Wednesday January 22, 2020

Scientists Explore Novel Ways to Attack Alzheimer’s in Wake of String of Disappointing Drug Failures

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"

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Drugs, Alzheimer, Dementia, Hospitalisation, Risk
Dr. William Burke goes over a PET brain scan, Aug. 14, 2018 at Banner Alzheimers Institute in Phoenix, Arizona. VOA

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.

Scientists, Alzheimers, Drug
When researchers at the University of Kentucky compare brains donated from people who died with dementia, very rarely do they find one. Pixabay

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. It’s far from clear that any will pan out, but “the field is now much more open-minded than it ever was to alternative ideas,” Wilcock said.

Breaking the plaque and tangle link

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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 — maybe several other things — also must play a role. One possible culprit: The brain’s unique immune cells, called microglia.

Scientists, Alzheimers, Drug
If they do, “we call it a unicorn,” said Donna Wilcock, an Alzheimer’s specialist at the university’s aging center. Pixabay

No surprise if you’ve never heard of microglia. Neurons are the brain’s rock stars, the nerve cells that work together to transmit information like memories. Microglia are part of a different family of 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 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 a little human tau. Sure enough, more tangles formed next to plaques in mice with weak microglia than in those with functional immune cells, they recently reported in Nature Neuroscience.

Why? 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 explained.

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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.”

Separately, biotech company Alector Inc. has begun first-step patient testing of a drug designed to boost TREM2 and better activate microglia.

 The germ conundrum

Could gum disease or herpes be to blame? The idea that infections earlier in life could set the stage for Alzheimer’s decades later has simmered on the edge of mainstream medicine, but it’s getting new attention. It sounds weird, but both the germ that causes gum disease and different strains of herpes viruses have been found in Alzheimer’s-affected brain tissue.

Researchers in New York are testing the herpes drug valacyclovir in 130 people with mild Alzheimer’s who have evidence of infection with certain herpes strains.

And Cortexyme Inc. is enrolling more than 500 early-stage patients around the country to test a drug that targets potentially neuron-damaging substances produced by gingivitis bacteria.

Whether the germ theory is a worthwhile pursuit was hotly debated at an international Alzheimer’s Association meeting in July. One skeptic, Dr. Todd Golde of the University of Florida, cautioned that germs’ mere presence doesn’t mean they caused dementia — they could be a consequence of it.

Still, a 2018 study from Taiwan offered a hint that treating herpes infection might lower later dementia risk. And 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, who co-authored that U.S. paper. But, “it looks at least plausible that some of these pathogens are capable of acting as accelerants of disease.”

 A common denominator

One key commonality among emerging Alzheimer’s theories is how aggressively the brain’s immune system defends itself — and thus how inflamed it becomes.

Inflammation is a normal part of the body’s response to illness and injury, one method of fighting infection or healing wounds. But 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? A few years ago Massachusetts General researchers found strikingly little inflammation surrounded all the gunky buildup in the resilient brains — but the Alzheimer’s-affected brains harbored a lot.

Research since has found similar inflammatory effects with other forms of dementia — like vascular dementia, where tiny blood vessels that feed the brain are lost or blocked, and dementias caused by Lewy bodies or other toxic proteins. A growing list of genes linked to inflammatory processes also may play a role.

A handful of drugs are being explored in the quest to tamp down inflammation’s damaging side without quashing its good effects. Take those microglia, which Holtzman said “may be a two-edged sword.”

Early on, before there’s too much plaque, revving them up may be good. But later on, a hyperactive swarm around growing plaques spews out inflammatory molecules.

In addition to their immune system job, microglia also secrete molecules that help nourish neurons, noted Kentucky’s Wilcock. The goal is to restore the natural balance of a healthy brain’s environment, she said, so microglia “can perform their essential functions without damaging surrounding tissue.”

Amyloid’s still in the picture

All those drug flops weren’t a waste of time.

“Every time there’s a failure it’s absolutely clear that we learn a lot,” Emory University neurologist Dr. Allan Levey recently told the government’s Alzheimer’s advisory council.

One lesson: Timing may matter. Most of the failed anti-amyloid drugs were tested in people who already had at least mild symptoms. Some studies seeking to prevent memory loss in the first place still are underway. Several anti-tau drugs also are being tested.

Another lesson: Most people have a mix of different dementias, which means they’ll need a variety of treatments.

“Now we have an opportunity, a real opportunity, to expand and try all these avenues,” said Alzheimer’s Association chief science officer Maria Carrillo. “The triggers as we understand them are broad.” (VOA)

Next Story

Here’s How Marijuana can Have an Impact on Your Driving Ability

Marijuana may affect driving ability for 12 hours after use

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Marijuana
Marijuana use may have an impact on driving ability even 12 hours after use. Pixabay

Researchers have found that marijuana use may have an impact on driving ability even 12 hours after use.

The study, published in the journal Drug and Alcohol Dependence, found that in addition to chronic, heavy, recreational cannabis use being associated with poorer driving performance in non-intoxicated individuals compared to non-users.

While several studies have examined the direct effect of cannabis intoxication on driving, no other studies until now have examined the effects on driving in heavy marijuana users who are not high.

“People who use cannabis don’t necessarily assume that they may drive differently, even when they’re not high,” said study researcher Staci Gruber from McLean Hospital in the US.

“We’re not suggesting that everyone who uses cannabis will demonstrate impaired driving, but it’s interesting that in a sample of non-intoxicated participants, there are still differences in those who use cannabis relative to those who don’t,” Gruber added.

Marijuana
While several studies have examined the direct effect of cannabis intoxication on driving, no other studies until now have examined the effects on driving in heavy marijuana users who are not high. Pixabay

For the findings, the research team used a customised driving simulator to assess the potential impact of cannabis use on driving performance.

At the time of study, marijuana users had not used for at least 12 hours and were not intoxicated.

Overall, heavy marijuana users demonstrated poorer driving performance as compared to non-users.

For example, in the simulated driving exercise, marijuana users hit more pedestrians, exceeded the speed limit more often, made fewer stops at red lights, and made more center line crossings.

When researchers divided the marijuana users into groups based on when they started using cannabis, they found that significant driving impairment was detected and completely localized to those who began using marijuana regularly before age 16.

“It didn’t surprise us that performance differences on the driving simulator were primarily seen in the early onset group,” said study researcher Mary Kathryn Dahlgren.

According to the authors, research has consistently shown that early substance use, including the use of cannabis, is associated with poorer cognitive performance.

“What was interesting was when we examined impulsivity in our analyses, most of the differences we saw between cannabis users and healthy controls went away, suggesting that impulsivity may play a role in performance differences,” Dahlgre added.

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“There’s been a lot of interest in how we can more readily and accurately identify cannabis intoxication at the roadside, but the truth of the matter is that it is critical to assess impairment, regardless of the source or cause,” she said. o

“It’s important to be mindful that whether someone is acutely intoxicated, or a heavy recreational cannabis user who’s not intoxicated, there may be an impact on driving,” she added. (IANS)