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New clues about the mechanisms preceding Alzheimer’s onset may eventually lead to novel treatment pathways. Image credit: SimpleImages/Getty Images.
  • There is still no cure for the most common type of dementia, Alzheimer’s disease.
  • The Food and Drug Administration (FDA) has now approved two new drugs for the treatment of Alzheimer’s disease in the United States, but repeated clinical trials have failed to demonstrate their efficacy in reducing symptoms.
  • Energy metabolism is known to change in the aging brain.
  • Now, a group of researchers have proposed that changes in the mitochondria that occur before beta-amyloid plaques appear could play a role in the development of Alzheimer’s disease.

Controversy has marred Alzheimer’s research over the past year due to disagreements about the Food and Drug Administration’s (FDA) accelerated approval of two drugs for the condition.

Alzheimer’s disease is a debilitating condition characterized by memory loss, but it also affects language and a person’s responses to their environment, according to the Centers for Disease Control and Prevention (CDC). There are currently no drugs that improve the symptoms of this condition.

Two drugs recently approved by the FDA for Alzheimer’s — aducanumab and lecanemab — are human monoclonal antibodies designed to clear the beta-amyloid plaques that build up in the brains of people with Alzheimer’s disease.

As clinical trials have not conclusively shown that these drugs improve Alzheimer’s symptoms, some researchers are asking if different targets for the pharmaceutical treatment of Alzheimer’s disease need to be considered.

For new targets to be identified, researchers need to explore other mechanisms underpinning the development of the condition.

One of those potential mechanisms concerns changes in energy metabolism. The brain uses up around 25% of the energy our body uses, and disruption to this can affect its ability to function normally.

A team of researchers based at the ​​Karolinska Institutet, Solna, Sweden, recently demonstrated that changes in the mitochondria—the powerhouse of the cell—can lead to neuronal damage over time in mouse models of Alzheimer’s disease.

Their findings were published in the journalMolecular Psychiatry.

Previous research has suggested that Alzheimer’s is set off by changes in the brain’s energy metabolism.

One study using induced pluripotent stem cells demonstrated that changes occur as we age to the way that brain cells take up and use glucose to make energy.

The authors of the current study hypothesized that this could predispose people to developing Alzheimer’s later in life. They also suggested this finding supported the idea that Alzheimer’s disease is a “multi-hit” disorder caused by many changes in the brain.

Energy metabolism in cells occurs in the mitochondria, which are small subcellular structures that convert the energy released in our food in the form of glucose into energy via a process called oxidative phosphorylation. This process creates adenosine triphosphate (ATP), a molecule that can be used for energy by the cell.

The disruption of any of these mechanisms can affect energy metabolism.

Disrupted energy metabolism has also been linked to inflammation in people with Alzheimer’s disease, another change to the brain that characterizes Alzheimer’s disease but is poorly understood.

Dr. Theodore Strange, associate chair of medicine at Staten Island University Hospital and a specialist in geriatrics, who was not involved in the research, told Medical News Today:

“[W]ith all phases of medicine now including heart disease and cholesterol, we’re dealing with the inflammatory piece. I think [this] will be the area that probably is where we’ll see some breakthrough [regarding Alzheimer’s], where we can target the immunologic response.”

The researchers used genetically altered mouse models that display Alzheimer’s disease pathology in the brain in a series of experiments to investigate how energy metabolism changes in the brain.

First, they deciphered which genes were being transcribed in neuron cells in an area of the mouse brain called the hippocampus by looking at the RNA, signaling molecules produced after reading the DNA. They also looked at the level of ATP and the oxygen levels in cells, as well as other markers, to determine how energy metabolism was functioning.

They found that before the mice developed Alzheimer’s disease pathology, mitochondrial activity had increased. Supporting this, they also discovered that genes involved in oxidative phosphorylation had also increased.

This finding was surprising as previous research has shown that Alzheimer’s disease can be predicted when oxidative phosphorylation decreases.

The researchers then showed that once amyloid beta plaques started forming in the brains of the mice, this increased metabolism in the mitochondria was reversed, perhaps as a compensatory mechanism.

At the same time, a strong inflammatory response occurred, suggesting that the initial increased oxidative phosphorylation observed caused the neurons to become vulnerable to oxidative damage, which can trigger an inflammatory response.

In further experiments, the researchers investigated the changes that appeared in the spaces between the brain’s neurons known as synapses.

They found that vesicles designed to degrade proteins had accumulated in them, affecting signaling and disrupting access to necessary proteins.

The authors of the study proposed this disruption could explain some of the symptoms seen in Alzheimer’s patients.

Co-lead study author Prof. Maria Ankarcrona, from the Department of Neurobiology, Care Sciences and Society, at the Karolinska Institute, told MNT in an interview that they were “very happy because it’s sort of confirming at least what I have been working on for many years with the role of mitochondria and Alzheimer’s disease.”

Co-lead author Dr. Per Nilsson, associate professor at the Department of Neurobiology, Care Sciences and Society, at the Karolinska Institute, said the use of this animal model of Alzheimer’s had allowed them to pinpoint the ages at which the changes took place

“Work in preclinical animal models offers us the possibility to follow things over time,” he explained. “And Alzheimer’s disease is really a time-dependent disease.”

“And then, of course, in humans there are some restrictions. What we can do in humans [is that] we can look at postmortem brain tissue, we can use imaging techniques to look at the brains of living patients. But here we can [look at it on] the molecular level, dissect things in more detail,” added Dr. Nilsson.

Dr. Viharkumar Patel, assistant professor in the Division of Clinical Pathology at UC Davis Health, Sacramento, CA, who researches the metabolomics of Alzheimer’s disease and has investigated energy metabolism changes, but was not involved in the current study, called the paper “exciting.”

“I think this is along the lines of what we need to be looking at in terms of Alzheimer’s disease pathogenesis,“ said Dr. Patel. “As you may know, a lot of what we know is from individuals who have had full-blown dementia due to Alzheimer’s disease that’s essentially at end stage kind of state.“

“And so, the plaques and tangles that we see, we know that they’re all probably prevalent there, but we don’t really know what drives them,” he added.

Dr. Strange said that though findings from mouse models did not apply to treating his patients, they did give him hope for an eventual cure for Alzheimer’s disease.

“I’m sure with our current scientific technique, and some of the things we now know that will come, that there will be a breakthrough. I think we’re close actually, I think we’re closer than we ever were,” he said.

“At least it gives hope to a disease that [once] had no hope. I think we always have to offer a glimmer of hope to both the families and the patients,” he told MNT.