APOE ε4 potentiates tau related reactive astrogliosis assessed by cerebrospinal fluid YKL40 in Alzheimer’s disease

Glial responses are involved in neurodegenerative processes, with tau pathology often associated with increased glial inflammatory responses in Alzheimer’s disease (AD). The apolipoprotein E (APOE) ε4 allele, the major genetic susceptibility gene for AD, might contribute to this process by modulating both tau pathology and inflammatory cascades in the brain. We used data from the Translational Biomarkers of Alzheimer’s Disease (TRIAD) cohort (n = 137) to investigate the association between YKL-40, a marker of reactive astrogliosis, and tau burden measured with PET imaging, while also exploring the involvement of APOE ε4 carriership. Statistical analyses included correlation and regression models controlling for age and sex. Here we show that tau pathology is positively associated with YKL-40 levels, reflecting regional patterns of astrocyte activity in the brain. Furthermore, this association is more widespread in individuals carrying the APOE ε4 allele, suggesting a genotype-specific modulation of the glial neuroinflammatory response. Our findings demonstrate a link between tau accumulation and astrocyte-mediated neuroinflammation in AD and highlight the modulatory role of APOE ε4 in this process. Taken together, our findings help inform the multifaceted role of tau-associated neuroinflammation in the progression of AD. Alzheimer’s disease is a brain disorder characterized by the accumulation of abnormal proteins, including tau, which contribute to memory loss and cognitive decline. Brain support cells called astrocytes respond to this protein build-up by becoming reactive, which can lead to inflammation in the brain. In this study, we used brain scans and cerebrospinal fluid samples from 137 participants to examine how astrocyte reactivity, measured by the protein YKL-40, relates to tau accumulation. We also investigated whether carrying a common genetic risk factor, APOE ε4, influences this relationship. We found that higher tau levels are associated with increased astrocyte reactivity, and this association is stronger in people carrying APOE ε4. These findings suggest that genetic risk may amplify inflammation in Alzheimer’s disease. Trudel et al. investigate the relationship between tau pathology and reactive astrogliosis in Alzheimer’s disease using PET imaging and CSF biomarkers. Their findings suggest that APOE ε4 amplifies tau-associated glial inflammation, offering insights into genotype-specific mechanisms driving AD-associated neuroinflammation.