This is a summary of Finze, A., Biechele, G., Rauchmann, BS. et al. Individual regional associations between Aβ-, tau- and neurodegeneration (ATN) with microglial activation in patients with primary and secondary tauopathies. (2023). https://doi.org/10.1038/s41380-023-02188-8, which appeared in Molecular Psychiatry.

The challenge

Tauopathies are a class of neurodegenerative disorders involving abnormal tau protein in the brain. They are divided into primary and secondary tauopathies. Alzheimer’s disease (AD) is a so-called secondary tauopathy because it is characterized by a build-up of a second protein that is considered the primary driver: beta-amyloid. Primary tauopathies include, for example, Pick’s disease or progressive supranuclear palsy (PSP). An accumulation of beta-amyloid plaques, tau protein aggregates, and neurodegeneration characterizes Alzheimer’s and primary tauopathies. These symptoms are categorized in a classification scheme for several biomarkers: the ATN (amyloid, Tau, neurodegeneration) framework.

But this framework only covers some mechanisms in the disease process, and we, therefore, aimed to expand it. We looked at inflammation specifically because it acts as a mediator in the aggregation and spread of amyloid and tau and disease progression: the ATI(N) framework. The interactions between amyloid, tau, and neuroinflammation have only rarely been investigated in atypical Alzheimer’s disease or primary tauopathies, which is what we, therefore, set out to study. Understanding how amyloid and tau contribute to neuroinflammation provides valuable insights into the disease mechanisms.

Our approach

As a biomarker for neuroinflammation, we used PET imaging to determine the activation of microglia – the active immune defense in the central nervous system. We investigated the interplay in different brain regions in a cohort of patients with primary and secondary tauopathies, including typical and atypical AD. We investigated the relationship between regional differences in the accumulation of misfolded proteins (amyloid and tau), blood flow, and volume changes within microglial activation at the individual patient level. Using a regression model, we calculated how much each biomarker contributes to microglial activation in the patient, as well as how individual responses of microglia to beta-amyloid and tau impact cognitive performance and cerebrospinal sTREM2 levels.

Our findings

Regional accumulation of tau was the strongest predictor of the activation of microglia in primary tauopathies and AD – we found a stronger association between regional aggregation of tau with microglial activation than for amyloid deposits. This finding aligns with a previous study, which suggests that microglial activation correlates strongly with tau aggregation in established AD and with amyloid deposition in mild cognitive impairment. Our results indicate that targeting microglial activation associated with tau pathology could be beneficial at later disease stages, whereas modifying microglial activation related to amyloid may be only helpful in the early stages of the disease.

The implications

Our results show that microglial responses related to tau and amyloid can serve as an assessment of neuroinflammation at the individual patient level. This is even more important in light of the recently revised NIA-AA framework that now also suggests assessment of neuroinflammation in Alzheimer’s disease. Therefore, our findings could have a significant impact on selecting appropriate immunomodulatory strategies by determining the current microglia response level in individual patients.

Creating SyNergies

This research was a collaboration of 7 of our Principal and Associate Investigators and colleagues from LMU, TUM, and DZNE. All in vivo imaging data was collected in the SyNergy-driven ActiGliA prospective cohort study since 2016. Future SyNergies will investigate the underlying mechanisms of different microglia response rates in individual patients by microglia phenotyping.