Alzheimer’s disease results from the slow degeneration of neurons, starting in the hippocampus (a brain structure essential for memory) and then spreading to the rest of the brain. It is characterized by disorders of recent memory, executive functions and orientation in time and space. The patient gradually loses his cognitive faculties and his autonomy.
We do not yet know how to cure this disease, but our knowledge of its risk factors and its mechanisms has changed dramatically in recent years.
Understanding Alzheimer’s disease
Rare before the age of 65, Alzheimer’s disease manifests itself first as memory loss, followed over the years by more general and disabling cognitive disorders.
Among the cases occurring in those under 65, 10% concern people with rare hereditary familial forms of the disease. After this age, the frequency of the disease rises to 2 to 4% of the general population. It increases rapidly to reach 15% of the population by age 80. Worldwide, at least 50 million people are believed to be living with Alzheimer’s disease or other dementias. According to the United Nations, that is more than the population of Columbia. If breakthroughs are not discovered, rates could exceed 152 million by 2050.
Older women seem to be more at risk since, out of 25 patients, 10 are men and 15 are women, but this difference could be linked to differences in life expectancy.
From memory loss to addiction
Memory impairment is the most common and most noticeable symptom associated with Alzheimer’s disease.
Disorders of executive functions (programming, sequence of achieving a goal, etc.) are also very evocative: for example, no longer knowing how to use your phone or how to prepare a recipe that was previously well known.
Problems of orientation in time and space are also revealing: people who develop the disease get lost on a usual route or no longer know their place in time.
More rarely, language disorders or elaborate vision (reading, locating objects, etc.) can be observed at the onset of the disease.
The spread of the disease results in progressive disturbances in oral (aphasia) and written language (dysorthography), movement (apraxia), behavior and mood (anxiety, depression irritability) and sleep (insomnia).
It should be emphasized, however, that this progression is neither unique nor necessarily catastrophic: all patients do not have the same clinical picture, do not experience the same course, or suffer from the same handicap. We can often continue to have a social, intellectual and emotional life with Alzheimer’s disease for a long time.
A mechanism identified, but …
Examined after death, the brains of patients with Alzheimer’s disease show two types of lesions: amyloid deposits and neurofibrillary degeneration. Each of these lesions is associated with a protein: the β-amyloid peptide for amyloid deposits, and the phosphorylated tau protein for neurofibrillary degeneration.
The β-amyloid protein, naturally present in the brain, accumulates over the years under the influence of various genetic and environmental factors. It ends up forming amyloid deposits, also called “senile plaques“. According to the “amyloid cascade” hypothesis, the accumulation of this peptide amyloid induces toxicity to nerve cells, resulting in increased phosphorylation of a structural protein in neurons, the tau protein.
Phosphorylation of the tau protein in turn causes a disorganization of the structure of neurons and a so-called “neurofibrillary” degeneration. Ultimately, the latter leads to the death of nerve cells. Very slow, this process takes several decades to establish before symptoms of the disease appear.
Formulated in the early 1990s, the amyloid cascade hypothesis remains valid, but it has gradually expanded and become more complex with the results of research. For example, it is now believed that once onset, neurofibrillary degeneration (or “tau disease”) spreads throughout the brain independently of the amyloid peptide. Likewise, we now know that there is also an inflammatory reaction in the brain, which seems to occur quite early in the process.
Age, genetics and environment, the cocktail of risk factors
The main risk factor for Alzheimer’s disease is age: the incidence of the disease increases after 65 years and skyrockets after 80 years.
The environment also plays an important role. Cardiovascular risk factors (diabetes, hypertension, hyperlipidemia) not taken care of at the middle age of life are, for example, associated with a more frequent occurrence of the disease, although it is not yet known by what mechanisms. Sedentary lifestyle is another risk factor, as well as cranial microtraumas observed in certain athletes (such as rugby players or boxers) or repeated anesthesias.
Conversely, having studied and having had a stimulating professional activity as well as an active social life, seems to delay the onset of the first symptoms and their severity. Under these conditions, the brain would benefit from a “cognitive reserve” which makes it possible to compensate, at least for a time, the function of the lost neurons. This effect is linked to cerebral plasticity, a phenomenon that reflects the permanent adaptability of our brain.
Individual susceptibility to the disease also has a genetic component, since the risk of developing the disease is on average multiplied by 1.5 if a first degree relative is affected, and by 2 if at least two are affected. Studies examining the whole genome (known as “genome-wide”) have revealed certain genes associated with a risk of developing the disease. This is particularly the case with the apolipoprotein E (APOE) gene. Carrying a particular form of this gene, the “epsilon 2” allele, will reduce your risk by more than half. On the other hand, the presence of an “epsilon 4” allele multiplies it by 3 or 4, and the carriers of two copies of this allele (homozygous carriers) see their risk multiplied by 15. Many alleles of other genes also modulate the risk of developing the disease and a combination of unfavorable alleles may increase the risk of developing the disease.
Take charge, on time
Alzheimer’s disease cannot be cured, but appropriate management can slow its progression and improve the life of the patient and those around him. It is still necessary to act in time …
A complaint about repeated forgetfulness interfering with daily life must alert and be formalized with a doctor: it is indeed essential to make a diagnosis as soon as possible. This is based first on the history of the disorders, then on tests of cognitive functions. They make it possible to assess the nature and severity of the attacks (memory loss, spatio-temporal orientation, executive functions, etc.) and to search for behavioral and mood disorders.
Brain imaging also helps in diagnosis, including at an early stage. MRI can rule out other causes and may reveal brain abnormalities associated with the disease: reduced brain size, especially in the posterior regions, and hippocampal atrophy are arguments in favor of the diagnosis of A. Alzheimer’s. The use of PET gives access to other brain regions such as the temporo-parieto-occipital junction and the precuneus.
To strengthen the diagnosis, biological markers can help confirm the origin of symptoms. It is now possible to measure three markers of the disease in the cerebrospinal fluid (CSF), accessible through a lumbar puncture: the amyloid beta protein, the tau protein and the phosphorylated tau protein.
These examinations sometimes make it possible to suggest the diagnosis of other degenerative pathologies (frontotemporal degenerations, Lewy body diseases, etc.) or vascular pathologies that may mimic Alzheimer’s disease.
Multidimensional, the management of Alzheimer’s disease combines a healthy lifestyle, activities, drug treatment and medico-social arrangements, from occasional day care to permanent accommodation in an institution. For patients, but also to help and relieve caregivers …
In all cases, the key word for care is “personalization”: beyond the fact that each patient is unique by nature, not all have the same symptoms, or the same course of their disease.
It is essential that the patient continues his usual activities – cognitive and / or physical – and maintains a social life as much as possible.
Equally important is a balanced diet. Some centers advocate a more active approach consisting in “stimulating” the patient by offering him activities.
However, offering him or even imposing on him an activity that he had never been interested in before his illness, or that puts him in check, can only increase his stress. Attention to the personality and the patient’s experience is therefore essential.
The challenges of research
Understanding the mechanisms
Genetic studies are constantly revealing new alleles, which are risk factors for the disease. But their individual effects remain weak.
However, by allowing the effects of these different alleles to be combined “virtually”, bioinformatics should in the near future help to identify the major biological pathways involved in Alzheimer’s disease.
Such approaches are already showing the role of previously unsuspected mechanisms, such as inflammation or immunity.
Many hypotheses arise as to the origin of the disease (trauma, role of sleep, prion-type propagation, etc.). But no lead has provided a measurable clue so far, a sign that there may be several causes of the disorders that are grouped under the term Alzheimer’s disease …
New brain imaging tests have recently emerged. Using positron emission tomography (PET), they make it possible to “see” the amyloid plaques and neurofibrillary degeneration in the brain of a living person (and not after death by pathological examination).
For this, it was necessary to develop injectable radiotracers that bind specifically to the beta amyloid peptide and, more recently, to the tau protein. They render undeniable services in research, for example to test the effect of drug candidates. But in the absence of a validated treatment, their clinical use is of little interest for the moment.
The most explored avenue currently for developing a treatment against Alzheimer’s disease is immunotherapy.
.It was first developed to remove the beta amyloid peptide. This strategy consists of injecting antibodies directed against the peptide (passive immunotherapy) or in vaccinating the patient against the beta amyloid peptide (active immunotherapy).
The results of the first clinical trials were disappointing: the amyloid plaque regresses, yes, but sometimes at the cost of significant side effects. In addition, clinical symptoms remain, and neurofibrillary degeneration continues to progress.
More effective anti-amyloid drugs are currently being tested. In addition, since the removal of amyloid plaques alone is not sufficient to halt the progression of the disease, many immunotherapy trials today target the tau protein.
Other approaches are also being developed, such as the use of several more conventional small therapeutic molecules, such as derivatives of methylene blue (which break up the tau filaments) or secretase inhibitors (which prevent the formation of the beta amyloid peptide). .
In short: a multitude of clinical trials, few net results today. However, it remains essential that patients continue to participate in these studies, which does not interrupt their usual treatment.
Research is moving towards treatment very early, before the symptoms of the disease to prevent its onset, with lesions several years before symptoms.