  | SCIENCE 561434222 Alzheimer's researchers rethink approach to the disease Scientists are exploring multiple ways of attacking a disease now considered too complex for a one-size-fits-all solution. By LAURAN NEERGAARD Associated Press SEPTEMBER 26, 2019 — 12:15PM  MARK CORNELISON – ASSOCIATED PRESSAlzheimer’s specialist Donna Wilcock said, “There are a lot of changes that happen in the aging brain.” |
When researchers at the University of Kentucky compare brains donated from people who died with dementia, very rarely do they find one that bears only Alzheimer’s trademark plaques and tangles — no other damage.
Contrary to popular perception, “there are a lot of changes that happen in the aging brain that lead to dementia,” said Donna Wilcock, an Alzheimer’s specialist.
For years researchers have been guided by one leading theory — that getting rid of a buildup of a sticky protein called amyloid would ease the mind-robbing disease. Yet drug after drug has failed. They might clear out the gunk, but they’re not stopping Alzheimer’s.
With more money — the government had a record $2.4 billion to spend on such research this year — scientists are rethinking Alzheimer’s and exploring multiple ways of attacking a disease now considered too complex for a one-size-fits-all solution.
‘Sort of a missing link’
No one knows what causes Alzheimer’s but amyloid deposits were an obvious first suspect, easy to spot in brain tissue. But it starts building up 20 years before any memory loss, and by itself is not enough to cause degeneration.
Contrary to popular perception, “there are a lot of changes that happen in the aging brain that lead to dementia,” said Donna Wilcock, an Alzheimer’s specialist.
For years researchers have been guided by one leading theory — that getting rid of a buildup of a sticky protein called amyloid would ease the mind-robbing disease. Yet drug after drug has failed. They might clear out the gunk, but they’re not stopping Alzheimer’s.
With more money — the government had a record $2.4 billion to spend on such research this year — scientists are rethinking Alzheimer’s and exploring multiple ways of attacking a disease now considered too complex for a one-size-fits-all solution.
‘Sort of a missing link’
No one knows what causes Alzheimer’s but amyloid deposits were an obvious first suspect, easy to spot in brain tissue. But it starts building up 20 years before any memory loss, and by itself is not enough to cause degeneration.
 MARK CORNELISON, ASSOCIATED PRESS This Aug. 14, 2019 photo provided by the University of Kentucky shows Donna Wilcock, of the Sanders-Brown Center on Aging in her lab in Lexington, Ky. She says that contrary to popular perception, "there are a lot of changes that happen in the aging brain that lead to dementia in addition to plaques and tangles." | Sometime after plaques appear, another protein named tau starts forming tangles inside neurons, heralding cell death. Yet autopsies show that some people die with large amounts of plaques and tangles, but escape dementia. Something else must play a role. One possible culprit: The brain’s immune cells, called microglia. Neurons are the brain’s rock stars, the nerve cells that transmit information. Microglia are cells long regarded as the neurons’ support staff. But “it’s becoming clear they’re much more active and play a much more significant role,” said Dr. Richard Hodes, director of the National Institute on Aging. |
One of its jobs is to gobble toxic proteins and cellular debris. Recently, a mutation in a gene called TREM2 was found to weaken microglia and increase the risk of Alzheimer’s. Dr. David Holtzman at Washington University in St. Louis said his team found more tau tangles clustered around amyloid plaques when people harbored TREM2 mutations. Normal microglia seem to restrict amyloid plaques, which limits damage to surrounding tissue — damage that can make it easier for tau to take hold, he said.
While it was known that amyloid buildup drives tau tangles, “we never had a good clue as to how it is doing that,” Holtzman said. The new findings “would argue that these cells are sort of a missing link.”
Is it germs? Is it inflammation?
The idea that infections earlier in life could set the stage for Alzheimer’s has simmered on the edge of mainstream medicine, but is getting new attention. Both the germ that causes gum disease and strains of herpes viruses have been found in Alzheimer’s-affected brain tissue.
Dr. Todd Golde of the University of Florida cautioned that the germs’ presence doesn’t mean they caused dementia — they could be a consequence of it.
A U.S. study found certain herpes viruses affected the behavior of Alzheimer’s-related genes. “Maybe these are just opportunistic pathogens that have space to spring up in the brains of people affected with Alzheimer’s disease,” said Benjamin Readhead of Arizona State University. But, “it looks at least plausible that some of these pathogens are capable of acting as accelerants of disease.”
One key commonality among emerging theories is how aggressively the brain’s immune system defends itself — and thus how inflamed it becomes. When inflammation is too strong, or doesn’t go away, it’s like friendly fire that harms cells. Remember how some people have lots of plaques and tangles but no dementia? Massachusetts General researchers found that strikingly little inflammation surrounded the gunky buildup in the resilient brains — but the Alzheimer’s-affected brains harbored a lot.
A handful of drugs are being explored to tamp down inflammation’s damaging side without quashing its good effects. The goal is to restore the balance of a healthy brain’s environment, Wilcock said, so microglia “can perform their essential functions without damaging surrounding tissue.”
“Now we have an opportunity, a real opportunity, to expand and try all these avenues,” said Alzheimer’s Association chief science officer Maria Carrillo.
While it was known that amyloid buildup drives tau tangles, “we never had a good clue as to how it is doing that,” Holtzman said. The new findings “would argue that these cells are sort of a missing link.”
Is it germs? Is it inflammation?
The idea that infections earlier in life could set the stage for Alzheimer’s has simmered on the edge of mainstream medicine, but is getting new attention. Both the germ that causes gum disease and strains of herpes viruses have been found in Alzheimer’s-affected brain tissue.
Dr. Todd Golde of the University of Florida cautioned that the germs’ presence doesn’t mean they caused dementia — they could be a consequence of it.
A U.S. study found certain herpes viruses affected the behavior of Alzheimer’s-related genes. “Maybe these are just opportunistic pathogens that have space to spring up in the brains of people affected with Alzheimer’s disease,” said Benjamin Readhead of Arizona State University. But, “it looks at least plausible that some of these pathogens are capable of acting as accelerants of disease.”
One key commonality among emerging theories is how aggressively the brain’s immune system defends itself — and thus how inflamed it becomes. When inflammation is too strong, or doesn’t go away, it’s like friendly fire that harms cells. Remember how some people have lots of plaques and tangles but no dementia? Massachusetts General researchers found that strikingly little inflammation surrounded the gunky buildup in the resilient brains — but the Alzheimer’s-affected brains harbored a lot.
A handful of drugs are being explored to tamp down inflammation’s damaging side without quashing its good effects. The goal is to restore the balance of a healthy brain’s environment, Wilcock said, so microglia “can perform their essential functions without damaging surrounding tissue.”
“Now we have an opportunity, a real opportunity, to expand and try all these avenues,” said Alzheimer’s Association chief science officer Maria Carrillo.
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