Alzheimer's disease

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A complex neurodegenerative disease which is becoming more widely understood

Alzheimer's disease is the result of slow neuron degeneration, which starts in the hippocampus (a cerebral structure essential for memory) and then spreads to the rest of the brain. It is characterized by disorders of short-term memory, executive function and temporospatial orientation. The patient gradually loses their cognitive faculties and autonomy.

We do not yet know how to cure this disease but our knowledge of its risk factors and mechanisms has improved spectacularly in recent years.

  • 900 people affected in France
  • out of every 25 sufferers, 10 are men, 15 are women
  • only 1.2 to 2% of cases are hereditary
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    15-20 min

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Report produced in collaboration with David Blum (Inserm Research Director, Alzheimer and Tauopathies team, Jean Pierre Aubert Research Center, Unit 1172 Inserm/Université de Lille), Luc Buée (Director of the Jean-Pierre Aubert Research Center) and Florence Pasquier (University Professor and Hospital Practitioner in neurology, CMRR Manager and Director of the Lille Centre of Excellence for Neurodegenerative Disorders LiCEND).

Loupe comprendre Understanding Alzheimer's disease

Rare up until the age of 65, its first sign is memory loss, followed over the years by more general and incapacitating cognitive impairment.

Among the cases occurring in the under-65s, 10% concern those with rare hereditary forms of the disease. After this age, the incidence of the disease rises to 2 to 4% of the general population. It increases rapidly, reaching 15% of the population at 80 years of age. Hence, approximately 900,000 individuals currently suffer from Alzheimer's disease in France. This figure is expected to reach 1.3 million in 2020, given the increasing life expectancy.

Elderly women appear to be more exposed: out of 25 patients, 10 are men and 15 are women. However, this difference could be related to the differences in life expectancy.

Rare up to the age of 65, 2% of the population
Reaches a peak at the age of 80, 15% of the population
With the increase of life expectancy, 1.3 million sufferers estimated for 2020

Tête perte de mémoire From memory loss to dependency

  • Memory disorder is the most common and perceptible symptom associated with Alzheimer's disease.
  • Executive function deficits (programming, sequence of achieving a goal…) are also highly indicative: for example, no longer knowing how to use the telephone, or how to prepare a familiar recipe.
  • Temporospatial orientation deficits are also telling signs: individuals who develop this disease get lost on their usual routes or lose their sense of time.
  • More rarely, language or elaborate vision disorders (reading, finding objects…) can also be observed at the beginning of the disease.

Spread of the disease is evidenced by progressive speech disorders (aphasia), writing disorders (disordered spelling), movement disorders (apraxia), behavioral and mood disorders (anxiety, depression, irritability), and sleep disorders (insomnia).

It must however be emphasized that this progression is neither unique nor necessarily catastrophic: not all patients present the same clinical picture, experience the same disease progression, or suffer the same incapacity. It is quite often possible to continue leading a long social, intellectual and emotional life with Alzheimer's disease...

Memory gaps: seek medical advice!

We all get memory gaps from time to time. However, when unusual memory gaps become a concern for the individual (or their loved ones) and interfere with their daily life to such an extent that they feel the need to discuss it with a doctor (primary care physician, neurologist, geriatrician or psychiatrist), the complaint should be taken very seriously and undergo specific evaluation. France has created a network of "memory centers" highly specialized in diagnosing these disorders, with over 400 consultation sites nationwide.

Rouages An identified mechanism, but…

Post mortem analysis of the brains of Alzheimer’s patients evidences the presence of two types of lesions: amyloid deposits and neurofibrillary degeneration. Each lesion is associated with a protein: ß-amyloid peptide for amyloid deposits, and phosphorylated tau protein for neurofibrillary degeneration.

Beta-amyloid protein, naturally present in the brain, gradually accumulates over the years under the influence of various genetic and environmental factors, until amyloid deposits start to form, which are also known as "senile plaques". According to the "amyloid cascade" hypothesis, accumulation of this amyloid peptide induces toxicity for nerve cells, evidenced by increased phosphorylation of a neuronal structural protein, the tau protein. Phosphorylation of the tau protein in turn leads to neuron structure disorganization and so-called “neurofibrillary” degeneration. Ultimately, this degeneration leads to the death of the nerve cells. This very slow process takes several decades to become established, before symptoms of the disease start to appear.

Formulated at the beginning of the 1990s, the amyloid cascade hypothesis remains valid but little by little has been enriched and complexified with research findings. For example, we now consider that, once triggered, neurofibrillary degeneration (or "tau disease") propagates throughout the brain independently of the amyloid peptide. Likewise, we now know that there also exists in the brain an inflammatory reaction, which appears to occur quite early in the process.

Alzheimer, la mémoire engloutie – film d’animation – 2 min 35 - extrait de la série À bord du Nanotilus (2011)

Buste attention Age, genetics and environment, a cocktail of risk factors

The main risk factor for Alzheimer's disease is age: the incidence of the disease increases after the age of 65, with a dramatic upturn after the age of 80.

The environment also plays a major role. Cardiovascular risk factors (diabetes, hypertension, hyperlipidemia) which are not treated in middle age are, for instance, associated with a more frequent onset of the disease, the mechanisms of which remain unknown. Sedentary lifestyle is another risk factor, together with cranial microtrauma observed in certain athletes (such as rugby players and boxers), and even repeated anesthesia.

In contrast, the fact of having studied and having a stimulating occupation and active social life appears to delay the onset and severity of the first symptoms. Under these conditions, the brain benefits from "cognitive reserve" allowing it to compensate, at least for a certain amount of time, for the function of the lost neurons. This effect is linked to brain plasticity, a phenomenon which reflects our brain’s ongoing ability to adapt.

Individual susceptibility also has a genetic component, because the risk of developing Alzheimer’s increases 1.5-fold on average if a first-degree relative has it and increases 2-fold if at least two are affected. Pangenomic studies (which examine the entire genome) have revealed some genes linked to a risk of its development. This is notably the case of apolipoprotein E (APOE). Being a carrier of a specific form of this gene, the "epsilon 2” allele, reduces the risk by more than half. However, the presence of an "epsilon 4" allele multiplies it by 3 or 4, and carriers of two copies of this allele (homozygous carriers) see their risk multiplied by 15. Numerous alleles of other genes also modulate the risk of developing the disease and a combination of unfavorable alleles can increase it.

Specific case relating to hereditary forms

Hereditary forms of Alzheimer’s disease account for 1.5% to 2% of cases. These always develop before the age of 65, and often around the age of 45. In half of such cases, rare mutations causing the disease are identified. These affect three genes: one encoding for an amyloid peptide precursor protein (APP, i.e., amyloid precursor protein) and two others for the presenilin 1 and presenilin 2 proteins, which play a role in APP metabolism. Inheriting mutations affecting one of these genes systematically leads to onset of the disease (autosomal dominant transmission).

Pictogramme bloc notes diagnostic et stéthoscope Timely management

While there is no cure for Alzheimer’s disease, appropriate management can slow its progression and improve the life of the patient and their loved ones. But time is of the essence…

First, detect!

Complaints of repeated memory gaps that interfere with daily life must be taken very seriously and be formalized by a doctor: it is essential to perform the diagnosis as early as possible. This diagnosis is based on a description of the disorders experienced, followed by the performance of cognitive function tests. These enable evaluation of the nature and severity of the symptoms (memory loss, temporospatial orientation, executive functions…) and the screening for behavior and mood disorders.

Brain imaging also contributes to the diagnosis, including in the early stages. MRI is used to rule out other causes and may reveal brain abnormalities associated with the disease: reduced brain volume, notably in the posterior regions, and hippocampal atrophy are arguments in favor of a diagnosis of Alzheimer’s disease. The use of PET scans enables access to other brain regions, such as the temporo-parieto-occipital junction and the precuneus.

To support the diagnosis, biological markers can help confirm the cause of symptoms. It is now possible to measure three markers of the disease in the cerebrospinal fluid (CSF), accessible via lumbar puncture: the beta-amyloid protein, the tau protein and the phosphorylated tau protein.

These investigations sometimes make it possible to diagnose other degenerative pathologies (frontotemporal dementia, Lewy body diseases…) or vascular pathologies that mimic Alzheimer’s.

Une signature pour Alzheimer – 3 min 25 -communiqué de presse vidéo  – vidéo de la série Histoire de recherche (2014)

Then manage

Multidimensional in nature, the management of Alzheimer’s disease includes lifestyle measures, activities, medication and medical-social provision - from the occasional use of day centers to permanent institutionalization: for the benefit of the patients and also to aid and relieve their carers… In all cases, the key word in management is "personalization": beyond the fact that each patient is unique by nature, and not all present the same symptoms or the same disease progression.

It is essential that the patient continue their usual activities - cognitive and/or physical - and maintain a social life where possible. A balanced diet is equally important. Some centers advocate a more active approach which involves "stimulating" the patient by proposing activities. However, suggesting or even imposing activities in which the patient had never shown an interest prior to the disease, or which place them in a situation of failure, can only increase their stress. It is therefore essential to take the patient’s personality and experience into account.

In terms of medication, four products are commonly prescribed. Three of them - donepezil (Aricept), rivastigmine (Exelon) and galantamine (Reminyl) - aim to increase the brain’s availability of acetylcholine, a neurotransmitter facilitating communication between the neurons, which is weakened by the disease. These medicines block the action of acetylcholinesterase, the enzyme which breaks down the neurotransmitter. Memantine (Ebixa) blocks a receptor for glutamate, a compound which damages the neurons. This last treatment acts on the "tau" component of the disease.

These medications suffer a disadvantage which is behind their recent removal from the list of medicines reimbursed by French national health insurance (which is still the subject of debate), in that their benefit is not evident for the patient and their loved ones. They do not improve the patient’s condition: in general, they slow their deterioration. Best case scenario: they stabilize it. This effect is offset by some unpleasant side effects, and the simple fact of prescribing an additional pill to elderly people who are often already being treated for other pathologies can be off-putting to loved ones and some carers. However, large-scale studies undisputedly prove that stopping these treatments reduces the patients’ autonomous life, and by deteriorating faster, they are institutionalized earlier. In other words, these medications provide real social and individual benefit even if it is difficult for the patient’s loved ones to perceive it immediately. Even if they are no longer reimbursed, these medicines remain affordable.

However, it is best to avoid "purified" pseudo-pharmaceutical preparations (caffeine, turmeric or other miracle-plant extracts), which represent a real risk of contamination with allergens. A balanced diet is sufficient to provide the patient with all the micronutrients and antioxidants they need.

Pictogramme microscope Challenges facing research

Understanding the mechanisms

Genetic studies continue to reveal new alleles - risk factors for the disease. But their individual effects remain weak. However, by enabling the effects of these different alleles to be combined in a "virtual" setting, bioinformatics should in the near future help identify the major biological pathways involved in Alzheimer’s. Such approaches are already revealing the roles of hitherto unsuspected mechanisms, such as inflammation or immunity.

Multiple hypotheses are arising as to the origin of the disease (injury, role of sleep, prion propagation...). But none of the avenues has produced any measurable indicators for the moment, signifying the potential existence of multiple causes of the disorders that are grouped under the term Alzheimer’s disease…

Detecting

New brain imaging examinations have recently emerged. Using positron emission tomography (PET), it is possible to "see" the amyloid plaques and neurofibrillary degeneration in the brain of a living person (rather than after their death by autopsy). To do this, it was necessary to develop injectable radiotracers which bind specifically to the ß-amyloid peptide and then, more recently, to the tau protein. They are undeniably useful in research, for example when testing the effect of drug candidates. However, in the absence of validated treatment, their clinical use is of little value at present.

Developing a treatment

The avenue currently most explored in the development of a treatment for Alzheimer’s disease is immunotherapy. It was first developed in order to eliminate the ß-amyloid peptide. This strategy involves injecting antibodies directed against the peptide (passive immunotherapy) or vaccinating the patient against ß-amyloid peptide (active immunotherapy). The results of the first clinical trials were disappointing: the amyloid plaque regresses, but not always without major side effects. What is more, the clinical symptoms remain and the neurofibrillary degeneration continues to progress. However, other more efficient anti-amyloid antibodies are currently being tested. In addition, since eliminating the amyloid plaque is not in itself sufficient to halt the progression of the disease, many immunotherapy trials are currently targeting the tau protein.

Other approaches are also being developed, such as the use of several more traditional therapeutic small molecules, such as methylene blue derivatives (which break down the tau filaments) or secretase inhibitors (which prevent the formation of ß-amyloid peptide).

In summary: a multitude of clinical trials but few stand-out results at present. Nevertheless, it remains essential for patients to continue to participate in these studies, in which their usual treatment is not interrupted.

Given that the lesions precede the symptoms by several years, research is oriented towards very early treatment - before the onset of these symptoms - in order to avoid the progression to full-blown Alzheimer’s disease.

The French neurodegenerative diseases plan (2014-2019)

The fourth national plan dedicated not just to Alzheimer’s and related diseases, but also to other degenerative pathologies, in particular motor pathologies, has 4 strategic orientations:

  • provide nationwide treatment and support
  • promote societal adaptation to the challenges of neurodegenerative diseases