Hippocampal GFAP in aging: Associations with AD and LATE‐NC pathologies and cognitive decline in older adults

INTRODUCTION Plasma glial fibrillary acidic protein (GFAP) is an emerging biomarker for Alzheimer's disease (AD) progression in clinical studies, yet the role of brain GFAP in AD/AD‐related dementias (ADRD) pathologies and cognitive decline remains unclear. METHODS GFAP burden from CA1‐subiculum of the hippocampus were quantified. Regression and mixed‐effect models, adjusting for demographics and other brain pathologies examined associations between hippocampal GFAP and AD/ADRD pathologies and separately with Alzheimer's dementia and cognitive decline. RESULTS Limbic‐predominant age‐related TDP‐43 encephalopathy neuropathologic changes (LATE‐NC), hippocampal sclerosis of aging (HS‐A), and neurofibrillary tangle density (but not amyloid‐beta) were associated with GFAP burden. Hippocampal GFAP was associated with increased odds of Alzheimer's dementia and faster decline in global cognition, episodic memory, semantic memory, and perceptual speed. LATE‐NC and tangles explained some but not all the association between hippocampal GFAP and cognitive decline. DISCUSSION GFAP burden in the hippocampus is related to LATE‐NC and tangles but may also be an independent contributor to cognitive decline.