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Cited by 39Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

APOE genotype determines cell-type-specific pathological landscape of Alzheimer’s disease

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Li, Zonghua, Martens, Yuka A., Ren, Yingxue, Jin, Yunjung, Sekiya, Hiroaki, Doss, Sydney V., Kouri, Naomi, Castanedes-Casey, Monica +22 more·2025·Neuron
DOI 10.1016/j.neuron.2025.02.017PMC PMC12333916
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Abstract

The apolipoprotein E (APOE) gene is the strongest genetic risk modifier for Alzheimer's disease (AD), with the APOE4 allele increasing risk and APOE2 decreasing it compared with the common APOE3 allele. Using single-nucleus RNA sequencing of the temporal cortex from APOE2 carriers, APOE3 homozygotes, and APOE4 carriers, we found that AD-associated transcriptomic changes were highly APOE genotype dependent. Comparing AD with controls, APOE2 carriers showed upregulated synaptic and myelination-related pathways, preserving synapses and myelination at the protein level. Conversely, these pathways were downregulated in APOE3 homozygotes, resulting in reduced synaptic and myelination proteins. In APOE4 carriers, excitatory neurons displayed reduced synaptic pathways similar to APOE3, but oligodendrocytes showed upregulated myelination pathways like APOE2. However, their synaptic and myelination protein levels remained unchanged or increased. APOE4 carriers also showed increased pro-inflammatory signatures in microglia but reduced responses to amyloid-β pathology. These findings reveal APOE genotype-specific molecular alterations in AD across cell types.

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  • The first snRNA-seq dataset was performed on temporal cortex tissue, and the second was performed on entorhinal cortex and superior frontal gyrus.

    “The former was performed on temporal cortex tissue, and the latter was performed on entorhinal cortex and superior frontal gyrus.”

    From PLCG2 downregulation impairs synaptic function and increases Alzheimer’s disease hallmarks in neuronal cultures (2026) · cites this paper as [22]

    The STAR Methods (page unavailable) describe isolating nuclei from frozen temporal cortex for this paper’s snRNA-seq work, supporting the former dataset’s tissue location. The passages in our copy do not establish that a second dataset was performed on entorhinal cortex and superior frontal gyrus; a search for those regions found no supporting passage. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • PLCG2 is also expressed in neurons, as evidenced in publicly available single-nucleus RNA-seq datasets from human brain.

    “However, PLCG2 is also expressed in neurons as evidenced in publicly available single-nucleus RNA-seq (snRNA-seq) datasets from human brain22,23”

    From PLCG2 downregulation impairs synaptic function and increases Alzheimer’s disease hallmarks in neuronal cultures (2026) · cites this paper as [22]

    The Results describe human-brain snRNA-seq data and identify neuronal populations, while the STAR Methods describe integration of publicly available datasets. Neither those passages nor searches for “PLCG2” and “PLCG2 expressed in neurons” found a passage reporting PLCG2 expression in neurons. Our copy therefore does not verify the specific expression claim. (LLM, conf=0.72)

    Experimental — accuracy not yet measured

  • PLCG2 is also expressed in neurons.

    “we and others found that PLCG2 is also expressed in neurons22–24”

    From PLCG2 downregulation impairs synaptic function and increases Alzheimer’s disease hallmarks in neuronal cultures (2026) · cites this paper as [22]

    The Results passages describe gene-expression changes in excitatory and inhibitory neurons, but do not identify PLCG2 as a neuron-expressed gene. Searches of our copy for “PLCG2” and “phospholipase C gamma 2 expression in neurons” found no passage addressing that claim. (LLM, conf=0.72)

    Experimental — accuracy not yet measured

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Sorted by citations

Authors
Li, Z., Martens, Y. A., Ren, Y., Jin, Y., Sekiya, H., Doss, S. V., Kouri, N., Castanedes-Casey, M., Christensen, T. A., Miller Nevalainen, L. B., Takegami, N., Chen, K., Liu, C.-C., Soto-Beasley, A., Boon, B. D. C., Labuzan, S. A., Ikezu, T. C., Chen, Y., Bartkowiak, A. D., Xhafkollari, G., Wetmore, A. M., Bennett, D. A., Reichard, R. R., Petersen, R. C., Kanekiyo, T., Ross, O. A., Murray, M. E., Dickson, D. W., Bu, G., & Zhao, N.
Affiliations
  • Mayo Clinic (US)
  • Rush University Medical Center (US)
Corresponding author
  • Bu, Guojun
  • Zhao, Na
ORCID
Venue
Neuron
Publisher
Elsevier BV
Published
2025-05
Volume
113
Issue
9
Pages
1380-1397.e7
ISSN
0896-6273 (ISSN-L)
DOI
10.1016/j.neuron.2025.02.017
PMC
PMC12333916
OpenAlex
W4408655150
Cited by
39
References
23
Citations by year
2026: 26 · 2025: 13
FWCI
25.10
Type
journal article
Language
en
Open access
Licence
Locations
  • Neuron (acceptedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (publishedVersion)
  • Rare & Special e-Zone (The Hong Kong University of Science and Technology) (submittedVersion)
Funders
  • Cure Alzheimer's Fund
  • BrightFocus Foundation
  • NIH (P30AG062677, RF1AG046205, R01AG66395, RF1AG057181, U01AG006786, U19AG069701, U54NS110435, R01AG087165)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
Alzheimer's disease, APOE genotype, APOE ε4, APOE2, APOE3, single-nucleus RNA sequencing, temporal cortex, synaptic pathways, myelination, oligodendrocytes, excitatory neurons, microglia, pro-inflammatory response, amyloid-beta pathology, cell type-specific transcriptomics
MeSH terms
Aged, Aged, 80 and over, Alzheimer Disease, Apolipoproteins E, Female, Genotype, Humans, Male, Neurons, Oligodendroglia, Synapses, Temporal Lobe, Microglia, Apolipoprotein E3, Apolipoprotein E4, Apolipoprotein E2

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