Alzheimer’s Disease: Swelling May Be Root Cause, New Drug May Slow Progression

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  • New studies have shed light on how to better detect and treat Alzheimer’s disease.
  • One study found that a drug approved to treat Alzheimer’s disease appears to slow its progression.
  • Another study found that swelling in the neurons caused by certain plaques may contribute to the symptoms of Alzheimer’s disease.

Clinical trial results published Wednesday in the New England Journal of Medicine show that the experimental drug lecanemab appears to slow the progression of Alzheimer’s disease.

But this phase 3 trial also raised safety concerns about the drug, with researchers calling for additional long-term studies on the drug’s safety and efficacy.

This comes over a year after the Food and Drug Administration approved another drug for Alzheimer’s disease, aducanumab.

This approval, though, was controversial, with experts raising questions about the drug’s efficacy and potential impact of its cost on Medicare.

Scientists are also making progress understanding other aspects of Alzheimer’s disease, a condition that is expected to affect nearly 14 million Americans by 2060.

In one recent study, researchers examined how changes in the brain that occur during Alzheimer’s disease may lead to the debilitating symptoms of this disease, which include memory loss, difficulty completing familiar tasks and mood changes.

In the second study, researchers identified a possible biomarker for diagnosing early forms of the disease. This could allow people to start treatments or lifestyle modifications earlier, and may open up the way to wide-scale screening.

More research is needed in both areas, but it highlights the important work that is being done to reduce the burden on people with this disease and their caregivers.

Swelling in nerve cells disrupts signals

A key feature of Alzheimer’s disease is the formation of amyloid plaques between the neurons, which disrupts the function of these brain cells. Plaques form when abnormal levels of the naturally occurring beta-amyloid protein clump together.

Certain medications — including lecanemab and aducanumab — are designed to reduce the level of these plaques in the brain, so far with mixed results in clinical trials.

In a new study published Nov. 30 in the journal Nature, researchers found that swelling in the neurons caused by these plaques may contribute to the symptoms of Alzheimer’s disease.

According to researchers, each amyloid plaque can affect axons of nearby neurons. The axon is the cable-like structure of the neuron that transmits messages to other neurons.

The plaque can cause spheroid-shaped swellings in the axons of nearby neurons.

This could amplify the damaging effect of the plaques on the brain.

“Amyloid plaques don’t take up a large amount of space in the brain, but they do affect hundreds of neurons that are near them or around them,” said Dr. Keith Vossel, professor of neurology and director of the Mary S. Easton Center for Alzheimer’s Research and Care at UCLA in Los Angeles.

In addition, “the value of this study is that the researchers are looking at the functional impact of the axonal spheroids in vivo [in living animals],” said Vossel, who was not involved in the new research.

Axonal swellings, which have been found in the brains of people with Alzheimer’s disease, result from the gradual accumulation of lysosomes within the nerve cells, researchers said.

Lysosomes are a type of organelles that are involved in breaking down excess or worn-out parts of the cell.

Researchers found that in mice genetically engineered to have a condition resembling Alzheimer’s disease, these swellings reduced the transmission of signals passing along the axon.

This suggests that local transmission problems may disrupt connections between different areas of the brain, they said. This could give rise to the memory problems and other cognitive symptoms of Alzheimer’s disease, they suggest.

Protein linked to nerve cell swelling

The authors of the new study also found that a protein in lysosomes called PLD3 was responsible for the organelles accumulating in the cells, which eventually led to swelling in the axons.

They tested the impact of this protein by using gene therapy to remove PLD3 from the neurons of mice with the Alzheimer’s-like disease. This led to a decrease in axonal swelling and an improvement in the functioning of neurons.

The researchers said PLD3 could be a potential target for future treatments. While other proteins are also involved in regulating lysosomes, they said one advantage of PLD3 is that it is found mainly in neurons.

More research is needed to know if lowering the levels of PLD3 in the neurons would improve symptoms in people with Alzheimer’s disease.

Vossel said researchers could potentially create human neurons in the lab using induced pluripotent stem cells (iPSC) technology.

Using these cells, they could see how changes in the level of PLD3 or other molecules affect the formation of axonal spheroids.

Limitations of study findings

“While these [lab-based] models simulate some aspects of the disease, they can’t simulate the full extent or duration of the disease,” Vossel said.

For that, clinical trials — preceded by additional animal studies — would be needed.

“The best way to get at it mechanistically in humans would be to develop some kind of a treatment that would target this process,” he said, “in order to see if it improves or slows the cognitive decline in these patients.”

These next steps, including clinical trials, could take up to a decade or longer.

Urinary biomarker may identify early-stage Alzheimer’s

Changes in the brain that occur in Alzheimer’s disease can begin before memory and other cognitive problems are noticeable.

Being able to easily screen people for Alzheimer’s disease before symptoms are present could allow people to start treatment earlier or make changes to their lifestyle to reduce their risk of symptoms developing.

Current ways of diagnosing Alzheimer’s disease include brain scans, cerebrospinal fluid (CSF) tests and blood tests. None of these are used for wide-scale screening — such as in people without cognitive symptoms.

“We have reliable biomarkers for Alzheimer’s disease, but they are expensive and/or invasive,” said Dr. Douglas Scharre, professor of neurology at The Ohio State University Wexner Medical Center in Columbus.

“We need to find better biomarkers … so that we can use them in analyzing the effectiveness of new treatments,” he added.

Study on biomarker for Alzheimer’s disease

In a study published Nov. 30 in the journal Frontiers in Aging Neuroscience, researchers identified a biomarker that could help doctors diagnose early-stage Alzheimer’s disease using a urine sample.

Having an accurate urine biomarker could make screening for Alzheimer’s disease more convenient and cost-effective.

The study included 574 people with normal cognition, or who had differing degrees of cognitive decline, including people with diagnosed Alzheimer’s disease.

Researchers analyzed participant’s urine and blood samples, and conducted several cognitive tests.

They found that formic acid levels were increased in the urine of all people with cognitive symptoms — including those with early-stage changes — compared to people with normal cognition.

Formic acid is a metabolic byproduct of formaldehyde. Earlier research by the same group of researchers showed that people with Alzheimer’s disease have higher levels of formaldehyde in their urine compared to healthy people.

However, the results of the new study suggest that urinary formic acid may be more sensitive to changes in formaldehyde, the researchers said.

Multiple biomarkers may provide a better picture

Scharre pointed out that the results showed a lot of overlap between the urinary formic acid levels in people with normal cognitive function, mild cognitive impairment and Alzheimer’s disease.

This would make it hard to diagnose a person’s cognitive impairment based on a single urine test, he said.

Vossel noticed the same thing. As a result, he expects formic acid would be used alongside other biomarkers, rather than by itself.

The researchers did combine urinary formic acid and formaldehyde levels with biomarkers found in the blood, finding that this combined score better predicted the stage of the disease.

“They’re looking at a marker that I consider to be non-specific, meaning it could be affected by many types of dementia,” said Vossel. “But when it’s added to more specific markers — such as measures of amyloid and tau — it could add to the diagnostic certainty.”

While there is currently no cure for Alzheimer’s disease, Vossel said screening could still identify people with a higher risk of developing the disease. This might encourage them to make lifestyle changes that reduce their risk of dementia.

This includes eating a healthy diet, staying physically and socially active, and avoiding tobacco and excess alcohol.

“I think if there were a simple test that could be done in a primary care clinic, that would be really useful even now,” he said.

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