Why is science changing the target for a cure?

More than a hundred years have passed since the first case of Alzheimer’s was described by a German doctor. To date, however, patients with the disease do not have an effective treatment. The path to unravel Alzheimer’s and find a cure seems to be a complicated criminal investigation: for many years, while scientists were targeting a single suspect for brain degeneration, other biological agents were at work.

Now the targets are changing. Investigators have expanded their hypotheses to find out who the villain is causing the loss of memory and the ability to do everyday tasks. Or what they are. New suspects are in the sights of science: it is believed that neuroinflammation, failures in the connection between one neuron and another and even defects in the work of eliminating the “junk” of the brain may be behind Alzheimer’s.

Disease causes loss of connection and death of neurons.
Disease causes loss of connection and death of neurons. Photograph: Robina Weermeijer/Unsplash

The disease starts in a sneaky way and affects more the elderly from 65 years old. Some scientists believe that Alzheimer’s begins to develop about 15 years before the first symptoms of memory loss. The lapses begin with difficulties in forming new memories. It’s common to forget where you left your keys or what the building number you live in.

Afterwards, even old memories are no longer accessed and it is difficult to do simple tasks, such as eating and brushing teeth. It’s like there’s a short circuit in the brain that causes neurons to stop communicating. THE World Health Organization (WHO) estimates that there are 55 million people with dementia, including Alzheimer’s, worldwide – in Brazil alone, there are 1.2 million cases, most of them still without a confirmed diagnosis.

The first known case of the disease was that of Auguste Deter, a 51-year-old woman treated at a psychiatric hospital in Frankfurt by Alois Alzheimer, the German neuropathologist who eventually named the disease. When attending to Auguste, the doctor noticed that she did not understand simple questions, did not remember objects seen before or her husband’s name. And she always repeated: “I got lost”.

Continues after advertising

Auguste Deter, a dementia patient who was considered the first reported case of Alzheimer's.
Auguste Deter, a dementia patient who was considered the first reported case of Alzheimer’s. Photograph: Reproduction/The Lancet Lancet

After Auguste died, Alzheimer discovered, through autopsy, that the patient’s brain had something abnormal: there were plaques, called, at that time, senile plaques. For eighty years, little progress was made in characterizing these structures due to lack of technical resources, until, in the 1980s, scientists showed that they were formed by a protein – beta-amyloid.

At amyloid beta plaques between neurons – in addition to other tangled structures within neural cells, formed by the tau protein – have become the markers of the disease. That is, they are the main biological characteristics of those who have Alzheimer’s.

And since they were the most obvious hallmarks of Alzheimer’s, scientists bet their chips on it to find treatments. What seemed to be the great villain of Alzheimer’s, however, turned out to be the “butler”, says Sergio Ferreira, professor at the Institutes of Biophysics and Medical Biochemistry at the Federal University of Rio de Janeiro (UFRJ). “It seemed the clear culprit. But maybe not.”

The fact that there are beta-amyloid plaques in the brains of people with Alzheimer’s does not necessarily mean that this is the cause – or the only cause – of the disease. Some research supports this hypothesis. Studies have already shown that even people with a high concentration of beta-amyloid in the brain do not have symptoms of dementia: they are called resilient brains.

Another clue comes from the treatments themselves: the first drug approved as a therapy for Alzheimer’s (and not just to relieve symptoms) last year in the United States attacks precisely the beta-amyloid plaques. The results of aducanumab, however, were disappointing: although it destroys these plaques, it has little effect on improving the condition of people with Alzheimer’s.

Aduhelm, the brand name for the drug aducanumab, approved last year to treat Alzheimer's.
Aduhelm, the brand name for the drug aducanumab, approved last year to treat Alzheimer’s. Photograph: Biogen/Disclosure

Continues after advertising

“One of the things that caused a bit of delay, within a context where there was not much money for research, was that the scientific community tried what seemed the most logical: to go after the amyloid cascade theory. All other possibilities have been erased,” says neuropathologist Lea Grinberg, a professor at the University of California, San Francisco (USA).

“There is perhaps a discreet effect of these drugs, but it is not the panacea”, she adds, stressing the importance of research that looks at other targets and begins to understand more and more what happens, at a molecular level, in each of the cells.

Studies with drugs that focus on the destruction of beta-amyloid plaques must continue – Biogen, the pharmaceutical company that developed aducanumab, has committed to present a new clinical study with the drug. Other drugmakers also expect to complete research on their anti-amyloid drugs soon.

Part of the scientific community argues that it is still necessary to carry out new tests with these drugs earlier, in people without symptoms of Alzheimer’s, before discarding the drugs. And that drugs that work against beta-amyloid can be useful if combined with other strategies. Another part has been skeptical about the results of research that follow this line.

In an article published in July in The Journal of Prevention of Alzheimer’s Disease, two neuroscientists highlighted that until recently, amyloid and tau proteins were the focus of most drugs in development. “The accumulated data suggest that anti-amyloid antibodies alone are unlikely to be sufficient to halt or reverse the course of the disease,” wrote Yuko Hara and Howard Fillit of the Alzheimer’s Drug Discovery Foundation in the United States.

They say the disease is linked to aging, but a number of processes appear to contribute to Alzheimer’s, such as inflammation and vascular problems. “A combination of drugs to treat many of these problems may be needed to treat them effectively. In recent years, an increasing number of drugs targeting these biological processes have emerged in the drug development pipeline.”

Disease causes brain 'blackout', but biological causes are still an enigma

Continues after advertising

Soluble structures and neuroinflammation

For Ferreira, although there are still researchers who defend the theory of amyloid plaques as a cause, the weight of the scientific literature has fallen on other smaller structures – originating from beta-amyloid – that travel through the brain and are more difficult to detect: oligomers.

“Today we know that they attach to synapses, the point through which neurons communicate, and promote biochemical changes that cause the synapse to stop working properly.”

But if the brain is complex, Alzheimer’s disease can be even more complex: more than one mechanism is likely to lead to the failure and death of neurons. And that’s where another line of investigation comes in: that these soluble structures participate in a harmful vicious cycle. They would be responsible for activating a system of defense cells in the brain. And this disturbance would then provoke a process of neuroinflammation that leads to the degeneration of neurons.

To understand, just remember the covid-19: most of the more serious symptoms were explained not by the virus itself, but by the inflammatory storm caused by the body in reaction to the virus. Inflammatory processes that occur in other parts of the body may also be linked to the development of Alzheimer’s, researchers suggest.

The problem is that taking an ibuprofen is not enough: studies are trying to find drugs capable of stopping inflammation and preserving the brain from degeneration. Among drug clinical trials supported by the US National Institute on Aging, there are eight studies targeting neuroinflammation – all still in early stages.

Insulin, oxidative stress and the ‘junk’ cells

Continues after advertising

Other studies are looking for drugs capable of restoring synaptic functions, that is, the communication mechanism between neurons. Also included in the equation are research to assess how insulin resistance – that is, the reduced ability of insulin to perform its functions in the brain – is linked to cognitive decline and dementia.

There are also lines of investigation that believe that Alzheimer’s begins with mild cognitive impairment caused by oxidative stress. Drugs could help brain cells get rid of excess oxidizing compounds, but they are still in the early stages of testing.

Also little studied, the role of other brain cells, which act as “garbage collectors” to ensure the proper functioning of the organ, gains strength. The focus here is to understand why these structures – called glial cells – stop removing toxic substances and stop doing their original role of protecting neurons.

Vicious cycle and individual process

The lines of study intersect at many points – and it is possible that several factors in combination are behind the onset and progression of Alzheimer’s disease. “Probably, they are combined fronts, it is difficult to have just one thing. It’s like a vicious cycle, a cascade of things that happen (in the brain) in the wrong way,” says Lea.

It is also likely that the biological mechanisms linked to the disease vary from person to person, but they reach the final common symptom: memory loss, says Marcio Balthazar, professor at the Department of Neurology at the State University of Campinas (Unicamp). “In the future, it may be possible to individually map the characteristics of Seu João and Dona Maria and give each of them a different remedy to treat the same problem.”

Studies aim at prevention

Continues after advertising

While drugs capable of changing the course of the disease are not available, scientists are also investing in understanding which habits can help prevent a person from developing Alzheimer’s or, at least, delay the progression of the disease: these are non-pharmacological intervention studies.

Research related to prevention focuses mainly on describing the role of physical activity, sleep, schooling and cardiovascular health. Delaying the progression of the disease is particularly important in cases of dementia that affect older people: delaying the first memory losses by ten years, for example, can mean, in practice, having a normal routine until the end of life.

Memory loss starts with difficulty forming more recent memories

About Abhishek Pratap

Food maven. Unapologetic travel fanatic. MCU's fan. Infuriatingly humble creator. Award-winning pop culture ninja.

Check Also

Telegram: term ‘mesário’ grows in Bolsonarist groups after TSE forces voters to hand in cell phones to vote | Elections 2022

From January to August this year, mentions of the word “mesário” jumped from 2 to …