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Alzheimer's: Killing the Mind First

Alzheimer's: Killing the Mind First

By Ben Brumfield | Published July 6, 2017

When George Wright buried his wife, Beth, in 2013, he was probably easing into the same illness that had killed her at age 84. But his adult children hadn’t yet noticed that he, too, had Alzheimer’s disease.

Their eyes had been fixed on their mother while her mind unraveled, and doctors had no way of stopping or slowing the deterioration. Her last three years had been particularly painful for them.

VIDEO: Killing the Mind First

“That was just real sad grief for me, a lot of crying time,” said Beth and George’s daughter, Alice Wright-Stephens. “Just watching that great lady disappear right before my eyes. She was there, but she wasn’t.”

That’s almost exactly how the first patient with “senile dementia” ever recorded by Dr. Aloysius Alzheimer described herself: “I’ve lost myself, so to speak,” Auguste Deter told the psychiatrist again and again in 1901.

Urgent need

In the 116 years since Dr. Alzheimer was unable to help Deter, unfortunately, not much has changed. The research path has been vexing, while the need for progress has become urgent — especially as people live longer.

Among people who make it to age 85, some 50 percent will have Alzheimer’s, which afflicts slightly more women than men. Consequently, most everyone knows someone who is suffering or has died from the disease.

Late last year, U.S. research on Alzheimer’s received a significant boost in funding. And recently — aided by new tools — scientists, doctors, and engineers around the world have been making fascinating inroads, including at the Georgia Institute of Technology, which collaborates with Emory University’s highly regarded Alzheimer’s research center.

Some of their insights include: Alzheimer’s may work much like mad cow disease. It also may have aspects of inflammatory disease. And a special light has caused immune cells in the brains of mice to clean up bad proteins that are a hallmark of Alzheimer’s.

Portrait of the four Wright siblings seated in a row on a couch in a living room

Van Earl Wright, Scotland Wright, Alice Wright-Stephens, and Bryant Wright. “That was just real sad grief for me, a lot of crying time,” Wright-­Stephens said of her experience watching her mother, Beth, decline. Beth died in 2013 from Alzheimer’s disease, and their father now has the same illness. Photo: Christopher Moore.

The Wrights

Chances are, if you reach your golden years, you or someone close to you will get Alzheimer’s — like the late Beth Wright and her husband, George, who now requires 24-hour care.

Their children — Alice, an etiquette teacher; Bryant Wright, an ­Atlanta-area pastor; Van Earl Wright, a TV sportscaster; and Scotland Wright, a business owner — hope that by sharing touching and harrowing moments from their parents’ decline, they can help others who are caring for loved ones with Alzheimer’s.

Healthy Brain vs. Severe Alzheimer's

Two sections of dissected brain, the left (healthy) shows a plump, full structure while the right (Alzheimer's) is withered with many holes and crevasses

Alzheimer’s kills so many neurons (core nerve cells) that it riddles the brain with gaping crevasses and can remove 30 percent of its total mass, debilitating mental functions. Image: National Institute on Aging, National Institutes of Health.

Alzheimer’s kills so many neurons (core nerve cells) that it riddles the brain with gaping crevasses and can remove 30 percent of its total mass, debilitating mental functions. But in the beginning, it can move slowly and cause momentary memory lapses or personality breakdowns, like those that beset Beth.

“There was an elegance about her, a genteelness about her,” Bryant recalled. “She was the consummate Southern lady, and so gracious,” Scotland said.

But suddenly, their mother began blowing up in rage, and extreme fear displaced her inborn self-confidence. “It was so opposite of the person we were reared by,” Van Earl said. “I remember us being on conference calls. We didn’t know what was going on.”

Square one

In 1906, Dr. Alzheimer autopsied Deter’s brain. Examining the tissue under the microscope, he found two characteristics that became the pillars of official Alzheimer’s diagnosis. “One was amyloid plaque, and the other was neurofibrillary tangles,” said Dr. Allan Levey, director of the Emory Alzheimer’s Disease Research Center.

Both the plaque, which is outside the neurons, and the tangles, which are inside them, are made of protein molecules that naturally exist in the brain, but they appear to have gone wrong. The amyloid beta plaque, in particular, forms scruffy, large clumps, and researchers have been fixated on it as the cause of Alzheimer’s for decades, resulting in a single-minded drug-development approach.

“The bias has been enormous,” Levey said. “Bias is a very conservative word in this example.”

Drugs focusing on removing amyloid beta plaque have all failed so far. “We’re now looking at a disease that is one of the leading causes of death, for which we don’t have a single treatment,” he said.

Research has sunk billions of dollars, and one failed drug can financially ruin a drug maker. “Many of the biggest pharmaceutical companies have gotten out of the Alzheimer’s business,” Levey said.

It’s time to go back to square one, he said, and really figure out what’s causing this disease.

Data detective

To guide future research, Levey would especially like to see the data collected in countless studies mined to sort the wheat from the chaff.

Cassie Mitchell does just that. The informaticist at the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory University has combed thousands of studies focused on the proteinaceous amyloid beta plaque and fibrillary tangles, which are made of a protein called tau, to mine suitable datasets for clearer associations with cognitive decline.

Cassie Mitchell sits in her wheelchair at a table in a bright room, and is in conversation with an undergraduate student, who has a laptop open in front of her.

Cassie Mitchell (right), an informaticist at the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory University, has combed thousands of studies focused on amyloid beta plaque and fibrillary tangles. Photo: Rob Felt.

In the composite data, amyloid beta plaque has not looked like a fruitful treatment target.

“When you pull everybody’s data together, there’s no correlation that can be seen through all the data,” Mitchell said. In other words, across masses of data, high levels of amyloid beta plaque in a brain do not correspond to more mental decline. (Alzheimer’s lab studies are based on models of diseased brains in mice.)

But data analyses look very different for the protein behind the fibrillary tangles — that tau, particularly “phosphorylated” tau, or p-tau. “There’s a very strong correlation with mental decline,” Mitchell said. “We need to look more into how p-tau fits into the picture.”

Phosphorylation is a normal part of cell life that makes protein molecules more chemically active, but in Alzheimer’s, too much tau gets phosphorylated, Mitchell said, and that may create those tangled fibrils inside of neurons.

Prion problems

Yury Chernoff agrees with the take on p-tau but has a slightly different assessment of amyloid beta.

He studies proteins gone bad, particularly prions, which are widely known as the cause of mad cow disease, which, like Alzheimer’s, destroys the brain. Chernoff implants human amyloids in yeast cells to experiment with them, and he firmly believes that bad versions of the protein are indeed the cause of Alzheimer’s disease, the way prions are the cause of mad cow disease.

“The whole mechanism is very similar to a lot of proteins which occur in different diseases and different organisms,” said Chernoff, a professor in Georgia Tech’s School of Biological Sciences.

But Mitchell’s conclusions make sense to him. Having amyloid beta bound up in clunky plaque wads might make it less able to enter neurons and damage tau. He has seen similar scenarios in which harmful proteins became less harmful as their accumulations grew.

Yuri Chernoff shown in closeup through the window of some equipment in his lab

Professor Yury Chernoff, who studies proteins gone bad, has found similarities between the prions that cause mad cow disease and the amyloid beta plaques found in the brains of people with Alzheimer’s. Photo: Rob Felt.

Chernoff thinks the culprits in Alzheimer’s may be short, very chemically reactive splinters of amyloid beta.

Like Mitchell, Chernoff believes malformed tau inside of neurons may ultimately be at the root of neuron breakdown. But Chernoff believes it’s likely that amyloid beta splinters touch tau, deforming that protein, leading to those fibrillary tangles.

“The proteins (tau) of these fibril structures are losing their normal cellular function,” Chernoff said. Robbing the neuron of a functioning protein could start the cognitive decline.

Disturbed ‘stranger’

Forgetful blunders, like fumbling an acquaintance’s name, are normal, even before aging makes them more confounding. They’re probably not due to Alzheimer’s.

But this was: “We got a very stressful call from Mom that we need to get over to the house, that there’s a stranger in the house,” Scotland Wright said. “It was Dad.”

George stood helplessly next to his wife, Beth, who beseeched him — the “stranger” — to go away. “For Dad, it was just so disturbing.”

Pull quote: "She was there, but she wasn't." — Alice Wright-Stephens on her mother's last three years living with Alzheimer's

A brain region instrumental in memory, the hippocampus, is one that Alzheimer’s attacks early and thoroughly. It’s the section of the brain also responsible for orienting us as we navigate our world, and Alzheimer’s damage can make patients wander haplessly.

“They get lost in unfamiliar places but also in familiar places, like between home and the store,” said Scott Moffat, an associate professor in Georgia Tech’s School of Psychology who studies Alzheimer’s as well as changes in brain performance during healthy aging. “Getting lost a lot may be a good early marker of someone having Alzheimer’s.”

Beth began leaving her car door open after driving to work, and she left the engine running. Then one day, she started meandering at the church where her son Bryant preaches. “She was found in the parking lot,” Bryant said. Near a very big street.

Beth could have wandered into traffic. Her children realized it was time for round-the-clock Alzheimer’s care.

Blood stains

The hippocampus has a reputation for having vulnerable tissue, and Alzheimer’s may start early there in part due to localized bleeding, said Levi Wood, an assistant professor in the George W. Woodruff School of Mechanical Engineering. Together with Assistant Professor Amit Reddi in Georgia Tech’s School of Chemistry, he’s inspecting heme (part of red blood cells) to see how it might influence amyloid beta plaque.

Levi Wood sits at a microscope in a darkened room and peers through the lenses while an image of fibers with small red nodes is shown on a computer screen next to him

Assistant Professor Levi Wood uses a 3-D microscope slide he developed, showing neurons in a way that represents their constellation in the brain. Photo: Rob Felt.

Heme might be breaking down clumps of amyloid into those potentially dangerous shorter splinters that interest Chernoff. “De-aggregated amyloid beta is much more toxic than clumped-up amyloid,” Wood said, “and it may be more inflammatory.”

Inflammation is important in Wood’s research. Some rare patients who have amyloid plaques don’t get Alzheimer’s in spite of that, and their immune response is markedly different from that of Alzheimer’s sufferers. Their brains don’t show inflammation typical in Alzheimer’s.

Amyloid Plaques

A microscope image showing many green nodes with long green fibers trailing behind them making a carpet-like structure, while blue nodes and red fibers are interspersed among the green.

Along with blood vessels (red) and nerve cells (green), this mouse brain shows abnormal protein clumps known as plaques (blue). Image: Along with blood vessels (red) and nerve cells (green), this mouse brain shows abnormal protein clumps known as plaques (blue).

Along with the effects of heme, Wood is studying proteins involved in brain inflammation. “What we’re trying to understand now is how a combination of these proteins may be triggering the immune response that in turn stresses out the neurons, causing them to die.”

To observe this, Wood uses a 3-D microscope slide he developed while getting his Ph.D. at the Massachusetts Institute of Technology. It’s a scaffold that holds neurons in a way that represents their constellation in the brain.

Wood also thinks brain immune cells called microglia, which are also responsible for pruning parts of neurons that are no longer needed, may get overly activated in inflammation and attack neurons.

Wood’s research is broader based for a reason. Like Emory’s Levey, he thinks the previous focus has been too narrow. In addition to neurons, for example, there is a brimming handful of other cell types in the brain “which are only recently getting substantial attention.”

Dreadful certainty

A doctor showed Beth Wright’s children an image of her brain activity. “One side was just black; the other side looked like brain matter,” her daughter, Alice, said.

A surprise cure for Alzheimer’s is unlikely, but researcher Annabelle Singer has had some jaw-dropping results with diseased mice using a simple light.

Singer has reversed the research approach. Instead of focusing on how proteins might cause brain dysfunction, she looks at how brain activity deficits might contribute to the disease.

“A particular activity is lacking. It’s called gamma,” said Singer, an assistant professor of neuroscience in the Wallace H. Coulter Department of Biomedical Engineering. Gamma is a kind of rhythm for neuron activity, like a techno dance beat for the brain, with a very specific frequency of 40 hertz.

“It’s lacking early in the disease, before mice develop any symptoms, before plaques develop,” Singer said. The research team she was on previously at MIT tried to stoke gamma to see if it improved things.

It was so simple, and it worked. The short version: They showed mice a light flickering at 40 hertz. That put microglia to work cleaning up bad proteins in the visual cortex of their brains.

“So, you can actually reduce the pathology of the disease (in mice). That’s really surprising,” Singer said.

Forty hertz is really fast, sort of like the quivering light from a faulty fluorescent bulb. But scientists caution against experimenting with this at home. They don’t know what could happen if someone got the frequency wrong, and flickering light can sometimes trigger seizures in epilepsy patients.

Goodbye mom

Bryant choked back tears as he recalled a dinner with his mother that left no doubt death was near. “She couldn’t swallow. She didn’t know how to bring the spoon or fork to her mouth. I realized that was it.”

Soon, the family gathered at Beth’s bedside, where they stayed for four days. “It was tears. It was hilarious. It was stories of growing up,” Alice said. They coped as they always had as a family — leaning on one another, on faith and on prayer.

George never seemed to understand what was wrong with his wife of 63 years. His children say caring for him has had harrowing moments, but fun ones as well. George has always had a great sense of humor and still does, despite Alzheimer’s.

Perhaps the disease will pass his children by. Only the rarest forms of Alzheimer’s are directly hereditary. In common Alzheimer’s, genetic risk factors do play a significant role, but many researchers believe a healthy lifestyle that is good for the heart can also protect the brain. And hopefully new inroads in medical research will bear fruits.

#30

Ben Brumfield is a senior science writer with Georgia Tech’s Institute Communications. He is a former CNN.com editor.

The National Institute on Aging has funded much of Emory University’s, Yury Chernoff’s, and Annabelle Singer’s work. The National Institute of Mental Health has funded Annabelle Singer’s past work. The National Institute of Neurological Disorders and Stroke has funded Cassie Mitchell’s work. The above agencies are members of the National Institutes of Health. The National Science Foundation has also funded Yury Chernoff’s work. Any opinions, findings, and conclusions or recommendations expressed in this material are those of the authors and do not necessarily reflect the views of the sponsoring organizations.

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