Scientists identify the primary driver of Alzheimer’s disease

Alzheimer’s disease slowly robs people of memory and thinking skills, affecting millions worldwide. For decades, the focus has been on amyloid plaques—clumps of misfolded protein that collect in the brain. Researchers long hoped that clearing these plaques could halt or slow the disease.

That hope has faced years of disappointment. Many drugs aimed at breaking down or blocking plaques have failed in trials, often showing only small benefits. A team at Yale University now believes the plaques may not be the main driver of the condition’s worst effects. Their work could shift the direction of future treatments.

Under the leadership of Dr. Jaime Grutzendler, the researchers discovered a previously overlooked biomarker tied to Alzheimer’s symptoms. Published in Nature, their study points to swelling near plaques—not the plaques themselves—as a possible trigger for cognitive decline.

These swellings form along hundreds of axons—the thin fibers that carry electrical signals between brain cells. When a plaque develops, balloon-like bulges begin to gather nearby, disrupting the brain’s complex communication network.

The culprit lies in a breakdown of cellular waste management. Lysosomes, the cell’s cleanup crew, start piling up inside axons. Instead of clearing debris, they form dense clusters that choke off normal activity. Over time, these blockages grow, making it harder for neurons to share information.

As the swellings spread, the damage compounds. “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. Grutzendler.

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. "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," said Dr. Grutzendler.

Alzheimer's disease is a devastating illness that affects millions of people worldwide. Currently, there is no cure, and available treatments can only help to manage symptoms.

However, the discovery of a new biomarker and potential therapeutic target for the disease is a significant step forward in the fight against Alzheimer's. The research team's findings provide hope for the development of new treatments that could improve the quality of life for those living with the disease.

The next step for the researchers is to further explore the role of PLD3 in Alzheimer's disease and to investigate other molecules that regulate lysosomes. They hope that their work will lead to the development of new therapies that can target the root cause of the disease, rather than just managing its symptoms.

The discovery of a new biomarker and potential therapeutic target for Alzheimer's disease is a significant breakthrough in the field of neurodegenerative disorders. It provides hope for the development of new treatments that could improve the lives of millions of people affected by the disease.

The researchers' findings represent a step forward in our understanding of the complex mechanisms underlying Alzheimer's disease, which has long been considered one of the most challenging and enigmatic conditions in medicine.

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.

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.

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