Grey matter ageing-related tau astrogliopathy: associations with brain pathologies and cognitive decline

Grey matter ARTAG pathology is common in aged brains and detected in multiple brain regions. However, the associations of grey matter ARTAG with Alzheimer's disease (AD) and other common age-related proteinopathies, as well as clinical phenotypes including Alzheimer's dementia and cognitive decline remain unclear. We examined 442 decedents (mean age-at-death=90 years, males=32%) from three longitudinal community-based clinical-pathological studies. Using AT8 immunohistochemistry, grey matter ARTAG pathology was counted in the the superior frontal, anterior temporal tip, and amygdala and summarized as a severity score from 0 (none) to 6 (severe). AD and other common age-related neuropathologies were also evaluated. The diagnosis of Alzheimer's dementia was based on clinical evaluations; annual tests of cognitive performance were summarized as global cognition and five cognitive domains. Multivariable logistic regression tested the associations of grey matter ARTAG pathology with an array of age-related neuropathologies. To evaluate associations of grey matter ARTAG pathology with Alzheimer's dementia and cognitive decline, we employed logistic regression and linear mixed effect models. Grey matter ARTAG pathology was seen in 324 (73%) participants, of which 303 (68%) participants had ARTAG in the amygdala, 246 (56%) in the anterior temporal tip, and 137 (31%) in the superior frontal region. Grey matter ARTAG pathology from each of the three regions was associated with pathologic diagnosis of AD and LATE-NC but not with vascular pathology. In fully adjusted models that controlled for demographics, AD, and common age-related pathologies, an increase in severity of grey matter ARTAG pathology in the superior frontal cortex, but not in the amygdala or the anterior temporal tip, was associated with higher odds of Alzheimer's dementia and faster decline in global cognition, episodic memory, and semantic memory. These results provide compelling evidence that grey matter ARTAG, specifically in the superior frontal cortex contributes to Alzheimer's dementia and cognitive decline in old age.