Alzheimer's Disease, forgetting as the only horizon

Better diagnosed, this incurable neurodegenerative disease is affecting more and more people due to the increased life expectancy. However, a few glimmers of hope are emerging on the horizon.

"What are you doing here? Who let you in?

Go away from my place, leave, sir, leave

I'm going to tell my parents, oh, you'll see

And who are all these people, what's this mess?"

The lyrics of the song "La Ritournelle" by Barbara Pravi touch on the theme of her grandmother's struggle with Alzheimer's disease, an affliction that quietly evolves over decades.

“Who are you?”

This neurodegenerative disease leads to a progressive degradation of the central nervous system, resulting in a decline in the cognitive abilities of the affected individual. Approximately 10% of people aged 65 and 15% of those over 80 are affected by this disease. It is the most prevalent form of senile dementia worldwide, and the numbers are increasing year by year. This is not only due to improved diagnosis but also because people are living longer.

Memory loss is a well-known symptom of this dementia. It gradually becomes irreversible and significantly impacts daily life. Over time, the individual may no longer remember simple elements of their life, such as the identity of their loved ones, or may confuse them. Loss of spatial-temporal orientation and executive function disorders (the organization of movement through thought and its execution) also develop in addition to these memory impairments. In severe cases, there is a progression towards an inability to perform simple tasks and disturbances in speech. Aggressiveness, along with anxiety, can be added to this already heavy burden.

Patients start requiring close medical supervision, as well as support from their loved ones, which can become challenging for a family. Although not all patients deteriorate to the same extent, these factors make Alzheimer's disease a complex issue that must be taken very seriously.

How does it work?

It was only in the 1960s that this dementia came to be considered a distinct disease rather than a normal consequence of aging. It would take until the 1980s to begin understanding the mechanisms responsible for this condition. Initially, deposits known as amyloids are observed, accumulating over the years on nerve cells as they consist of peptides from the β-amyloid protein. Initially harmless, their progressive accumulation over several decades leads to the formation of plaques, called senile plaques, which destabilize the structure of neurons by triggering, the tau protein (Alzheimer's disease is classified as tauopathies). This leads to neurofibrillary degeneration and causes the first symptoms of the disease.

It is important to distinguish between two forms of the disease: a hereditary form, which represents a small proportion of patients (between 1 and 5%) and mainly affects individuals under 65. Genetic abnormalities have been identified in three different genes depending on the patients: APP, PSEN1, and PSEN2. These abnormalities each lead to an accumulation of β-amyloid peptides. Depending on the mutated gene and the type of mutation, patients express symptoms differently, but it leads to the same disease. The second form is non-familial and depends on a variety of risk factors.

An entire life leading to the disease

The risk factors for the onset of Alzheimer's dementia identified by studies are numerous and varied, with some studies listing as many as 40! Conditions such as diabetes, hyperlipidemia, or high blood pressure increase the risk of developing the disease, while intellectual stimulation is rather protective and delays the onset of symptoms through the phenomenon of brain plasticity. However, there is a caveat. Remember that the development of Alzheimer's disease takes place over decades. The difficulty in establishing a reliable list of risk factors is almost inevitable. Indeed, when a study is based on data collected from individuals at different stages of the disease, how can one determine whether these factors are causes or consequences of the disease? More and more studies are attempting to include controls and analyze the time of onset of dementia in relation to the observation of the studied factor. If the diagnosis is made less than 10 years later, there is a strong possibility that it is actually a consequence of the disease. Whereas if the interval is more than 20 years, the causality is more evident.

In addition to lifestyle-related factors, there is a genetic factor that, depending on the gene, increases the risk 1.5 to 2 times the normal of developing this dementia. One of the studied genes is APOE (apolipoprotein E), and certain forms of this gene can increase the danger up to 15 times. In 2022, scientists in Lille identified 75 genetic regions associated with Alzheimer's disease and established a risk score to monitor the progression of the disease.

How to help the patients?

Currently, the management is multidisciplinary (lifestyle, medications, neuropsychological support to facilitate the daily lives of patients and relieve family caregivers). The goal is to keep patients active and "in" their lives. There are four molecules available in the market to help patients live better. Three of them act by improving communication between neurons, and the last one blocks a toxic molecule that worsens neurodegeneration. Despite not leading to improvement but rather stabilizing the disease, these medications have recently been delisted. In reality, they provide valuable assistance in maintaining a normal life for patients, although challenging to quantify through scientific studies.

Toward new challenges

To address the lack of medical treatments, numerous research teams are currently focused on identifying antibodies for use in immunotherapy. These antibodies would target β-amyloid peptides, aiming to eliminate them rather than allowing them to accumulate on neurons. The Japanese company Eisai has developed one such antibody, Lecanemab, and obtained FDA (Food and Drug Administration) market authorization in January 2023. It has demonstrated efficacy in both amyloid deposit markers and cognitive function. This first American authorization is a genuine hope for patients, even though this medication does not enable complete cure.

Screening is also a challenge for research in the years to come. Currently based on cognitive function tests and brain imaging examinations, recent research has identified a marker found in urine, the formic acid, which could be measured early before the onset of symptoms. If such a test becomes feasible, it could revolutionize the management and progression of the disease.

As the end of the Global Action Plan on Public Health Response to Dementia 2017-2025 approaches, established by the World Health Organization (WHO), efforts continue, and the primary goal remains to improve the quality of life for patients. Research on Alzheimer's disease is advancing, and hopes are high for the future.