In France, 900,000 people suffer from Alzheimer’s or a related disease. The risk of developing Alzheimer’s disease depends on genetic and environmental factors. Among the latter, various epidemiological studies suggest that regular, moderate caffeine consumption slows age-related cognitive decline and the risk of developing Alzheimer’s disease. In a new study [1] , researchers from Inserm, the Lille University Hospital and the University of Lille, within the Lille Neuroscience and Cognition research center, have taken a further step towards understanding the mechanisms underlying the development of Alzheimer’s disease. They have just demonstrated that the pathological increase in certain receptors in neurons at the onset of the disease favors synapse loss, and hence the early development of memory disorders in an animal model of the disease. Their results also confirm the value of conducting clinical trials to measure the effects of caffeine on the brains of patients at an early stage of the pathology. They are published in the journal Brain .
Alzheimer’s disease is characterized by impaired memory, executive functions and orientation in time and space. It results from a slow degeneration of neurons, starting in the hippocampus (a brain structure essential for memory) and spreading to the rest of the brain. Patients suffering from this pathology present two types of microscopic lesions in their brains: senile plaques (or amyloid plaques) and neurofibrillary degeneration (or Tau pathology), which contribute to neuronal dysfunction and disappearance [2].
Previous research had shown that the expression of certain A2A receptors was increased in the hippocampus of Alzheimer’s disease patients. However, the impact of deregulation of these receptors on the development of the disease and associated cognitive disorders remained poorly understood until now. In a new study, a research team led by Inserm researcher David Blum has addressed this issue.
Scientists have succeeded in reproducing an early increase [3] in A2A adenosinergic receptor expression, as observed in patient brains, in a mouse model of Alzheimer’s disease that develops amyloid plaques. The aim was to assess the consequences of this increase on the disease and to describe the mechanisms involved.
The results of their research show that the increase in A2A receptors promotes the loss of synapses [4] in the hippocampus of "Alzheimer mice". This results in the early onset of memory disorders in the animals. The scientists then showed that a dysfunction of certain brain cells, the microglial cells, partly responsible for the cerebral inflammation observed in the disease, could be involved in the loss of synapses, in response to an increase in A2A receptors. Similar mechanisms had previously been described by the team, this time in another model of the disease developing Tau lesions [5] .
"These results suggest that increased A2A receptor expression alters the relationship between neurons and microglial cells. This alteration could be at the origin of an escalation of effects leading to the development of the memory disorders observed", explains study co-author Émilie Faivre, a researcher at the Lille Neuroscience and Cognition research center (Inserm/Université de Lille/CHU de Lille).
Caffeine: an interesting treatment option for early prevention of cognitive decline?
Several studies have already suggested that regular, moderate caffeine consumption (equivalent to 2-4 cups of coffee a day) can slow age-related cognitive decline and the risk of developing Alzheimer’s disease.
In 2016, the same research team had described one of the mechanisms by which caffeine could have this beneficial action in animals, reducing cognitive impairment associated with Alzheimer’s disease. The scientists showed that caffeine’s effects were linked to its ability to block the activity of A2A adenosinergic receptors, the same receptors whose expression is abnormally increased in the brains of people with Alzheimer’s disease [6] .
"By describing, in our new study, the mechanism by which the pathological increase in A2A receptor expression results in a cascade of effects leading to a worsening of memory disorders, we confirm the interest of therapeutic avenues that could act on this target. We are therefore once again highlighting the value of testing caffeine in a clinical trial on patients suffering from early forms of the disease. Indeed, it is conceivable that by blocking these A2A receptors, whose activity is increased in the patient, this molecule could prevent the development of memory disorders or even other cognitive and behavioural symptoms", continues David Blum, Director of Research at Inserm, and co-writer of the study.
A Phase 3 clinical trial [7], led by the Lille University Hospital, is currently underway. Its aim is to evaluate the effect of caffeine on cognitive function in patients with early to moderate Alzheimer’s disease.
[1] This work was supported by the Alzheimer’s Foundation, the FRM, the ANR, CoeN (LICEND), Inserm, the University of Lille, the CHU de Lille and the labEx Distalz (Development of Innovative Strategies for a Transdisciplinary Approach to Alzheimer’s Disease) as part of the future investment program.
[2] Read the dossier on Alzheimer’s disease and consult the Inserm comic strip which graphically explains the cellular and molecular mechanisms involved in the development of the disease.
[3] At a stage when animals do not normally suffer from memory problems.
[4] Zones that allow the transmission of information between neurons.
[5] Exacerbation of C1q dysregulation, synaptic loss and memory deficits in tau pathology linked to neuronal adenosineA2A receptor, Brain, Volume 142, Issue 11, November 2019, Pages 3636-3654, https://doi.org/10.1093/brain/awz288
[6] Read the
[7] The CAFCA Phase 3 clinical trial is led by neurologist Thibaud Lebouvier, in association with the LilNCog laboratory and the Centre Mémoire at Lille University Hospital. https://www.cafca-alzheimer.fr/
