ApoE4-Driven Neurodegeneration in Alzheimer’s Disease: From Brain Atrophy to Inhibitory Neuron Loss
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ApoE4-Driven Neurodegeneration in Alzheimer’s Disease: From Brain Atrophy to Inhibitory Neuron Loss

Yutong Li 1*
1 University of Santa Barbara
*Corresponding author: rachelyt0510@gmail.com
Published on 2 October 2025
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TNS Vol.140
ISSN (Print): 2753-8826
ISSN (Online): 2753-8818
ISBN (Print): 978-1-80590-399-4
ISBN (Online): 978-1-80590-400-7
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Abstract

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, amyloid plaque accumulation, and tau pathology. The Apolipoprotein E4 (ApoE4) allele is the strongest genetic risk factor for late-onset AD, contributing to increased amyloid burden, neuroinflammation, and brain atrophy. However, the cellular and structural mechanisms underlying ApoE4’s impact on disease progression remain incompletely understood. In this paper, we analyzed multi-modal datasets from the Seattle Alzheimer’s Disease Brain Cell Atlas (SEA-AD) to investigate differences between ApoE4+ and ApoE4- individuals. 116 parameters were assessed, including neuropathology, imaging, and clinical outcomes and we identified 15 key parameters that are more significant and representative between the groups. ApoE4+ individuals exhibited earlier cognitive decline, greater tau and amyloid pathology, and accelerated brain atrophy, particularly in cortical and subcortical regions. RNA sequencing of the Prefrontal Cortex (PFC) and Middle Temporal Gyrus (MTG) revealed significant reductions in Sst Chodl, Sncg, and Vip interneurons in ApoE4+ individuals. These findings suggest that ApoE4 carriers experience widespread neurodegenerative changes, including altered inhibitory neuron composition, which may contribute to disease progression. Understanding how ApoE4 affects inhibitory networks could provide new insights into Alzheimer’s pathology and potential therapeutic targets.

Keywords:

apolipoprotein E4 (ApoE4), Alzheimer’s disease, neurodegeneration, brain atrophy, inhibitory interneurons

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Li,Y. (2025). ApoE4-Driven Neurodegeneration in Alzheimer’s Disease: From Brain Atrophy to Inhibitory Neuron Loss. Theoretical and Natural Science,140,30-41.

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Cite this article

Li,Y. (2025). ApoE4-Driven Neurodegeneration in Alzheimer’s Disease: From Brain Atrophy to Inhibitory Neuron Loss. Theoretical and Natural Science,140,30-41.

Data availability

The datasets used and/or analyzed during the current study will be available from the authors upon reasonable request.

About volume

Volume title: Proceedings of ICBioMed 2025 Symposium: Interdisciplinary Frontiers in Pharmaceutical Sciences

ISBN: 978-1-80590-399-4(Print) / 978-1-80590-400-7(Online)
Editor: Alan Wang, Xiangdong Xue
Conference date: 11 September 2025
Series: Theoretical and Natural Science
Volume number: Vol.140
ISSN: 2753-8818(Print) / 2753-8826(Online)