Diversifying cures for Alzheimer’s Scientists see multiple causes of its symptoms
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.
If they do, “we call it a unicorn,” said Donna Wilcock, an Alzheimer’s specialist at the university’s aging center. 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.”
That hard-won lesson helps explain how scientists are rethinking Alzheimer’s.
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 inevitable worsening. Today’s treatments only temporarily ease symptoms. The new mantra: diversify.
With more money — the government had a record $2.4 billion to spend on Alzheimer’s research this year — the focus has shifted to exploring multiple novel ways of attacking a disease now considered too complex for a one-size-fits-all solution. On the list, researchers are targeting the brain’s specialized immune system, fighting inflammation, even asking if simmering infections play a role. Most of these fresh starts are in the earliest research stages.
No one knows what causes Alzheimer’s but amyloid deposits were an obvious first suspect, easy to spot when examining brain tissue. But it turns out that gunk starts silently building up 20 years before any memory loss, and by itself it’s not enough to cause degeneration.
Sometime after plaques appear, another protein named tau starts forming tangles inside neurons, heralding cell death and memory loss.
But again, not always: Autopsies show sometimes people die with large amounts of both plaques and tangles, yet escape dementia.
So something else also must play a role. One possible culprit: The brain’s unique immune cells, called microglia. “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 microglial job is to gobble up 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 took a closer look — and says microglia may be key to how the amyloid-tau duo turns toxic.
In donated human brains, his team found more tau tangles clustered around amyloid plaques when people harbored microglia-weakening TREM2 mutations. The researchers altered the TREM2 gene in mice and seeded their brains with human tau. More tangles