For the first time, a combination of the diabetes medicine metformin and a lifestyle intervention is being tested in the prevention of memory disorders. Speaking in the Kuopio Alzheimer Symposium, Professor Miia Kivipelto presented the MET-FINGER study to be launched in three countries.
The 9th Kuopio Alzheimer Symposium was organised as a joint event together with the Nordic Memory Clinic Conference on 23–25 August 2022.
According to Professor Miia Kivipelto, research into the prevention of memory disorders is moving towards tailored interventions that take the individual risk profile better into consideration. An example of this is the MET-FINGER study to be launched in Finland, Sweden and the UK.
“Participants who have an elevated risk for memory disorders as well as risk factors for type 2 diabetes will have metformin included in their lifestyle intervention. This combination has not been tested before,” said Kivipelto in the symposium press conference. She works in both the University of Eastern Finland and the Karolinska Institutet in Sweden.
“Previous studies have associated metformin with a lower risk of Alzheimer’s disease, and it has also been shown to have an impact on key disease mechanisms, such as neuroinflammation and beta amyloid and tau protein deposition. However, we don’t yet know what the optimal metformin dose for the brain is.”
The Finnish FINGER study was the first in the world to show that memory disorders can be prevented through a lifestyle intervention that includes dietary counselling, exercise, memory training, and effective management of the risk factors for cardiovascular diseases. The intervention has already been applied in 45 countries through the World-Wide FINGERS network led by Kivipelto, and it has been found particularly effective among carriers of the common APOE4 risk gene, which has been associated with Alzheimer’s disease. In the new MET-FINGER study, at least half of the participants are carriers of the APOE4 gene.
“According to results that are yet to be published, the lifestyle intervention can significantly reduce the effects of other risk genes as well.”
Subtypes of Alzheimer’s disease will be treated in the future
Publishing its results in spring 2022, the European EADB project has carried out one of the largest genome-wide risk gene studies on Alzheimer’s disease so far. The study identified 75 genes associated with the risk of Alzheimer’s disease, 42 of which were previously unknown. The pathogenesis of Alzheimer’s disease may vary depending on the individual genetic background, which means that a single medication is unlikely to work for everyone.
“In the past, drug development for Alzheimer’s disease could only be targeted at symptoms because the root causes of the disease were unknown. Although we’ve made progress on that front, we still don’t know enough. However, I do believe that we’ll find effective treatments for different subtypes of the disease, such as for carriers of certain risk genes,” said Professor Philip Scheltens, Director of the Alzheimer Center Amsterdam.
Several medicines are being developed for Alzheimer’s disease, also targeting its different disease mechanisms. As promising examples already undergoing extensive trials, Scheltens mentioned beta-amyloid antibodies, lecanemab developed by BioArctic, and gantenerumab developed by Roche.
“Lecanemab has significantly reduced amyloid deposits in the brain, and I believe the effect will be seen in patients’ symptoms. Gantenerumab was initially thought to be a disappointment, but we are now awaiting results from studies with higher doses.”
Last year, the first Alzheimer’s medicine that removes amyloid deposits from the brain, aducanumab, was approved for use in the US. However, according to the European Medicines Agency, there are questions about its effectiveness and safety, and the manufacturer, Biogen, has withdrawn its marketing authorisation application in Europe.
Precision diagnostics and treatment are facilitated not only by genetic data, but also by the development of other biomarkers measured from patients.
“Just 20 years ago, protein deposits in the brain could only be seen in an autopsy, whereas the current methods enable their earlier detection from cerebrospinal fluid, brain images – and more recently – even from blood samples,” said Professor Henrik Zetterberg from the University of Gothenburg.
Professor Jon Snaedal of the NIDD expert working group of the Nordic Network in Dementia Diagnostics and of the National University Hospital of Iceland pointed out that new medicines expected to enter the market in the upcoming years will also pose challenges to memory clinics.
“Patients expect to receive a medicine, but if the medicine is targeted at a specific disease mechanism, it will only work for some, and the screening of patients may require expensive studies. Another challenge is to identify the different stages of the disease and to initiate medication at the right time. New medicines are also very expensive at first.”
Snaedal also anticipates that in the future, the treatment of Alzheimer’s disease will become subtype-specific, even if such a distinction cannot be made just yet.
“In the end, the different subtypes can be so distinctive that they are no longer even referred to as Alzheimer’s disease.”
Genes can also protect against disease
“Besides to risk genes, also genes that protect against Alzheimer’s disease provide a basis for drug development,” said Professor Mikko Hiltunen, one of principal investigators of the EADB project.
Hiltunen leads a research group on the molecular genetics of Alzheimer’s disease at the University of Eastern Finland, and the group is now focusing on factors identified in the EADB project that protect against Alzheimer’s disease.
“We are looking into whether some of the protective mechanisms that occur naturally in carriers of these genetic mutations could be used in treatment.”
“Many of these protective genetic factors are very rare. For example, a genetic mutation that reduces amyloid production in the brain was originally found in Iceland, and there are 20,000 carriers of this mutation in Finland. Not only will they avoid Alzheimer’s disease, but their mind will stay sharp long into old age,” Hiltunen said.
“Extensive studies on risk genes are also of great interest to the general public. When we published the results of the EADB project, many ordinary people contacted us to ask whether genetic data could be utilised in the treatment their parents, or to reduce their own risk of disease. However, the introduction of genetics in the treatment of patients still requires a lot of expensive research, for which there is not enough support in Europe,” said Research Director Jean-Charles Lambert of the French National Institute of Health and Medical Research, Inserm, and of the Institut Pasteur de Lille.
Also Hiltunen, who leads the Neuroscience Research Community of the University of Eastern Finland, says that neurosciences are underfunded in relation to the burden caused by brain diseases.
“Last year, for example, only 1.6% of the funding granted by the Academy of Finland was targeted at neuroscience research.”
A key theme of the Kuopio Alzheimer Symposium and the Nordic Memory Clinic Conference was patient involvement and, in addition to scientific presentations, patient testimonials were also heard as part of the programme.
“These testimonials were important especially for many junior researchers who hadn’t encountered someone with a memory disorder before,” Hiltunen said.
“Earlier, patients used to be just the object of a study, but now they are invited to contribute to decisions about how the study will be implemented.”
In the EURO-FINGERS study led by Kivipelto, a steering committee consisting of patients made a significant contribution to the study.
“For example, we talked with them about whether biomarker or genetic data should be disclosed to the patient, and whether the narrative should focus on prevention, risk reduction, or brain health. Their involvement was important not only because the funder so required, but because it had an impact on the clinical work with patients.”
