Alzheimer’s: where does the search for new therapies stand?
Saturday 21 September 2024 marked World Alzheimer’s Day, established in 1994 by the World Health Organisation and Alzheimer’s Disease International. The neurodegenerative disease, whose numbers are set to grow globally with an ageing population and for which no effective therapies yet exist, is a global health challenge.
Fortunately, research has made progress: new discoveries are revealing the role of inflammation and immune activation in the origin and progress of the disease. The hope is that these discoveries will pave the way for the development of more effective therapeutic and preventive approaches.
Michela Matteoli – Professor at Humanitas University and Director of the Neuroscience Research Programme at Humanitas – told us about this. Professor Matteoli is studying the link between inflammation and neurodegeneration with a special focus on the role of the brain’s immune cells, the microglia, in diseases related to ageing and neurodevelopment.
What is Alzheimer’s?
Alzheimer’s is the most common form of dementia, a neurodegenerative disease that causes the progressive death of neurons and the consequent loss of cognitive functions, leading to the total impairment of the patient’s autonomy. It accounts for about 60 per cent of all dementia cases.
In Italy more than 600,000 patients suffer from Alzheimer’s, a number that is set to double by 2050 due to the increase in the average age of the population – a widespread phenomenon in all industrialized countries. This is why finding effective therapies that can prevent or slow down the course of the disease is crucial.
The drugs currently used in Europe are symptomatic and have a modest effect. Their effect occurs only in the early stages of the disease and not in all patients. These drugs act by increasing or reducing signal transmission between different types of neurons, depending on how this transmission is altered by the disease, but they do not act on the underlying mechanisms of the disease. Attempts to go beyond the symptomatic approach and act at the source, which have so far focused on reducing beta-amyloid plaques, have not proved successful.
The limits of beta-amyloid therapies
For many years, research has focused on eliminating beta-amyloid plaques, a protein build-up long thought to be the main cause of neuronal degeneration.
However, despite the efforts of major pharmaceutical companies, attempts to slow down the disease by using monoclonal antibodies capable of attaching to and degrading the beta-amyloid protein have had little success. The first of these drugs to be approved by the US FDA in 2021 was aducanumab, but due to poor effectiveness data and significant side effects associated with the treatment, its production and distribution was discontinued by the manufacturing company itself.
Other similar FDA-approved drugs are lecanemab and donanemab. While both have significant side effects, they also appear to be more effective than aducanumab in slowing the disease’s progression. These are, however, mild clinical effects, which is why the EMA, the European Medicines Agency, has decided not to approve lecanemab for marketing (it has not yet ruled on the newer donanemab, which was not approved in the US until July 2024).
‘There is now a consensus that the reduction of amyloid plaques alone is not sufficient to block or slow down the disease and that it doesn’t always have a clinically significant effect. Even if these monoclonal antibodies work better in the early stages of the disease and without major side effects, there is no evidence that they can be as effective in the more advanced stages of Alzheimer’s,’ says Matteoli. ‘It is clear that there are multiple players involved in the disease, which is why we need to think about the possibility of employing new combined strategies, directed not only against the beta-amyloid protein but also against other targets and molecular mechanisms.’
The role of inflammation
In recent years, the scientific community has begun to explore other mechanisms underlying the disease, such as brain inflammation. As neurons deteriorate, they release factors that trigger an inflammatory cascade, and the inflammation is then further amplified by the microglia surrounding the protein plaques.
‘Studies into the genetics of Alzheimer’s have further broadened this focus on inflammation: two key studies published in the New England Journal of Medicine have shown that the variants of several genes active in the microglia response increase the risk of developing Alzheimer’s. In particular, a gene called TREM2 – on which we are focusing our research efforts – increases the risk of developing the disease by a factor of 2-3 and could become a potential therapeutic target in the future,‘ says Matteoli.
But there’s more: susceptibility to Alzheimer’s disease could be linked in two ways to what happens in the developmental stages of the brain. Mutations in TREM2 could in fact make the areas of the brain devoted to memory more prone to neurodegeneration, as some recent studies conducted in Humanitas laboratories suggest.
New perspectives: combined therapies and lifestyle
‘The key to effectively treating Alzheimer’s is likely to be a combination of drugs that act on several mechanisms simultaneously: from beta-amyloid to inflammation,’ Matteoli points out. Alongside these new therapies, adopting lifestyles that reduce chronic inflammation is crucial. ‘A healthy diet, regular physical activity and quality sleep are all factors that can help keep inflammation levels low, slowing down brain ageing and reducing the risk of Alzheimer’s.’
The AllenaMENTE project – which will start in Humanitas and build on the experience of a previous research study carried out in collaboration with the CNR and called Train the Brain – promotes precisely this integrated approach: keeping the brain active through mental and physical exercises that help prevent cognitive decline and studying how these exercises affect inflammatory levels.