Medial temporal ageing-related tau astrogliopathy below 66 years is associated with neurodegeneration

Ageing-related tau astrogliopathy (ARTAG) refers to aggregates of pathological tau protein in astroglial cells in the brain. Thorny astrocytes at the level of the glia limitans and/or white matter and granular/fuzzy astrocytes in the grey matter are characteristic for ARTAG, which is correlated with ageing. However, also rare cases with ARTAG below the age of 66 years have been reported. We studied a cohort of 157 brains from donors deceased between 48 and 65 years of age received from the Leuven neuropathological research group and Netherlands Brain Bank in order to gain insight into ARTAG in the medial temporal lobe at younger age and to find underlying correlates that might be obscured by age-related co-pathologies in older cohorts. Analyses were also performed on two comparison cohorts (Leuven, 268 cases; and Netherlands, 397 cases), with ages ranging from 66 to 99 years. Twenty-six of 157 cases (16.6%) between 48 and 65 years of age had ARTAG, mostly restricted to the medial temporal lobe. Only six cases exhibited ARTAG in lobar regions. ARTAG was found in all five previously described morphologies and locations: subpial, subependymal, perivascular, white matter and grey matter. In our young cohort, a significant correlation was found between ARTAG and the presence of neurodegenerative conditions of any kind and between ARTAG and age. When correcting for age and sex, the association between ARTAG and the presence of neurodegenerative conditions was upheld. There were no significant associations between ARTAG and specific proteinopathies, although trends were observed for α-synucleinopathy, tauopathy and TDP-43 proteinopathy diagnoses. The presence of lobar ARTAG was related to ARTAG severity in the young cohort. In the older cohorts, only age was significantly associated with ARTAG. These results suggest a link between ARTAG in the medial temporal lobe of young individuals and pathological protein aggregation of any kind in the brain independent of age and might lead us to question whether ARTAG points to astrocytes as important players for selective vulnerability for the aggregation of pathological proteins in distinct brain regions in this patient population.