"We are at the beginning of a new era in the treatment of Alzheimer's," declared Alberto Lleó, director of the neurology service at the Sant Pau hospital, before the arrival of the first drugs that could stop the progression of the disease. For doctors who have been diagnosing people with Alzheimer's for decades without being able to offer them anything to prevent disease progression, these drugs are an unprecedented source of hope.
“The tide is turning and a new era in Alzheimer's care is emerging,” neurologists from the Universities of Harvard, Pennsylvania and California in San Francisco agree in a joint article published in JAMA Neurology. In this new era, they predict, "an accurate clinical diagnosis will be made in the initial phases, opening the way to specific molecular therapies" with the aim of preventing the disease from progressing towards dementia.
But the enthusiasm of neurologists contrasts with the reality of patients at a time when none of these new treatments are yet approved in Europe and early diagnosis techniques are only used in a minority of cases. We are on the threshold of a new era but we have not fully entered it yet, admits Lleó.
Improved treatments are based on an increasingly precise understanding of what happens in the brain as Alzheimer's progresses. Although the initial cause of the disease remains unknown, two key proteins have been identified that are altered in the brain of patients.
First, the beta-amyloid protein is altered, which accumulates forming plaques on the outside of neurons for years without affected people even having symptoms of cognitive impairment.
Then the tau protein fails, which accumulates abnormally inside the neurons, at which time the symptoms of the disease will manifest. A recent study co-led by Alberto Lleó, from the Sant Pau hospital, has shown that abnormal forms of the tau protein are transmitted from one neuron to another through synapses, which may explain how Alzheimer's damage spreads from the region from the brain where they have started to other brain regions.
The fact that alterations in the beta-amyloid protein occur before alterations in tau indicates that beta-amyloid possibly has a causal role in the origin of the disease, while tau has a more important role in its development. progression. This idea, known as the amyloid hypothesis, has led several pharmaceutical companies to develop drugs against the beta-amyloid protein.
The first drugs tested against the beta-amyloid protein did not bring any significant improvement to the volunteers who took them, which led to questioning the amyloid hypothesis. But the situation has changed in the last eight months after knowing the results of two antibodies that have reduced the amount of beta-amyloid in the brain and that have slowed down the progression of the disease in its early stages.
Alzheimer's has progressed 27% more slowly in people who have received the lecanemab antibody for 18 months than in people who have received a placebo, according to results of a clinical trial with 1,795 patients presented last September. The progression of the disease has been assessed using brain imaging techniques and tests and questionnaires for people with Alzheimer's and their caregivers to assess their deterioration throughout the study.
Although lecanemab does not cure Alzheimer's or prevent its progression, the fact that it progresses more slowly raises the hope that patients who receive it will enjoy more years with a high degree of autonomy, a good quality of life and without dementia.
Neurologists are concerned about the possible side effects of the drug, which may include inflammation of the brain and cerebral microhemorrhages in some cases, which will make it necessary to individually assess which patients to prescribe the treatment.
In the United States, the Food and Drug Administration (FDA) has already approved lecanemab, developed by the companies Eisai and Biogen, through an accelerated approval process. The European Medicines Agency (EMA) is in the process of evaluating the drug, which could be approved in the last quarter of the year.
A second antibody against beta-amyloid, donanemab, appears to be slightly more effective, according to results announced by Eli Lilly on May 3. The company has reported that an 18-month course of donanemab slows cognitive decline by 35%. Detailed results of the clinical trial, which will allow a better assessment of the drug's efficacy and side effects, will be presented at a conference in Amsterdam in July.
Eli Lilly plans to apply for approval of donanemab in the United States in the next two months, the journal Nature has reported, while approval in Europe is likely to come in 2024.
Having prioritized the development of drugs against beta-amyloid, some companies have given up looking for treatments against tau. But the confirmation in recent years of the importance of this protein, both in Alzheimer's and in other neurological diseases, has fueled interest in finding antitau drugs.
Although these drugs are not in as advanced a phase of clinical trials as those for beta-amyloid, the first results are encouraging. A Biogen company drug has shown for the first time that it can partially eliminate abnormal tau protein from the brain, according to a phase 1 clinical trial involving 46 patients presented at the International Conference on Alzheimer's and Parkinson's Diseases held in late February. March in Gothenburg (Sweden).
The fact that accumulations of tau can be eliminated from inside neurons "is an extraordinary result that makes us think that some Alzheimer's damage may be reversible," says Alberto Lleó. "In the future it is possible that a treatment with several drugs may be able to stabilize the disease." A diagnosis of Alzheimer's would no longer have a prognosis for dementia.
The Biogen company has started a phase 2 clinical trial with 735 patients from the United States and Canada that will evaluate whether 72 weeks of treatment with its experimental drug BIIB080 reduces neurodegeneration and restores cognitive abilities in people with mild symptoms of Alzheimer's.
If treatments against beta-amyloid and tau are confirmed to be effective in the early stages of Alzheimer's, it will be desirable to have techniques to diagnose the disease before it causes severe symptoms.
These techniques already exist but are not yet used on a large scale, reports Arcadi Navarro, director of the Fundació Pasqual Maragall. One reason why they are not applied more is that, in the absence of therapies capable of slowing the progression of Alzheimer's, early diagnosis does not translate into early treatment. But when effective drugs are available in the future in these initial phases of symptoms, early diagnosis will be necessary to access treatment.
Diagnosis is based on an analysis of the level of beta-amyloid and tau proteins in the cerebrospinal fluid, which is obtained by lumbar puncture. This test is done only in people with symptoms that suggest they have Alzheimer's. In 70% of cases the first symptom is impaired memory of recent episodes.
Looking to the future, early diagnosis tests are being developed using a blood test before the onset of symptoms. The level of a form of the tau protein called phosphorylated tau indicates whether a middle-aged person will develop Alzheimer's symptoms in the future, although the diagnosis must be confirmed later with a cerebrospinal fluid analysis.
“We know that by the time symptoms start, neurodegeneration is quite advanced. Early detection through blood tests opens the way to act before the onset of symptoms ”, declares Arcadi Navarro.
Initially, however, lecanemab and donanemab will only be prescribed to people who already have symptoms, since this is the group in which these drugs have proven to be effective. Studies are currently underway to test its effectiveness in people with abnormal levels of phosphorylated tau protein who do not yet have symptoms.
The arrival of the first drugs capable of slowing the progression of Alzheimer's will force the healthcare system to adapt so that patients who can benefit from them receive them. This will force action in two areas.
First, it will be necessary to increase the capacity for early diagnosis, which at the moment is limited to a few medical centers with specialized services. “Until now there has not been a great demand for early diagnosis of Alzheimer's because there were no treatments. But this is going to change in the coming years and the health system is not ready”, warns Alberto Lleó, who was one of the six coordinators of the National Alzheimer's Plan (2019-2023) of the Ministry of Health.
Then it will be necessary to find financing for the treatments. In the US, lecanemab costs $26,500 per year per patient (24,700 euros at current exchange rates). In Europe, where no beta-amyloid antibody is yet approved, the prices that governments negotiate with pharmaceutical companies are likely to be lower. But if 16% of people diagnosed with Alzheimer's are candidates for receiving these drugs -according to a calculation made in the United States population- and there are 86,000 people diagnosed in Catalonia, there would be 14,000 people candidates for receiving the drug from the moment of its approval. Assuming a cost of the order of 15,000 euros per year per patient, some 210 million euros per year would be needed to finance the pharmacological treatment. This amount would increase in the following years as the number of early diagnosed patients increased.
Since antibodies against beta-amyloid are not yet approved in Europe, the health system has time to prepare for the arrival of these drugs. "We should take advantage of this golden time to be ready when the time comes, but we are not doing it," says Alberto Lleó.
“I hope that the health system does a well-done cost-benefit analysis. I have no doubt that the data will indicate that, in the long term, it will be worth stopping the progression of the disease before it causes symptoms”, declares Arcadi Navarro. “We have reasons for optimism. We are getting closer to Pasqual Maragall's dream of a future without Alzheimer's”.
