In recent years, it has become clear that the brain's immune system and the inflammatory processes that result from it - also known as "neuroinflammation" - play a key role in the development of Alzheimer's disease. Against this background, the scientists analyzed various immunological biomarkers that are characterized by good detectability in the cerebrospinal fluid and reproducible results. "It was already known that these markers indicate immune processes in the context of Alzheimer's disease. Until now, however, people had not investigated as comprehensively as we have now how these markers are related to brain volume, cognitive performance and other parameters," explains Prof. Michael Heneka, who led the current study as part of his many years at the DZNE and University Hospital Bonn (UKB). Since the beginning of this year, he has been director of the Luxembourg Centre for Systems Biomedicine.
"We have found that some of these inflammatory markers are conspicuous even when there are no symptoms of dementia yet," Heneka said. "Based on the data we have so far, we can't specify the lead time yet. But my estimate is that it is at least ten to twenty years."
Extensive database
The starting point for the investigations was data from the so-called DELCODE study, in which the DZNE researches dementia and its preliminary stages together with several university hospitals throughout Germany. The current study project included findings from around 300 women and men, all over the age of 60. The group of subjects included cognitively normal adults, those with memory problems of varying severity, and people with Alzheimer's dementia. Samples of cerebrospinal fluid and standardized memory tests were available from all study participants, and magnetic resonance images of the brain were generated from most of them. The data included at least one follow-up examination one year later in addition to the initial examination. For some subjects, the findings spanned multiple follow-up examinations from a period of up to five years.
Noticeable 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 the cerebrospinal fluid. Their measurement levels usually change even before symptoms of dementia appear, which is considered a sign of nerve-damaging processes. "We wanted to know whether inflammatory markers respond in a similar way," says Dr. Frederic Brosseron, a scientist at the 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 nerve cell damage is elevated. This is true even if these individuals do not yet have symptoms of dementia. So the inflammatory markers we captured are particularly useful for studying neuroinflammation at early stages of disease."
Evidence for neuroprotection
Two of these markers in particular - proteins of the "TAM receptor family" - appear to be related to a damage limitation program. This is because in study participants with particularly high levels of these markers, brain volume was comparatively large and cognitive functions declined more slowly over time. To verify these findings, Heneka's team analyzed data from a study cohort at the ACE Alzheimer Center Barcelona with more than 700 adults and predominantly mild cognitive impairment. Conclusion: The results from the DELCODE study were confirmed.
"Inflammatory processes are not bad per se, but rather a normal, protective reaction of the immune system to threatening stimuli, especially at the beginning. But they must not continue for too long; to do so, they must be regulated," says Heneka. TAM family proteins are known to influence immune responses and promote cellular waste disposal, he explains. "Supporting this protective function would be an interesting starting point for pharmaceutical research. This is where I see potential applications for the markers we have identified. Measuring these markers is too costly for early detection of dementia in routine care. But when testing new drugs in clinical trials, there are other technical possibilities. For such studies, indicators are needed to assess whether interventions are working and whether tested drugs are effective. The TAM markers could be very useful for this."