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.
Keywords: Alzheimer's disease; Astrocytes; GFAP; LATE‐NC; TDP‐43; cognition; dementia; digital pathology; tangles.
© 2026 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.