Summary: Researchers have identified an early immune response in people who carry genetic mutations that predispose them to Alzheimer’s disease.
Source: DZNE.
Immune cells in the brain become active years before symptoms of dementia appear
Scientists at the Munich site of the German Center for Neurodegenerative Diseases (DZNE) and the Ludwig Maximilian University (LMU) hospital have discovered that the brain’s immune system shows measurable activity long before clinical signs of Alzheimer’s disease emerge in people with an inherited risk. The team found abnormal immune reactions in cerebrospinal fluid roughly seven years prior to the expected onset of dementia in mutation carriers. These findings indicate that inflammatory processes in the brain are dynamic and may precede cognitive decline, and they point to a measurable protein that could help clinicians track disease progression.
The researchers measured levels of the protein TREM2 in cerebrospinal fluid (CSF). TREM2 is produced by microglia, the resident immune cells of the brain, and the soluble form (sTREM2) released into CSF reflects microglial activity. Because the timing of dementia onset can be precisely estimated in families with autosomal dominant (inherited) Alzheimer’s disease, the team was able to document how TREM2 levels rise several years before symptoms would be expected.
“Microglial activity appears to be triggered by dying neurons rather than by amyloid plaques alone,” explains Prof. Christian Haass. The study suggests microglia may initially act protectively, but their response diminishes as the disease advances. Based on this, Haass and colleagues are investigating therapies aimed at boosting microglial function as a potential strategy to delay or reduce neuronal damage.
Study conducted within the DIAN network
The study involved 127 individuals carrying Alzheimer’s-related mutations who participated in the Dominantly Inherited Alzheimer Network (DIAN), an international collaboration focused on the inherited form of the disease. Participants averaged about 40 years of age and most were cognitively normal or had only subtle impairments. Because the inherited form of Alzheimer’s has a predictable clinical timeline, these participants provide a valuable window into the early biological changes that precede dementia.
Prof. Michael Ewers notes that the inherited and the far more common sporadic forms of Alzheimer’s share many biological features. Consequently, sTREM2 in CSF could be a broadly useful biomarker to monitor immune system activity as Alzheimer’s progresses, regardless of whether the disease is inherited. TREM2 may also be useful as a therapeutic marker to evaluate responses to drugs that target microglial activity; future work will explore these applications.
Funding: The research received support from the European Research Council, the Deutsche Forschungsgemeinschaft, and other funding bodies.
Source: Marcus Neitzert – DZNE
Image Source: NeuroscienceNews.com image is in the public domain.
Original Research: Abstract for the study “Early changes in CSF sTREM2 in dominantly inherited Alzheimer’s disease occur after amyloid deposition and neuronal injury” published in Science Translational Medicine.
Early changes in CSF sTREM2 in dominantly inherited Alzheimer’s disease occur after amyloid deposition and neuronal injury
Emerging evidence supports an important role for innate immunity and microglia in Alzheimer’s disease pathophysiology, yet markers of microglial activity have not been fully integrated into models that describe the disease’s temporal progression. TREM2 is a transmembrane protein expressed selectively by microglia and genetically linked to Alzheimer’s and other neurodegenerative disorders. Its ectodomain is released as a soluble form (sTREM2) that is detectable in cerebrospinal fluid. In this study of autosomal dominant Alzheimer’s disease, researchers compared sTREM2 levels in mutation carriers (MCs) and noncarriers (NCs) to determine when increases in CSF sTREM2 occur relative to expected symptom onset and to established markers of amyloid deposition and neuronal injury.
The analysis included 218 participants (127 mutation carriers and 91 noncarriers) from the Dominantly Inherited Alzheimer Network. Results showed that CSF sTREM2 was elevated in mutation carriers beginning approximately five years before expected symptom onset and remained significantly higher up to five years after the expected onset. Importantly, increases in sTREM2 followed earlier changes in amyloid markers and measures of neuronal injury, suggesting that microglial activation is a secondary but early event in the disease cascade—occurring after amyloidosis and neuronal damage have already begun.
This temporal pattern supports the idea that microglial responses may initially be protective but become insufficient as pathology progresses, and that sTREM2 may serve as a useful biomarker to monitor immune activation and therapeutic effects in Alzheimer’s disease.