Alzheimer's disease: a new step in understanding the genetics of the disease.

Updated: September 2022

Today in France, more than one million people are affected by Alzheimer's disease, with 225,000 new cases each year. It's worth noting that Alzheimer's disease most often appears after the age of 65 and is the most common neurodegenerative disease in the population over 80. At the Pasteur Institute in Lille, the team led by Dr. Jean-Charles Lambert, Inserm Research Director (U1167), is dedicated to Alzheimer's disease. The work carried out by this team aims to understand the genetic susceptibility to this disease in order to better combat it. Two recent studies have allowed research to take a new step forward in understanding the genetics of the disease, offering hope for new diagnostic tools and personalized medicine.

A European DNA bank to decipher the missing heritability of the disease.

The EADB (European Alzheimer and Dementia Biobank) consortium, coordinated by Dr. Jean-Charles Lambert, whose results were recently published in Nature Genetics (Editor's note: a highly reputable American scientific journal), constitutes the world's largest genetic analysis study by comparing the genome of patients to that of controls. 

This study includes more than 115.000 patients and 600.000 controls. The statistical power of such a study has allowed for the characterization of numerous already known genetic determinants, an essential step in validating existing knowledge. Thirty-three signals have thus been validated, confirming their role in Alzheimer's disease, and 42 new signals have been characterized, more than doubling our understanding of the genetics of the disease. Alzheimer's disease. 16 European countries participated in this study with remarkable efficiency, and in a dynamic designed to last.

This European study provides a better understanding of the pathophysiological processes involved and reinforces existing knowledge, particularly the involvement of microglial cells(1), the "garbage collectors of our brain," as Dr. Lambert calls them. These cells appear to "eat" amyloid peptides(2), which are thought to be partly responsible for the disease. If these microglial cells malfunction, they promote the presence of these amyloid peptides, and therefore their toxicity to our brain. The second point, which constitutes the most significant advance at the pathophysiological level, is the involvement of the TNFα (Tumor Necrosis Factor) axis, clearly identified by this analysis, which strengthens the role of inflammation in the development of the disease. This opens up a therapeutic avenue for targeting this TNF axis.

For Dr. Lambert, this is the first time in the case of Alzheimer's that such well-defined cell signaling has been identified through genetic data. Beyond this, a translational application is emerging, since with 75 genetic markers, it is now possible to develop genetic risk scores. which can help to better define at-risk populationsThese are research tools whose use shows that people with more or less contrasting genetic profiles may have greater or lesser risks of developing Alzheimer's disease, whether in the general population or in populations with mild cognitive impairment (MCI). This tool is not currently intended for clinical practice, but it could be very useful in setting up therapeutic trials to categorize participants according to their risk and better assess the effectiveness of the drugs being tested. The next step will be to integrate this genetic information into therapeutic trials, with the aim of moving towards personalized medicine, which is already well advanced in the treatment of certain multifactorial diseases such as cancer. 

Rare variants associated with the risk of developing the disease have been clearly identified.

A second study conducted in Lille, based on ultra-high-throughput sequencing, provides complementary information to that described previously, focusing on so-called rare variants. This study characterized eight rare genes associated with the risk of developing Alzheimer's disease, but this time through the aggregation of rare variants. These genes are even more important than the others, as they likely constitute key elements governing the mechanisms of disease development. 

When the information from these two studies is combined, our genetic understanding of Alzheimer's disease has been greatly improved. These latest genetic approaches allow us to clearly identify the most important genetic elements in the disease's development. In the long term, this work should facilitate the development of treatments to correct the defects caused by these genetic determinants and which underlie the disease. 

Sources: New insights into the genetic etiology of Alzheimer's disease and related Dementias Bellenguez et al
Nature Genetics, February 2022
https://www.nature.com/articles/s41588-022-01024-z 

1. Microglia cells are the resident macrophages of the central nervous system (CNS). Microglia have a crucial function in CNS homeostasis as they constitute the first line of defense against pathogens, contributing to immune responses, but are also involved in tissue repair. 
2. Amyloid peptide (or β-amyloid) is a peptide belonging to the amyloid family of substances. Under certain circumstances, it is harmful to the central nervous system. The combined presence of β-amyloid aggregates and tau proteins are characteristic signs of Alzheimer's disease. 

Two research areas to study the mechanisms

"Our proposal aims to develop complementary strategies for studying the cellular and molecular mechanisms of Alzheimer's disease. Combined with ongoing research, we believe these new approaches are essential to accelerating progress in research on Alzheimer's disease and other age-related illnesses." explains Dr. Marcos Costa, neuroscientist in charge of the organoid research project, a miniature imitation of the human brain.

Microfluidics: Modeling neural circuits

Thanks to this technology, researchers were able to observe that a significant number of genes associated with the risk of developing Alzheimer's disease did, in fact, have a synaptic function. Certain brain lesions revealed the aggregation of a protein, amyloid-β, responsible for neuronal death.

"This innovative approach could lead to new therapeutic avenues for improving neuronal transmission and preventing cognitive decline." "In short," summarizes Dr. Jean Charles Lambert, "the study of Alzheimer's disease requires patience more than ever. These new approaches, which are long-term in nature, are promising and offer the prospect of developing new treatments for this scourge."

A “mini-brain” to better understand disorders

Developing a new brain organoid model a million times smaller than a human brain is the new challenge undertaken by researchers at the Pasteur Institute in Lille. By culturing them in a way that mimics the environment of brain development, stem cells differentiate and organize themselves into a structure resembling the developing brain.

The organoid, more commonly known as the “mini-brain”, constitutes a three-dimensional cell culture system that can serve as living material to mimic disease and evaluate the effectiveness of new treatments.

“Once we know what the disease changes in neurons, we can then begin to transform blood cells taken from Alzheimer's patients into neurons, to study the specific alterations in each individual. We hope this will be possible within 5 to 10 years.” explains Dr. Costa. A process as long as the disease takes to develop in the human brain, and costly research, made possible thanks to the ongoing support of the foundation's donors.

A researcher's journey

Ana-Raquel MELO DE FARIAS: "Contributing to research to improve the lives of those with illnesses and their families."

Ana-Raquel is a young Brazilian student currently working on her PhD with Professor Amouyel's Alzheimer's research team. She studies human cells and the expression of genes associated with the risk of developing Alzheimer's disease. Having been in France for two years, Ana-Raquel explains in fluent French that her career choice was influenced by her mother, a science professor at a university in Brazil. "My mother is a role model for me. The first time I went into a laboratory, it was hers, and it was a revelation!" Ana tells us. It was another Brazilian researcher, Marcos Costa, director of the Master's program Ana-Raquel completed in a neuroscience laboratory in Brazil, who advised her to take the competitive exam to pursue her PhD in France.

Alzheimer's disease is also the most common neurodegenerative disease in Brazil. Ana-Raquel explains that she found in this thesis an opportunity to contribute to the fight against a disease that affects so many people, and to do something useful for all populations. She enjoys the constant challenge of this profession and the knowledge that the work she has done can be continued by other researchers to, as she puts it, "contribute to improving the lives of people affected by this terrible disease and their families." Ana-Raquel also hopes that her work will open up opportunities for many other women to advance in their scientific careers. After her thesis, Ana-Raquel wants to pursue applied research in neuroscience and gene therapy. We wish her every success in her research so that one day she can offer all those suffering from the disease hope for a cure.

To learn more about Alzheimer's disease

In France, Alzheimer's disease is the fourth leading cause of death. More than 900,000 people are affected by this condition, and a new case is diagnosed every three minutes. To combat this scourge, risk factors such as age, a sedentary lifestyle, diabetes, high blood pressure, cardiovascular problems, and minor head injuries must not be overlooked.

Symptoms

Initially, Alzheimer's disease most often manifests as memory problems. Subsequently, other brain functions are affected, with the progression varying considerably from one patient to another. Gradually, as the disease progresses, everyday tasks become difficult to perform and adapting to new situations becomes particularly challenging.

How can you remember everything, or almost everything?

Today, studies show that it seems possible to modify the onset of Alzheimer's disease. Researchers are aware of a number of risk factors and environmental factors that can be more or less influenced. A genuine prevention strategy for Alzheimer's disease is emerging. It is with this in mind that Professor Philippe Amouyel, unit director at the Pasteur Institute in Lille, published his book "The Anti-Alzheimer's Guide." It lists preventative advice to implement in order to maximize the chances of avoiding Alzheimer's disease. "Reprogramming our lifestyles for the benefit of our health." Indeed, if the first signs are delayed long enough, we can hope to die without having experienced any symptoms of the disease. The book outlines three main areas of prevention for Alzheimer's disease and, more generally, for the decline in cognitive function inherent to aging.

To keep your brain healthy, it's essential to exercise it. The professor explains that the best way to exercise it is through reading, as reading is incredibly effective for our brains. Other seemingly non-intellectual activities, such as gardening and traveling, are also excellent for our brains. When gardening or planning a trip, our brains anticipate the future. This anticipation allows for conceptualization, which is important for maintaining our brain health.

Taking care of it

It is crucial to avoid impacts. This includes both external impacts, such as those from a tackle in rugby or heading the ball in football, and internal impacts. These impacts are not immediate. Initially, we are protected by our blood-brain barrier, which filters out harmful substances, but over time, nicotine and alcohol eventually pass through. Once this barrier is damaged, anything can get through, and we are no longer protected. Taking care of your brain also means not suppressing sneezes and coughs. This may seem amusing, but this advice is quite real. It's important to know that our bodies contain very small blood vessels that transport blood throughout our system, and some of these vessels are less well-formed and can, under the pressure of a suppressed cough, rupture and lose a small amount of blood. While this may not have immediate consequences, over time, these micro-ruptures can lead to the loss of a number of neurons in the brain.

Taking care of one's health

The first fundamental element of our health is hearing. Indeed, we must truly pay attention to our hearing. Not only because it can create a breakdown in social connections, but also because hearing loss alters our brain structures. It is important to get hearing aids when necessary. Next, we must know that our brain's best friend is our heart. Taking care of our heart is paramount. Thus, diet plays a crucial role in mitigating the risk of Alzheimer's disease. Mediterranean diets based on fish, vegetables, fruit, and olive oil are excellent. Then, between the ages of 45 and 65, it is important to be screened for major risk factors: cholesterol levels, diabetes, excess weight, blood pressure, etc. Physical activity is also an essential element of brain health. Without going so far as to talk about sports, it's about moving more, being more mobile. The important thing is not to aim for performance but to engage in physical activity, especially walking. In conclusion, fighting Alzheimer's disease involves interaction. We must live with others. Humans need other people to thrive. Isolation is a significant aggravating factor. Whenever possible, we shouldn't be alone. Being with another person reduces the risk of developing Alzheimer's disease by two to three times. Seeing friends, playing games, going to the movies, having conversations, even arguing—all these activities increase the number of synaptic connections and are therefore beneficial to our brains. Finally, cultivating optimism also helps us fight Alzheimer's disease.