patients, cited a common memory test called the Mini-Mental State Examination. Most people would receive a 30 out of 30 on the test, with people would be disappointed with 15 out of 30, he explained.
"The main thing that we do when we see them in the clinic is trying to solve-solve with the caregiver. What challenges are they facing? What things do we need to do to keep the faith? "O'Brien said. "That's pretty much the state of Alzheimer's care."
Professor of Neurology James Burke added that these drugs can not be effective at improving performance.
Years have passed since the last Alzheimer's treatment was approved by the Food and Drug Administration. The last one was memantine, a drug for severe AD, which hit the markets in 2003.
Why have more than 15 years passed without another approved treatment?
"It's not for lack of trying," Burke said. "There's been a large emphasis on developing treatments for Alzheimer's disease. The problem is that all of the symptomatic and disease-modifying therapies have been unsuccessful. There have been more than 100 clinical trials, and none of the drugs have been successfully brought to market. "
One of the causes behind the lack of new treatments may be the relatively stagnant funding for Alzheimer's and dementia research.
From 2008 to 2013, NIH funding for AD grew $ 92 million from $ 412 million to $ 504 million, a modest increase over the $ 425 million increase for this upcoming year alone. The passage of the National Alzheimer's Project Act in 2011 called for expansion of Alzheimer's research and the National Plan to Address Alzheimer's Disease. The first plan set a goal to "prevent and effectively treat" AD by the year 2025.
Several years after the act's passage, the budget allotment for Alzheimer's and related climates to $ 929 million for the 2016 fiscal year and jumped to $ 1.42 and $ 1.92 billion in 2017 and 2018, respectively.
Carol Colton, Professor of Neurology, who researches Alzheimer's in her lab, praised the funding increase. She is credited with the NIH and Alzheimer's Association for pushing for the funding increase.
"People have decided-world governments, agencies throughout the world have decided that we really do not have enough unabated Alzheimer's disease," Colton said.
Burke said that the pool of funds researchers in the 2000s made it harder to compete for a piece of the pie, as well as more often than not.
"If you have something where you have a limited supply of money, it is natural for them to think that they should have a surefire success in order to give money to one another," he said. "That tends to lead to more conservative approaches-it tends to lead to more of the status quo."
'A thousand different theories'
O'Brien explained that the leading hypotheses for the molecular basis of the disease focus on two proteins found in abnormal states in the brains of patients suffering from Alzheimer's-amyloid-β and tau.
The amyloid protein can misfold and create plaques in the brain that are commonly associated with Alzheimer's. Its partner in crime, tau, can become defective at its usual benign job of stabilizing cells and begin to form harmful tangles within the brain.
O'Brien added that researchers are still unsure of whether these two hallmark neurological abnormalities are actually causing Alzheimer's or just byproducts of pathways gone haywire. Establishing whether amyloid and tau malfunctions are causes or symptoms remains a crucial step forward.
"Right now, all of the research is focused on two things out of the brain with antibodies, and there are a few things that are going on," he said.
Colton commented that the hypothesis of an amyloid hypothesis is "easy out" and that clinical studies have not fully supported the theory.
Despite the effort devoted to targeting amyloid, trial results have yielded little success. A 2014 study published in Alzheimer's Research & Therapy found that clinical trials with drugs targeting amyloid had a 99.6 percent failure rate.
Colton emphasized that the amyloid hypothesis was "up in the air" and that researchers should not be solely on amyloid. Instead, they should blend that angle with other ideas and theories in their investigation of AD.
"I think we need to get a better understanding of the cause of AD, because after 25 or 30 years of trying to find a way to reduce amyloid and a way to AD cure by removing amyloid, we have not made much progress, "she said.
Amyloid and tau, however, are related to their relative popularity in the Alzheimer's research field, O'Brien noted. He said that they would rather make large investments in the future. One such example is Biogen's billion-dollar financing of an amyloid clinical trial.
"What pharma would tell you is the reason everything is focused on [amyloid] "And that's the only thing that everyone agrees on in the field," he said. "Beyond those two, there are a thousand different theories and no consensus around any of them."
How Duke researchers are contributing
Researchers at Duke are studying a number of these theories in order to get closer to an eventual therapy that treats AD.
Ornit Chiba-Falek is one of these researchers. Her lab focuses on the genetic changes that can be predisposed to the environment.
In fact, Duke has been closely linked to Alzheimer's genetics research for a number of years. It was in Duke's own Joseph and Kathleen Bryan Alzheimer's Disease Research Center where researchers pinpointed the APOE4 gene, the most significant known genetic contributor to AD in 65 people.
Kathleen Welsh-Bohmer, director of the center, explains that studying the genetics behind AD is a strength of Duke research.
"Our center has actually been exploring the fundamental role of genetics in Alzheimer's disease from a variety of research perspectives," she said.
It is possible that the algorithm may be imminent that it may be imminent.
The name of the trial alludes to another Alzheimer's risk gene, TOMM40, which is located near APOE in the genome and produces a protein found in mitochondria-cells' powerhouses. The drug being tested in the study targets the mitochondria, it explained, and results from the Phase 3 trial will be announced later in October.
Patrick Sullivan, associate professor in medicine, also studies APOE gene in his lab. He wrote in an email to the Chronicle that approximately 25 percent of humans carries the high-risk APOE4 version of the gene.
"However, not all APOE4 carriers get AD, which causes other genetic modifiers or other non-genetic risk factors (e.g., Western diet, low physical activity, chronic stress) contribute to increased risk," he wrote.
APOE4 is one of the leading causes of APOE4. Another of his projects is developing better animal models of Alzheimer's to test "a novel natural compound formulation" that could "get to the market much faster than conventional drugs," Sullivan added.
Colton, another one of Duke's AD researchers, is fascinated by the interaction between the immune system and the brain. Initially, his work was met with skepticism.
At her first presentation as a postdoctoral researcher, she was prepared to speak about the presence of immune cells called microglia within the brain. However, the famous scientist who introduced the topic of the presentation -which has been rejected by the opposition to the contrary, is not a problem.
Scientists eventually came to accept that they were immune cells in the brain, and now Colton studies how these cells interact with the process of metabolizing food in the brain. She hypothesized that AD could be a chronic infection resulting from subtle cellular shifts in response to a virus or bacteria.
"We have actually come up with some very novel proteins-I'm so excited about this-that are new to AD and have not been studied in the brain," she said. "We have recently discovered these proteins in the brain. They're directly related to switching metabolites from one pathway to another. "
On the road to a treatment
Eliezer Masliah, director of the division of neuroscience at the National Institute on Aging, wrote in a statement to the Chronicle that he was hopeful that the recent funding would advance knowledge in the field.
"We have made significant progress in improving the understanding of the epidemiology of the disease and the disease." for Alzheimer's disease and related dementias, "he wrote.
One area of increased funding is allotted for further research into genomics and personalized medicine. Another point of emphasis is the creation of "translational infrastructure programs to enable rapid sharing of data" to improve the reproducibility of research.
Several researchers The Chronicle spoke with the idea of expanding the field of research and investing in the field of medicine.
"We oftentimes think that we know the best way money can be spent, but often, it comes out of the left field," Burke said. "I think it's really promising to have another half a billion dollars to look at some of the more unusual ideas. There are lots of hypotheses about Alzheimer's. "
He added that, to the additional windfall, researchers can look more into genetics, inflammatory mechanisms and metabolic pathways. Funding should focus on amyloid and tau should continue, Burke said, but not be expanded dramatically.
Chiba-Falek added that regarding the systemic disease-involving the entire body and not just the brain-might yield some promising clues. Additionally, it is important for scientists to follow up on previous studies, she noted.
"I think we are coming out of the box and looking at Alzheimer's disease at different levels," she said. "We may want to see more of a systemic disease."
Regardless of the new theories, Colton echoed the other researchers in the field of Alzheimer's research. She added that one of the ideas can not work, one unconventional idea that leads to an important development is worth it.
"Stopping ideas like they're developing when you have a terrible disease like Alzheimer's disease," Colton said.
As it's going to be, it's going to be difficult to meet.
Chiba-Falek suggests that the new funding might make the target date, and Welsh-Bohmer added that the progress in the last 10 years has made her "cautiously optimistic" about the goal.
However, it is difficult to treat treatment time.
"I think that's an aspirational goal and not a realistic one. I think that people do better when they're given a timeline as opposed to just an open-ended promise, "he said. "The reality of drug development is that unless you have a drug for general distribution by 2025."
O'Brien was unsure about the 2025 time frame but predicted that AD would eventually become "somewhat preventable."
"Once you understand what causes these diseases, those pathways will be druggable. In many people, these diseases will be prevented, "he said. "I think that prevention is probably more likely than treatment."
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