There is evidence of increased activity of the brain’s immune system long before the onset of dementia. Based on a study of over 1,000 older adults, researchers from DZNE and the University Hospital Bonn (UKB) have reached this conclusion. To that end, various proteins in cerebrospinal fluid were measured: they served as so-called biomarkers that indicate inflammatory processes in the nervous system. As it turns out, some of these molecules appear to be part of the immune system’s damage control program, which could be useful in the development of new drugs. The findings of the study have been 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” – play a significant role in the development of Alzheimer’s disease. In light of this, the researchers investigated a number of immunological biomarkers with high detectability in cerebrospinal fluid and reproducible results. “These markers were already known to 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 thoroughly as it is now “Prof. Michael Heneka, who led the current study during his long tenure at DZNE and UKB, explains. He has been the director of the Luxembourg Centre for Systems Biomedicine since the beginning of this year.
“We discovered that some of these inflammatory markers are visible even when there are no symptoms of dementia,” Heneka explains. “We can’t estimate the lead time based on the information we have so far. But, in my opinion, it will take at least ten to twenty years.”
We discovered that some of these inflammatory markers are visible even when there are no symptoms of dementia. These markers were already known to indicate immune processes in the context of Alzheimer’s disease. We can’t estimate the lead time based on the information we have so far. But, in my opinion, it will take at least ten to twenty years.Prof. Michael Heneka
The investigations began with data from the DELCODE study, in which the DZNE investigates dementia and its early stages in collaboration with several university hospitals across Germany. The current study project included findings from approximately 300 women and men over the age of 60. This group included cognitively normal adults, people with varying degrees of memory problems, and people with Alzheimer’s dementia.
Cerebrospinal fluid samples and standardized memory tests were available from all study participants, and magnetic resonance imaging of the brain was obtained from the majority of them. The data included the baseline examination and at least one follow-up one year later for each study participant. Some subjects had multiple follow-ups over a five-year period, and the findings spanned multiple follow-ups.
Striking Even Without Dementia
“Amyloid and tau biomarkers are well-established. These are proteins that build up in the brain and can also be found in cerebrospinal fluid in Alzheimer’s disease. Their levels usually change even before symptoms of dementia appear, which is thought to be a sign of neuronal damage processes. “We wanted to know if inflammatory markers respond in the same way,” says Dr. Frederic Brosseron, a scientist at DZNE and one of the study’s first authors.”
“In fact, we discovered that most inflammatory markers are elevated, especially when a neuronal damage marker is elevated. This is true even if these people do not yet exhibit symptoms of dementia. As a result, the inflammatory markers we discovered are especially useful for studying neuroinflammation in the early stages of disease.”
Evidence for Neuroprotection
Two of these markers in particular, proteins from the “TAM receptor family,” appear to be linked to a damage control program. Brain volume was comparatively large in study participants with high levels of these high markers, and cognitive functions declined more slowly over time. To validate these findings, Heneka’s team analyzed data from an ACE Alzheimer Center Barcelona study cohort of over 700 adults, the majority of whom had mild cognitive impairment. This analysis confirmed the findings of the DELCODE study.
“Inflammatory processes are not inherently harmful; rather, they are a normal, protective response of the immune system to potentially harmful stimuli, particularly in the early stages. However, they should not last too long, so they must be regulated “Heneka explains. TAM family proteins are known to influence immune responses and promote cellular waste disposal, he says.
“Supporting this protective function would be an intriguing avenue of investigation for pharmaceutical research. This is where I see the potential for using the markers we’ve identified. Measuring these markers in routine care is too complicated for early detection of dementia. However, there are other technical options when testing new drugs in clinical trials. In clinical trials, indicators are required to determine whether interventions are effective and whether tested drugs are effective. TAM markers could be very useful in this case.”
This study was funded in part by the international PREADAPT project, which is part of the EU Joint Programme for Neurodegenerative Disease Research (JPND).