Apolipoprotein E Proteinopathy Is a Major Dementia-Associated Pathologic Biomarker in Individuals with or without the APOE Epsilon 4 Allele
Open accessAbstract
The amygdala is vulnerable to multiple or "mixed" mis-aggregated proteins associated with neurodegenerative conditions that can manifest clinically with amnestic dementia; the amygdala region is often affected even at earliest disease stages. With the original intent of identifying novel dementia-associated proteins, the detergent-insoluble proteome was characterized from the amygdalae of 40 participants from the University of Kentucky Alzheimer's Disease Center autopsy cohort. These individuals encompassed a spectrum of clinical conditions (cognitively normal to severe amnestic dementia). Polypeptides from the detergent-insoluble fraction were interrogated using liquid chromatography-electrospray ionization-tandem mass spectrometry. As anticipated, portions of peptides previously associated with neurologic diseases were enriched from subjects with dementia. Among all detected peptides, Apolipoprotein E (ApoE) stood out: even more than the expected Tau, APP/Aβ, and α-Synuclein peptides, ApoE peptides were strongly enriched in dementia cases, including from individuals lacking the APOE ε4 genotype. The amount of ApoE protein detected in detergent-insoluble fractions was robustly associated with levels of complement proteins C3 and C4. Immunohistochemical staining of APOE ε3/ε3 subjects' amygdalae confirmed ApoE co-localization with C4 in amyloid plaques. Thus, analyses of human amygdala proteomics indicate that rather than being only an "upstream" genetic risk factor, ApoE is an aberrantly aggregated protein in its own right, and show that the ApoE protein may play active disease-driving mechanistic roles in persons lacking the APOE ε4 allele.
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ApoE is a major component of plaques.
“ApoE is a major component of plaques51.”
From APOE4 to APOE2 allelic switching in mice improves Alzheimer’s disease-related metabolic signatures, neuropathology and cognition (2025) · cites this paper as [51]
The Results report strong ApoE staining in a plaque core and extensive ApoE localization in plaque-like structures. These findings support ApoE’s presence in plaques, but the paper does not establish that it is a major component of plaques. (LLM, conf=0.82)
Experimental — accuracy not yet measuredPathological ApoE protein aggregation might explain the lack of gradient in ApoE IHC signal.
“This might be explained by pathological ApoE protein aggregation, together with or independent to other protein aggregates as it has been observed in demented cases [10].”
From Distinct tau neuropathology and cellular profiles of an APOE3 Christchurch homozygote protected against autosomal dominant Alzheimer’s dementia (2022) · cites this paper as [10]
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The diagnostic and therapeutic significance of apolipoprotein E in personalized medicine
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- Authors
- Gal, J., Katsumata, Y., Zhu, H., Srinivasan, S., Chen, J., Johnson, L. A., Wang, W.-X., Golden, L. R., Wilcock, D. M., Jicha, G. A., Cykowski, M. D., & Nelson, P. T.
- Affiliations
- University of Kentucky (US)
- Houston Methodist (US)
- Corresponding author
- Nelson, Peter Tobias
- ORCID
- Venue
- The American Journal of Pathology
- Publisher
- Elsevier BV
- Published
- 2022-03
- Volume
- 192
- Issue
- 3
- Pages
- 564-578
- ISSN
- 0002-9440 (ISSN-L)
- PMC
- PMC8895423
- OpenAlex
- W4200572642
- Cited by
- 17
- References
- 102
- Citations by year
- 2026: 3 · 2025: 4 · 2024: 2 · 2023: 6 · 2022: 2
- FWCI
- 1.73
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- American Journal Of Pathology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (P30 AG072946, R01 AG061111, R01 AG062550, RF1 NS118584, R21 AG061551, R01 AG042419, R21 NS095299, R01 AG042475, R01 AG057187, R01 AG060056)
- 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
- apolipoprotein E, APOE ε4, amygdala, amyloid plaques, complement C4, complement C3, Alzheimer's disease, disease biomarkers, neurodegeneration
- MeSH terms
- Alleles, Alzheimer Disease, Apolipoproteins E, Dementia, Detergents, Genotype, Humans, Biomarkers, Amyloid beta-Peptides, Apolipoprotein E4
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