Alzheimer's disease involves slow neuron degeneration, which starts in the hippocampus then spreads to the rest of the brain. It is characterized by short-term memory disorders, executive function and temporospatial orientation deficits. The patient gradually loses their cognitive faculties and autonomy. Knowledge of the risk factors and mechanisms behind this disease has developed spectacularly in recent years. This progress has led to the implementation of highly promising therapeutic strategies, and will continue to do so.
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Understanding Alzheimer's disease
Alzheimer's disease is rare under the age of 65 years. Less than 2% of Alzheimer's cases occur before then, mainly among individuals with rare hereditary forms of the disease. After the age of 65 years, the incidence of the disease rises to 2 to 4% of the general population, rapidly reaching 15% 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, due to increasing life expectancy.
Women are more exposed to this disease: out of 25 patients, 10 are men and 15 are women. However, this difference could be related to the differences in life expectancy.
Memory loss, the first sign
- Memory disorder is the most constant and perceptible symptom associated with Alzheimer's disease.
- Executive function deficits are also highly indicative of this disease: 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.
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).
Memory gaps: seek medical advice!
Many individuals complain about recurrent memory gaps. When this problem becomes a concern for the patient (or family members) and it starts to interfere with their daily life to such an extent that the patient feels the need to discuss it with a doctor, this complaint should be taken very seriously and undergo specific evaluation. In the past 15 years, France has managed to create an extensive network of "memory centers" highly specialized in diagnosing these disorders, with over 400 clinics available nationwide.
Two culprits: beta-amyloid peptide and phosphorylated tau protein
Analysis of the brain of patients suffering from Alzheimer's disease evidences the presence of two types of lesions, hallmarks which confirm the diagnosis of Alzheimer's disease: amyloid plaques and neurofibrillary degeneration. These two types of lesions are both associated with a protein compound, which in itself is linked to disease progression: beta-amyloid peptide for amyloid plaques, and phosphorylated tau protein for neurofibrillary degeneration.
Beta-amyloid protein, naturally present in the brain, gradually accumulates over the years, under the influence of different genetic and environmental factors, until amyloid plaques start to form (also known as "senile plaques"). According to the "amyloid cascade" hypothesis, accumulation of this amyloid peptide would appear to induce toxicity for nerve cells, evidenced by increased phosphorylation of a neuronal structural protein, the tau protein. This phenomenon is said to affect the hippocampus, a brain structure which is the site of the short-term memory.
Phosphorylation of the tau protein causes disorganization of neuron structure and "neurofibrillary" degeneration which ultimately causes nerve cell death. The sequential mechanism for these pathological processes has yet to be determined. Scientists suspect abnormal protein aggregation phenomena, which could thus spread from cell to cell, and affect the whole brain, from the hippocampus region to the entire cerebral cortex.
This very slow process takes several dozen years to become established, before symptoms of the disease start to appear.
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 65 years of age, with a dramatic upturn after the age of 80 years. However, like all chronic disorders, individual susceptibility is also a factor which creates conditions more or less favorable to onset of the disease, according to the aging process and other environmental risk factors.
The risk of developing the disease increases 1.5-fold on average if a relative of the first degree suffers from the illness. This increases two-fold if at least two are affected. This individual susceptibility is partly conveyed via the genome. The IGAP (International Genomics of Alzheimer's Project) international consortium, created as part of the Plan on Alzheimer 2008-2012 and led by France, has already identified 21 genes and genomic regions behind this susceptibility. Approximately fifteen or so others are currently undergoing validation. The level of individual susceptibility is defined by a complex combination of these genes.
Knowledge of these genes will provide a better understanding of how this disease develops. Certain genes are implicated in amyloid peptide metabolism, such as those encoding apolipoprotein E (APOE) or clusterin. Others play a role in lipid metabolism, innate immunity, inflammation, synaptic or hippocampus function. This diversity indicates the highly complex mechanisms behind the disease.
Some of these genetic susceptibility factors may increase the risk of onset of the disease; however, other may reduce this risk and act as protective factors: having one or two epsilon 2 alleles of the APOE gene reduces the risk of Alzheimer's disease by more than half, whereas the presence of one or two epsilon 4 alleles increases this risk two- or fifteen-fold, respectively.
The environment also appears to play a major role in the onset of Alzheimer's disease, although the factors implicated remain unclear. 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 underlying mechanisms for this relationship have yet to be elucidated; however, it is thought that these could bring about impaired cerebrovascular performance, exacerbating the pathological process. Sedentary lifestyle is another risk factor, together with cranial microtrauma observed in certain athletes (such as American footballers 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. This protective effect is said to be related to the brain plasticity phenomenon which indicates the brain's permanent ability to adapt. This could compensate for lost neuron function. Likewise, caffeine consumption is said to be associated with a reduced risk of onset of the disease.
Specific case relating to hereditary forms
Hereditary forms of Alzheimer's disease account for 1.5 % to 2 % of cases. This concerns cases with autosomal-dominant hereditary transmission, occurring before the age of 65 years, often around the age of 45 years. In half of these early-onset 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 encoding the presenilin 1 and presenilin 2 proteins which play a role in APP metabolism. Inheriting mutations affecting one of these genes leads to onset of the disease.
Several instruments facilitating early diagnosis
As soon as the patient has made a formal complaint and seen a doctor, it is essential to make a diagnosis in the earliest possible stages. This diagnosis is initially based on cognitive function tests and neuropsychological tests. These serve to evaluate the nature and severity of the disorders (memory loss, temporospatial orientation, executive functions, etc.), and often rule out an underlying problem, such as depression which may favor the development of symptoms similar to those seen in Alzheimer's disease.
To support the diagnosis, biological markers can help confirm the cause of symptoms. It is now possible to measure three markers in the cerebrospinal fluid (CSF), accessible via lumbar puncture. These correspond to the beta-amyloid protein, the tau protein and the phosphorylated tau protein. The levels of these different markers are able, in certain cases, to confirm the diagnosis of Alzheimer's disease. Research is currently under way on the use of other markers found in the CSF, which could further improve the precision of the diagnosis for Alzheimer's disease.
Brain imaging is also used to assist in the diagnosis of Alzheimer's disease, including in the early stages. MRI is able to visualize cerebral abnormalities associated with the disease. A reduction in brain volume and atrophy of the hippocampus are arguments supporting the diagnosis. Furthermore, new brain imaging examinations, which are more specific and performed in earlier stages, are currently in development. These are based on positron emission tomography (PET). This technique involves injecting patients with radioactive tracers which bind specifically to brain lesions characteristic of the disease, amyloid plaques (amyloid peptide) and neurofibrillary degeneration (tau protein). Further studies are still necessary in order to determine the validity of these highly promising new procedures. Approximately 20% to 30% of individuals aged over 70 years with no clinical signs of Alzheimer's disease nonetheless display positive signals with amyloid markers.
Cognitive reserve could delay the onset of the first symptoms
The disease does not progress at the same speed in all patients. It is influenced by different genetic and environmental factors, together with the varying degrees of brain plasticity which is able to compensate for the impact of disease progression.
Prospective cohort studies in the general population, such as the PAQUID study, or the Three Cities study in France, have shed more light on the natural course of the disease. These studies follow up volunteers aged over 65 years and not presenting any cognitive disorders at entry into the cohort, over several decades, so as to monitor the possible onset of Alzheimer's disease. Detailed analysis of the neuropsychological tests on subjects included in these studies has shown that these individuals already presented changes in their cognitive function more than 10 to 15 years before developing any symptoms. This confirms that the pathological process progresses very slowly with compensation for varying lengths of time, according to the individuals.
Greater compensation is observed the higher the level of education. The underlying biological hypothesis is that education, the degree of brain stimulation and social relationships apparently stimulate the development of a dense neuronal network which allows compensation over longer periods for lesions induced by Alzheimer's disease. This is known as cognitive reserve.
Hence, stimulating the brain so as to encourage the development of this cognitive reserve is said to delay the first signs of the disease.
Challenges facing research
Fundamental research and clarification of the mechanisms behind Alzheimer's disease have made it possible to evidence new therapeutic targets for slowing or attempting to treat this disorder. Several therapeutic agents are currently in development. Most of these aim to block the accumulation of amyloid peptides. Others, such as methylene blue derivatives, attempt to fight against tau protein aggregation.
The currently most widely developed approach is still nonetheless immunotherapy, used to eliminate the beta-amyloid peptide. This strategy involves injecting highly specific antibodies directed against the peptide (passive immunotherapy) or vaccinating patients against it (active immunotherapy). The second approach is based on injecting a peptide with a similar structure, to stimulate the immune system and increase its efficacy in eliminating amyloid proteins which accumulate in the brain.
The results of clinical trials implemented to date have proven disappointing. The strategy is able to induce an immune reaction, but without an apparent reduction in symptoms. However, insofar as the patients treated in these trials are in the moderate stages of the disease, even if these treatments are effective, the state of their brain and the limitations of their cognitive reserve no longer allow them to regain sufficient intellectual function. It would thus be necessary to test these treatments earlier, before the first symptoms appear.
This poses major ethical problems, particularly regarding the need to test for and diagnose the disease in healthy subjects, years before the first signs of Alzheimer's disease develop. However, two trials are currently in progress in early-onset familial forms, in which high-risk patients can be identified with almost complete certainty thanks to genetic tests. This concerns the DIAN-TU trial (Dominantly Inherited Alzheimer Network Trial), which is testing two products which aim to eliminate the amyloid peptide from the brain: gantenerumab (a monoclonal antibody administered by subcutaneous injection every 4 weeks) and solanezumab (another monoclonal antibody delivered intravenously, also every 4 weeks). This trial is coordinated at CHU de Rouen in France.
Another trial, API (Alzheimer’s Prevention Initiative), is currently being conducted in Colombia where dozens of members of a very large family suffer from the hereditary form of the disease. The authors have identified the causative mutation in more than 500 members of this family, and have initiated an immunotherapy trial, also targeting the beta-amyloid protein. The study product is a third monoclonal antibody (crenezumab).
Antibodies directed against the phosphorylated tau protein are also being tested, together with vaccines against this protein (namely the ACI-35 vaccine).