In individuals with a genetic predisposition to Alzheimer’s disease (AD), microglia begin exerting a protective effect up to two decades before the first symptoms appear, according to a new study. These scientists now aim to develop drugs that target the TREM2 receptor, which is found on microglia.
Their research included more than 200 volunteers. It was carried out by a team from Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE) and Ludwig-Maximilians-Universität (LMU) München. The team’s report is featured in The Lancet Neurology.
About one percent of all people with Alzheimer’s develop the disease as a result of hereditary gene mutations. This study used data from the international DIAN (Dominantly Inherited Alzheimer Network) observational study, which includes adults who carry gene mutations that cause Alzheimer’s as well as their close relatives without mutations.
The current research was led by molecular biologist Christian Haass, research group leader at DZNE and professor of biochemistry at LMU München, and neurologist Estrella Morenas-Rodríguez, postdoctoral researcher in the Haass team at the time of the investigation and now junior group leader at Hospital Universitario 12 de Octubre in Madrid.
They analyzed how signatures of microglial activation were related to the development of certain biomarkers of Alzheimer’s disease. Cerebrospinal fluid and cognition were assessed over a period of several years in 248 participants with varying stages of Alzheimer’s disease.
“This [TREM2] is a receptor on the surface of microglia, but parts of it can detach and are then detectable in the cerebrospinal fluid. It is known from laboratory studies, particularly in mice but also from our earlier human studies, that levels of TREM2 in the cerebrospinal fluid are a good indicator of microglial activity. TREM2 is a kind of activity switch. As TREM2 levels increase, so do microglial protective activities,” said Haass.
“For a long time, it was assumed that microglia mainly cause damage in the course of Alzheimer’s disease, as they can fuel chronic inflammatory processes. However, there is growing evidence from my laboratory and many others that microglia have a protective effect at least at the beginning of the disease. This hypothesis is supported by our current data,” he added.
People with a genetic predisposition to Alzheimer’s usually develop the disease at a similar age as relatives with the same mutations. As a result, the researchers were able to estimate the time until the onset of symptoms for study participants.
“We found that TREM2 levels in the cerebrospinal fluid rise as early as 21 years before the estimated onset of the disease,” Haass says. “We also observed that the faster TREM2 increases over the years, the slower pathological events progress in the brain that are typical of Alzheimer’s. We can infer this from biomarkers for so-called amyloid proteins and tau proteins.”
Brain examinations using MRI and PET supported this finding. In study participants whose TREM2 levels rose rapidly, deposits of amyloid proteins developed more slowly and brain volume declined more slowly. “Besides the relationship with a slower pathological process, one of our most important and promising findings was to see how strikingly the faster TREM2 increase correlated with a slower cognitive decline in an early stage of Alzheimer´s disease. This has important implications for treatment,” Morenas-Rodríguez noted.
“We see our findings as evidence that TREM2-mediated microglial activity has a protective effect,” Haass says. “In our view, microglia become active as soon as the first amyloid proteins are deposited in the brain, a process, which we call seeding. In other words, at a very early stage of Alzheimer’s and that is what we and our colleagues at the DZNE-Tübingen also observe in animal models.”
