Alzheimer’s is the most expensive disease in the United States, costing an estimated $277 billion in 2018, according to the Alzheimer’s Association. It is now clear that during early stages of the disease, neurons start losing the connections, called synapses, allowing them to communicate and store memories. However, trying to fix the human brain is very ambitious, with its 80 billion neurons and a hundred trillion connections. The degree of complexity is staggering. Defining which synapses are lost first and preventing neurons from becoming disconnected represents an interesting therapeutic avenue if we can first understand the signaling mechanisms involved.  We talked to prof. Franck Polleux whose research laboratory is located at Columbia University in the Department of Neuroscience and the Zuckerman Mind Brain Behavior Institute in New York, where his team studies the cellular and molecular mechanisms underlying the establishment of connectivity in the developing brain and how these mechanisms become dysfunctional during neurodegeneration.

“Neuroscience is the ultimate frontier in biology for a reason. We are dealing with something that’s so uniquely complex, that it’s difficult to fix. A lot of people in the field of neurodegeneration are hoping that we can instead of being forced to fix the diseased brain in Alzheimer’s disease, we might prevent the damage. The hope in the Alzheimer’s field right now is in prevention or intervention at a very early stage of the disease. There is a lot of hope that with new genetic markers and better biomarkers of the early disease progression, researchers might either prevent the disease progression or at least identify the patients before they show the symptoms. “If you have any intervention, the only hope is to identify the patients before they are symptomatic. This has been a huge challenge for the field. There is significant progress in that area”, says prof. Polleux.

Several new clinical trials of a kind

Several companies are performing for the first time clinical trials on patients that are pre-symptomatic. “The advance in defining combinations of biomarkers that are predictive enough to identify patient populations before they develop irreversible cognitive symptoms allows for the first time to attempt therapeutic interventions at early stages of the disease progression.  That’s a potentially significant step and could lead to a complete revolution in the identification of new treatments. We will know in a few years if this approach has a significant therapeutic benefits”, says prof. Polleux.

For decades, research programs have been set up to understand the disease mechanisms and find strategies to alter the progression of Alzheimer’s and other forms of dementia. “The field has made tremendous progress over the past 20 years in doing the ground work of understanding some aspects of the disease mechanisms. Amyloid beta is definitely a culprit, tau is definitely a culprit, the field has evidence that other risk factors such as ApoE4 allele are also playing important roles in neurodegeneration. Recently, it has been recognized that immune system and inflammation is playing also playing key roles in the disease progression. The field right now is trying to understand how those factors interact to mediate the early stage of the disease, which synaptic loss, years before patients ultimately lose neurons at later stages. How do those culprits interact to trigger synaptic loss. That’s a big question.”

Synaptic loss in the hippocampus and associated structures happens in the very early stages of AD. “Months before you see plaques and tangles, it’s clear now that specific neurons in the brain of Alzheimer’s patients lose a significant number of synapses, disrupting connectivity in circuits involved in learning, memory and cognition.” The Polleux lab has unraveled a key ‘stress-response’ signaling pathway (CAMKK2-AMPK) that triggers synaptic loss. “We have a cellular and molecular mechanism explaining how amyloid beta triggers synaptic loss by over-activating this kinase pathway. We are trying to find ways to block the over-activation of this kinase pathway by Abeta oligomers in order to maybe prevent this early synaptic loss. Now that we have demonstrated the causal relationship between this pathway and the ability of amyloid beta to trigger synaptic loss, we are now collaborating with other groups and biotech companies to develop small molecule inhibitors of some of the enzymes in this signaling pathway”, says Polleux. This approach alone will probably not be sufficient. The field is trying to evaluate whether or not intervening on multiple aspects of the pathway cumulatively could have a clinical effect. “The hope is that maybe in combination these approaches might have substantial therapeutic effects.”

We are not sure if Alzheimer’s is a single disease

According to Prof. Polleux, we are probably about half way in the understanding of the pathological mechanisms underlying Alzheimer’s disease. And the hope is that the tremendous progress by basic neuroscientists in understanding how brain circuit function and how connectivity is maintained throughout the life of the individual, we will be in a better position to intervene. Currently, we still do not fully understand how the many cellular and molecular culprits such as Amyloid-b oligomers, phosphorylated tau, ApoE4, inflammation, microglia activation interact during early stages of the disease. One exciting possibility is that there might be a common signaling pathway linking all those pathophysiological events. And if there is a common link, is intervening on this signaling pathway able to prevent the loss of synapses early and later loss of neurons. “One word of caution is we are not sure if Alzheimer’s is a single disease. It’s also possible that there are multiple ways to trigger Alzheimer’s disease and that not all patients develop the disease through the same mechanisms.”