So what we did was, during the last 25 years, we collected CSF of the patients who came into the Amsterdam Memory Clinic. So at the Amsterdam Memory Clinic, which is part of the Amsterdam UMC, we perform a lumbar puncture as part of the diagnostic routine. And then sometimes we also perform repeated lumbar punctures over time for specific studies. But they’re incredibly hard to perform. So it took a really long time to get a big enough sample size to investigate the molecular sequence of events that surround the key hallmarks of Alzheimer’s disease...
So what we did was, during the last 25 years, we collected CSF of the patients who came into the Amsterdam Memory Clinic. So at the Amsterdam Memory Clinic, which is part of the Amsterdam UMC, we perform a lumbar puncture as part of the diagnostic routine. And then sometimes we also perform repeated lumbar punctures over time for specific studies. But they’re incredibly hard to perform. So it took a really long time to get a big enough sample size to investigate the molecular sequence of events that surround the key hallmarks of Alzheimer’s disease. So now, we were able to gather serial CSF samples from almost 200people across the clinical spectrum and a big group of people had initially intact cognition and normal amyloid markers. And we measured repeated amyloid and tau as well as untargeted mass spec. And with the untargeted mass spec, we were able to detect many many many proteins. And so what we did was to look into changes over time of all these proteins and to understand which of these proteins have changing levels over time that are consistent across these different disease stages. And I think one really interesting finding is that within this group of control individuals, 10% of these people developed abnormal amyloid levels over time. So we were able to catch the very start of Alzheimer’s disease. And during that process, a group of about 45 proteins started to increase together. And they remained really high across all these different disease stages. So to me, that indicates that there is this reaction to very early amyloid aggregation that is sustained throughout the disease. And so amongst these proteins were also proteins that predicted the future rates of aggregating amyloid and also tau. But the few proteins that were related to developing these abnormal levels, they were related to immune-related processes, which I guess is very interesting because most of the GWAS findings that we have converge on genes that are in glia. And this data suggests that something happens while amyloid is aggregating that triggers this glial response. And so to me that suggests that this immune response might be very early and a trigger also of the pathology in sporadic AD, at least for a subset of individuals. In later disease stages, you also see different groups of proteins involved with immune-related responses, but sometimes these changes were not so consistent across disease stages. So this might reflect stage-specific effects. It might also reflect biological heterogeneity, that for some people there might be an over-activation of innate immune functioning, and maybe in some people there’s a dampened response. So now we’re expanding our sample size in terms of people and number of samples to be able to perform more detailed analysis of how these disease trajectories might also differ between people, and then that will be a starting point for developing personalized treatment strategies.
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