“The Amyloid Hypothesis Debunked: Is Protein the Hero in Alzheimer’s?”

Protein declared villain

Since the mid-1980s, researchers have linked Alzheimer’s to clumps of the protein beta-amyloid that accumulate in the brain.

This so-called amyloid hypothesis was given a boost in 2006 when neurologist Sylvain Lesné of the University of Minnesota in the US showed that young mice developed Alzheimer’s when he injected beta-amyloid into their brains.

The researcher showed pictures of how the protein gradually built up in the brains of the mice, until they lost their memory and became demented.

The discovery led scientists worldwide to focus for 15 years on amyloid beta as the cause of Alzheimer’s disease.

The amyloid hypothesis was leading until 2021, when neurologist Matthew Schrag of Vanderbilt University in the US discovered something was wrong.

The pictures in the article about the beta-amyloid mouse brain looked suspiciously manipulated, and in later articles Sylvain Lesné had used the same pictures as evidence in other experiments, all of which supported the amyloid hypothesis.

This case is now with the US health authorities and is also being investigated by the journals that published Lesné’s articles. The magazine is already warning Nature, that published the paper in 2006, prompted researchers not to use the findings.

Matthew Schrag’s revelation raises the question of whether beta-amyloid plaques in the brain really cause Alzheimer’s, or whether scientists have gone astray in the search for a cure for the disease.

Millions of people have long waited for medication for the disease, which causes two out of three cases of dementia in the elderly. There are now approximately 50 million patients, and with the high life expectancy that could be 150 million in 2050.

The disease affects the brain’s nerve cells, and once symptoms appear in the form of memory problems, it takes an average of just seven years for the brain to be destroyed to the point of death.

Medical results are confusing

When looking for a cure for Alzheimer’s, scientists mainly follow one strategy: they focus on plaques (accumulations) of the protein beta-amyloid in the brain.

But after decades, more and more researchers question the validity of the amyloid hypothesis, because their results are contradictory.

In 2019 proved neurologist Delphine Boche of the University of Southampton in England says that the plaques disappear from patients’ brains with the administration of a vaccine, after which the immune system produces antibodies against beta-amyloid – but it does not prevent dementia from progressing.

The pharmaceutical company Biogen saw the same disappointing results with the drug aducanumab, which consists of antibodies directed against plaques.

Clinical trials show that the plaques largely disappear from the brain after a year of treatment with the antibody, but patients continue to become more and more demented until they die from the breakdown of brain tissue.

To complete the confusion, Biogen published more positive ones in 2022 Results for the antibody lecanemab.

Like aducanumab, this antibody attacks beta-amyloid and removes plaque from the brain, but it also has a positive effect on dementia.

Patients with mild Alzheimer’s who received lecanemab had 27 percent less loss of cognitive abilities over a year and a half than patients who received a placebo during that period.

The suspect has been acquitted

Now researchers are wondering why lecanemab slows the progression of dementia and aducanumab does not, even though both drugs remove the plaques that the amyloid hypothesis suggests cause Alzheimer’s disease.

The explanation may be found in a new research from October 2022. In it, neurologist Andrea Sturcio of the Karolinska Institute in Sweden followed 232 Alzheimer’s patients for three years to see how their dementia progressed.

Plaques and free beta-amyloid that had not yet aggregated were measured in all patients.

For example, it turned out that patients with a lot of free beta-amyloid retained their cognitive abilities, regardless of their plaques.

So amyloid beta is not the villain that leads to Alzheimer’s, but rather the hero that protects us from the disease. Plaques play only a minor role and have no influence on whether or not dementia develops.

After that surprising conclusion, the researchers took a closer look at what beta-amyloid actually does.

Studies show that it has multiple functions, including regulating the amount of cholesterol in the blood, but most interestingly, the protein has an antimicrobial effect, thus killing bacteria and viruses.

Herpesvirus in de spotlights

Several researchers are now leaning towards the virushypothese instead of the amyloid hypothesis. The virus hypothesis states that the real cause of Alzheimer’s is the herpes virus HSV-1, which invades the brain and attacks nerve cells.

To protect themselves, nerve cells make amyloid beta so that HSV-1 cannot multiply. The more virus enters the brain, the more beta-amyloid the nerve cells produce, and at some point there are so many proteins that they begin to clump together into plaques.

If the virus prevails and beta-amyloid becomes unstoppable, the nerve cells die, and clumps of excess beta-amyloid build up as plaque on the dead nerve cells.

According to the virus hypothesis, it therefore makes sense to make medication that prevents beta-amyloid from clumping, even if the nerve cells produce a lot of it.

The new hypothesis also provides an explanation for the difference in the effect of the two antibodies Biogen tested.

If lecanemab attaches to beta-amyloid at the exact site that proteins normally use to bind to each other, the antibody can prevent plaque formation and thus keep levels of free beta-amyloid high.

Aducanumab, on the other hand, probably only attaches to beta-amyloid that is already forming plaques, and thus does not lead to higher levels of free beta-amyloid.

However, this is not certain yet. Biogen is not releasing detailed information about the amount of free beta-amyloid in patients’ brains after treatment with the two antibodies — and the study may not even have been done yet.

It is therefore impossible to determine whether the virus hypothesis holds, and after all the experience with the amyloid hypothesis, researchers will probably keep more options open in the hunt for the villain behind Alzheimer’s.