• The exact cause of Alzheimer’s disease (AD) is unknown, but amyloid plaques in the brain are widely thought to initiate the pathological cascade that leads to many of the symptoms.
• Recently, research has questioned this ‘amyloid hypothesis’, suggesting that the plaques may be a result, rather than a cause of AD.
• A new study now suggests that amyloid may have another role — causing two proteins to pair, stimulating the accumulation of tau proteins.
• When tau proteins accumulate, they damage brain cells and impair a person’s ability to think and remember.

A recent study published in the Lancet forecast that by 2050, there would be more than 150 million dementia cases worldwide. The commonest form of dementia, Alzheimer’s disease (AD), causes around 70% of cases, according to the World Health Organization, meaning that by 2050, more than 100 million people around the world could be living with AD.

AD is a neurodegenerative disorder, which causes a range of symptoms, including:

• memory loss
• cognitive deficits
• coordination and balance problems
• personality or behavior changes.

Over time, symptoms worsen. Although treatments may alleviate the symptoms, the condition is incurable.

As yet, the exact cause of AD has not been identified, although two proteins — beta-amyloid and tau — which form plaques and tangles in the brain, are widely thought to interact in complex ways leading to many of the symptoms.

Now, new research from Columbia University has found that amyloid causes two proteins to pair up, triggering rapid accumulation of tau proteins. The researchers suggest that preventing this pairing may be a good target for therapy.

The research is published in Science Advances.

“This study uses novel genetic technology to investigate how changes in gene expression happen in Alzheimer’s disease in response to the accumulation of amyloid beta, a hallmark biomarker in the disease. The researchers found a specific combination of gene expression factors that responds to amyloid beta to increase the expression of disease-associated genes.”

— Dr. Percy Griffin, Ph.D., Alzheimer’s Association director of scientific engagement

Amyloids’ role in AD

Beta-amyloid (Aβ), particularly Aβ42, has, for many years, been the prime suspect as the cause of AD. This sticky compound accumulates in the brain of people with AD, disrupting communication between brain cells and, ultimately, leading to the death of brain cells.

However, this ‘amyloid hypothesis’ — which has been widely accepted since a 2006 study showed that beta-amyloid impaired memory — has been questioned. Recently, some scientists suggested that images in that study might have been manipulated.

But other evidence has supported the hypothesis, as Dr. Emer MacSweeney, CEO and consultant neuroradiologist at Re:Cognition Health, told Medical News Today:

“The amyloid hypothesis has been validated by the successful results of the global clinical trial for lecanemab, a monoclonal antibody demonstrated to remove toxic amyloid protein from the brain, in Alzheimer’s disease. But the disease is very complex, and the extent of spread of abnormal tau protein, in the brain, actually has the closest correlation with memory loss and other symptoms of cognitive decline.”

This new study lends support to the role of amyloid in the development of AD, but by a different pathway.

Dr. Griffin told MNT that the work “is interesting because it helps add to our understanding of how the accumulation of [beta-amyloid] is an initiating event which leads to downstream disease-associated changes such as the development of tau tangles and gene expression changes.”

Dr. David Merrill, Ph.D., geriatric psychiatrist and director of the Pacific Neuroscience Institute’s Pacific Brain Health Center at Providence Saint John’s Health Center in Santa Monica, California, agreed:

“The study provides an interesting look into the molecular basis of amyloid’s toxic effects on the brain. The amyloid itself isn’t directly causing the damage, but its effects on other proteins is.”

Interactions between 2 proteins

The researchers used isolated nerve cells from rat hippocampi for their research. The cells were cultured, in vitro, then treated with Aβ42.

They found that Aβ42 caused 2 proteins — ATF4 and CREB3L2 — to bind together. The pairing of these 2 proteins is linked to about half of the gene expression changes that happen in brain cells of people with AD.

“The new discovery from Dr. Hengst’s research unit at Columbia University, that amyloid protein initiates a pairing between two other proteins, inside the brain cells, is very interesting. Especially, as this protein linking is associated with about 50% of the gene changes found in Alzheimer’s. These gene changes are believed, in turn, to be responsible for the abnormal accumulation of tau protein.”
— Dr. Emer MacSweeney

This CREB3L2-ATF4 pair then activates other proteins that make tau protein deposits accumulate inside nerve cells. These tau tangles eventually lead to the death of the cells.

Although the two proteins are found separately in healthy nerve cells, they appear to cause damage when excess amyloid makes them bind together.

A new target for Alzheimer’s treatment

“The novel mechanisms of causing two other proteins to stick together demonstrates a new potential target for prescription drug intervention.”
— Dr. David Merrill

The researchers suggest that because this protein pair does not seem to have any other function, it may be a good target for therapy. They have identified an FDA-approved drug, dovitinib, that interferes with the effects of the protein pair. It has yet to be tested as an AD treatment.

“It’s exciting that there is already a drug identified that could be tried in clinical trials. It would be interesting to learn if it is that drug in particular, or if other drugs of the same type could work through the same or similar mechanism,” Dr. Merrill told MNT.

Most AD treatments aim to alleviate symptoms, rather than cure the disorder. New disease-modifying therapies, such as aducanumab and lecanemab, that clear amyloid plaques, may slow or stop the progress of AD, but there are questions about their efficacy.

Preventing protein pairing

According to the researchers, therapies that interfere with the protein pairing, rather than targeting amyloid, might be effective. Instead of removing the amyloid, such therapies would prevent the amyloid causing damage to the nerve cells in the brain.

They suggest that, for even greater therapeutic effect, the treatment might be combined with amyloid-reducing drugs.

While recognizing the potential importance of the findings, Dr. Griffin urged caution:

“It is worth noting that the factors which promote gene expression usually produce several effects. In order to translate this into the clinic we need to understand which of those effects are specific to the death of brain cells. We want to design treatments that block that process with limited side effects.”

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