Long before the onset of dementia, there is evidence of increased activity of the brain’s immune system. Researchers from DZNE and the University Hospital Bonn (UKB) come to this conclusion based on a study of more than 1,000 elderly people. To this end, various proteins were measured in the cerebrospinal fluid: they served as so-called biomarkers that indicate inflammatory processes in the nervous system. It turned out that some of these molecules seem to be part of an immune system damage control program, which could be useful for the development of new drugs. The results of the study were published in the scientific journal neuron.
In recent years, it has become clear that the brain’s immune system and associated inflammatory processes – also known as “neuroinflammation” – contribute significantly to the development of Alzheimer’s disease. In this perspective, the scientists analyzed various immunological biomarkers which are characterized by good detectability in cerebrospinal fluid and reproducible results. “It was already known that these markers indicate immune processes in the context of Alzheimer’s disease. However, the relationship between these markers and brain volume, cognitive performance and other parameters had not been studied as well. depth than we are currently doing,” says Professor Michael Heneka. , who led the current study during his long tenure at DZNE and UKB. Since the beginning of this year, he has been director of the Luxembourg Center for Systems Biomedicine.
We found that some of these inflammatory markers are visible even when there are no dementia symptoms yet. Based on the data we have so far, we cannot specify the delivery time at this stage. But my estimate is that it’s at least ten to twenty years.”
Professor Michael Heneka
The starting point for the investigations was the data from the so-called DELCODE study, in which the DZNE studies dementia and its preliminary stage in collaboration with several university hospitals across Germany. The current study project included results from approximately 300 women and men, all over the age of 60. This group included normal cognitive adults, people with more or less severe memory problems and also people with dementia of the Alzheimer type. Cerebrospinal fluid samples and standardized memory tests were available for all study participants, and magnetic resonance images of the brain were taken for most of them. For each study participant, data included the initial examination and at least one follow-up one year later. For some subjects, the results spanned multiple follow-ups over a period of up to five years.
Striking even without dementia
“There are established biomarkers for amyloid and tau. These are proteins that accumulate in the brain in Alzheimer’s disease and can also be detected in cerebrospinal fluid. Their levels usually change even before symptoms of dementia appear, which is considered a sign of process for neuronal damage. We wanted to know if the inflammatory markers react in a similar way”, explains Dr. Frédéric Brosseron, scientist at DZNE and one of the first authors of the current publication in ‘Neuron’. “In fact, we found that most inflammatory markers are elevated, especially when a marker of neuronal injury is elevated. This applies even when these people do not yet show symptoms of dementia. Thus, the inflammatory markers we recorded are particularly useful for studying neuroinflammation. in the early stages of the disease.
Evidence of neuroprotection
Two of these markers in particular – proteins belonging to the “TAM receptor family” – appear to be linked to a damage-fighting program. In study participants with particularly high levels of these elevated markers, brain volume was relatively large and cognitive functions declined more slowly over time. To verify these results, Heneka’s team evaluated data from a study cohort from the Barcelona ACE Alzheimer Center with more than 700 adults, most of them with mild cognitive impairment. This analysis confirmed the results of the DELCODE study.
“Inflammatory processes are not inherently bad, but rather a normal, protective reaction of the immune system to threatening stimuli, especially at first. But they shouldn’t last too long, so they need to be regulated,” says Heneka. TAM family proteins are known to influence immune responses and promote the elimination of cellular waste, he explains. “Supporting this protective function would be an interesting approach for pharmaceutical research. This is where I see the potential for application of the markers that we have identified. For early detection of dementia in routine care, measuring these markers is too complex. drugs in clinical trials, there are other technical options. In trials, indicators are needed to assess whether the interventions work and whether the drugs being tested are effective. TAM markers could be very useful for this.
DZNE – German Center for Neurodegenerative Diseases
Brosseron, F. et al. (2022) Soluble TAM receptors sAXL and sTyro3 predict structural and functional protection in Alzheimer’s disease. Neuron. doi.org/10.1016/j.neuron.2021.12.016.