Researchers discover the true culprit in Alzheimer’s disease

[Dec 13, 2022: Bill Hathaway, Yale University]

The formation of amyloid plaques in the brain is a hallmark of Alzheimer’s disease. (CREDIT: Getty Images)

The formation of amyloid plaques in the brain is a hallmark of Alzheimer’s disease. But drugs designed to reduce accumulations of these plaques have so far yielded, at best, mixed results in clinical trials.

Yale researchers have found, however, that swelling caused by a byproduct of these plaques may be the true cause of the disease’s debilitating symptoms, they report Nov. 30 in the journal Nature. And they identified a biomarker that may help physicians better diagnose Alzheimer’s and provide a target for future therapies.

According to their findings, each formation of plaque can cause an accumulation of spheroid-shaped swellings along hundreds of axons — the thin cellular wires that connect the brain’s neurons — near amyloid plaque deposits.

The swellings are caused by the gradual accumulation of organelles within cells known as lysosomes, which are known to digest cellular waste, researchers found. As the swellings enlarge, researchers say, they can blunt the transmission of normal electrical signals from one region of the brain to another.

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This pileup of lysosomes, the researchers say, causes swelling along axons, which in turn triggers the devasting effects of dementia.

“We have identified a potential signature of Alzheimer’s which has functional repercussions on brain circuitry, with each spheroid having the potential to disrupt activity in hundreds of neuronal axons and thousands of interconnected neurons,” said Dr. Jaime Grutzendler, the Dr. Harry M. Zimmerman and Dr. Nicholas and Viola Spinelli Professor of Neurology and Neuroscience at the Yale School of Medicine and senior author of the study.

Further, the researchers discovered that a protein in lysosomes called PLD3 caused these organelles to grow and clump together along axons, eventually leading to the swelling of axons and the breakdown of electrical conduction.

When they used gene therapy to remove PLD3 from neurons in mice with a condition resembling Alzheimer’s disease, they found that this led to a dramatic reduction of axonal swelling. This, in turn, normalized the electrical conduction of axons and improved the function of neurons in the brain regions linked by these axons.

The researchers say PLD3 may be used as a marker in diagnosing the risk of Alzheimer’s disease and provide a target for future therapies.

Swelling surrounding amyloid plaques (light blue) in Alzheimer’s patients may be a culprit in dementia symptoms. (CREDIT: Yale University)

“It may be possible to eliminate this breakdown of the electrical signals in axons by targeting PLD3 or other molecules that regulate lysosomes, independent of the presence of plaques,” Grutzendler said.

Who has Alzheimer’s Disease?

In 2020, as many as 5.8 million Americans were living with Alzheimer’s disease.
Younger people may get Alzheimer’s disease, but it is less common.
The number of people living with the disease doubles every 5 years beyond age 65.
This number is projected to nearly triple to 14 million people by 2060.
Symptoms of the disease can first appear after age 60, and the risk increases with age.

What is known about Alzheimer’s Disease?

Scientists do not yet fully understand what causes Alzheimer’s disease. There likely is not a single cause but rather several factors that can affect each person differently.

Age is the best known risk factor for Alzheimer’s disease.
Family history—researchers believe that genetics may play a role in developing Alzheimer’s disease. However, genes do not equal destiny. A healthy lifestyle may help reduce your risk of developing Alzheimer’s disease. Two large, long term studies indicate that adequate physical activity, a nutritious diet, limited alcohol consumption, and not smoking may help people.
Changes in the brain can begin years before the first symptoms appear.
Researchers are studying whether education, diet, and environment play a role in developing Alzheimer’s disease.
There is growing scientific evidence that healthy behaviors, which have been shown to prevent cancer, diabetes, and heart disease, may also reduce risk for subjective cognitive decline.

What is the burden of Alzheimer’s disease in the United States?

Alzheimer’s disease is one of the top 10 leading causes of death in the United States.
The 6th leading cause of death among US adults.
The 5th leading cause of death among adults aged 65 years or older.
In 2020, an estimated 5.8 million Americans aged 65 years or older had Alzheimer’s disease. This number is projected to nearly triple to 14 million people by 2060.

In 2010, the costs of treating Alzheimer’s disease were projected to fall between $159 and $215 billion. By 2040, these costs are projected to jump to between $379 and more than $500 billion annually.

Death rates for Alzheimer’s disease are increasing, unlike heart disease and cancer death rates that are on the decline.

Dementia, including Alzheimer’s disease, has been shown to be under-reported in death certificates and therefore the proportion of older people who die from Alzheimer’s may be considerably higher.

For more science news stories check out our New Discoveries section at The Brighter Side of News.

Note: Materials provided above by Yale University. Content may be edited for style and length.

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