APOE2 orchestrated differences in transcriptomic and lipidomic profiles of postmortem AD brain
Open accessAbstract
Background: The application of advanced sequencing technologies and improved mass-spectrometry platforms revealed significant changes in gene expression and lipids in Alzheimer’s disease (AD) brain. The results so far have prompted further research using “multi-omics” approaches. These approaches become particularly relevant, considering the inheritance of APOEε4 allele as a major genetic risk factor of AD, disease protective effect of APOEε2 allele, and a major role of APOE in brain lipid metabolism. Methods: Postmortem brain samples from inferior parietal lobule genotyped as APOEε2/c(APOEε2/carriers),APOEε3/3, and APOEε4/c (APOEε4/carriers), age- and gender-matched, were used to reveal APOE allele-associated changes in transcriptomes and lipidomes. Differential gene expression and co-expression network analyses were applied to identify up- and downregulated Gene Ontology (GO) terms and pathways for correlation to lipidomics data. Results: Significantly affected GO terms and pathways were determined based on the comparisons of APOEε2/c datasets to those of APOEε3/3 and APOEε4/c brain samples. The analysis of lists of genes in highly correlated network modules and of those differentially expressed demonstrated significant enrichment in GO terms associated with genes involved in intracellular proteasomal and lysosomal degradation of proteins, protein aggregates and organelles, ER stress, and response to unfolded protein, as well as mitochondrial function, electron transport, and ATP synthesis. Small nucleolar RNA coding units important for posttranscriptional modification of mRNA and therefore translation and protein synthesis were upregulated in APOEε2/c brain samples compared to both APOEε3/3 and APOEε4/c. The analysis of lipidomics datasets revealed significant changes in ten major lipid classes (exclusively a decrease in APOEε4/c samples), most notably non-bilayer-forming phosphatidylethanolamine and phosphatidic acid, as well as mitochondrial membrane-forming lipids. Conclusions: The results of this study, despite the advanced stage of AD, point to the significant differences in postmortem brain transcriptomes and lipidomes, suggesting APOE allele associated differences in pathogenic mechanisms. Correlations within and between lipidomes and transcriptomes indicate coordinated effects of changes in the proteasomal system and autophagy—canonical and selective, facilitating intracellular degradation, protein entry into ER, response to ER stress, nucleolar modifications of mRNA, and likely myelination in APOEε2/c brains. Additional research and a better knowledge of the molecular mechanisms of proteostasis in the early stages of AD are required to develop more effective diagnostic approaches and eventually efficient therapeutic strategies.
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Brain samples from APOE2 LOAD patients exhibit elevated levels of CAR, SM, PC, and LPE compared to APOE3 and APOE4 LOAD patients.
“These observations are consistent with data showing that brain samples from APOE2 LOAD patients exhibit elevated levels of CAR, SM, PC, and LPE compared to APOE3 and APOE4 LOAD patients [86].”
From Analysis of early effects of human APOE isoforms on Alzheimer’s disease and type III hyperlipoproteinemia pathways using knock-in rat models with humanized APP and APOE (2024) · cites this paper as [86]
The Results section on distinct lipid profiles (page not provided) reports lower PC and SM in APOEε4/c samples than in either APOEε2/c or APOEε3/3 samples. It does not establish that APOEε2/c samples have higher PC and SM than APOEε3/3 samples, and the passages found do not report the claimed CAR or LPE comparisons. (LLM, conf=0.87)
Experimental — accuracy not yet measuredMany of the lipids differing between APOE4s2G and controls were glycerophospholipids, including many PC and CER species.
“In agreement with previous postmortem AD studies22,23, many of these lipids were glycerophospholipids, including many phosphatidylcholine (PC) and ceramide (CER) species.”
From APOE4 to APOE2 allelic switching in mice improves Alzheimer’s disease-related metabolic signatures, neuropathology and cognition (2025) · cites this paper as [22]
The Results section (page unavailable) reports differences in phospholipids, including PC, among APOE-genotype groups with AD. It does not report an APOE4s2G-versus-control comparison or identify many differing ceramide (CER) species. (LLM, conf=0.88)
Experimental — accuracy not yet measuredmRNA translation is upregulated in the brains of APOE2 carriers relative to those of APOE3 homozygotes and APOE4 carriers, based on examination of previously published transcriptomic and proteomic Alzheimer's datasets.
“Supporting the idea that our findings may have broader disease implications, our examination of previously published transcriptomic and proteomic Alzheimer’s datasets revealed that mRNA translation is a pathway that is upregulated in the brains of APOE2 carriers relative to those of APOE3 homozygotes and APOE4 carriers (41,42).”
From Apolipoprotein E2 Stimulates Protein Synthesis and Promotes Melanoma Progression and Metastasis (2023) · cites this paper as [41]
We have recently reported a correlation of snoRNAs with APOE genotype in postmortem brain tissue of AD patients.
“We have recently reported a correlation of snoRNAs with APOE genotype in postmortem brain tissue of AD patients (Fig. 4) (Lefterov et al., 2019).”
From Small nucleolar RNAs in plasma extracellular vesicles and their discriminatory power as diagnostic biomarkers of Alzheimer's disease (2021) · cites this paper as Lefterov et al., 2019
Decreases of major lipid species (PA, PC, PE, PS and sulfatide) were previously observed in AD APOE4 carriers.
“Decreases of major lipid species (i.e., PA, PC, PE, PS and sulfatide) were previously observed in AD APOE4 carriers (43).”
From <i>APOE3</i> -Jacksonville (V236E) variant reduces self-aggregation and risk of dementia (2021) · cites this paper as [43]
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Glass, C. K. (2015) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.114.304051 · Cited by 25 · see citing works
Apolipoprotein E, Cognitive Function, and Dementia in a General Population Aged 85 Years and Over
Juva, K., Verkkoniemi, A., Viramo, P., Polvikoski, T. M., Kainulainen, K., Kontula, K., & Sulkava, R. O. (2000) · International Psychogeriatrics · doi:10.1017/s1041610200006487 · Cited by 23 · see citing works
Age-Related Changes in Frontal and Temporal Lobe Volumes in Men: A Magnetic Resonance Imaging Study
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Rare Variants and Transcriptomics in Alzheimer disease
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Genotype Copy Number Variations using Gaussian Mixture Models: Theory and Algorithms
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Endomembrane remodeling in autophagic membrane formation
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Flagged first, then by citations
Cited by
Sorted by citations
ApoE in Alzheimer’s disease: pathophysiology and therapeutic strategies
Raulin, A.-C., Doss, S. V., Trottier, Z. A., Ikezu, T. C., Bu, G., & Liu, C.-C. (2022) · Molecular Neurodegeneration · doi:10.1186/s13024-022-00574-4 · Cited by 756 · see citing works
Brain lipidomics: From functional landscape to clinical significance
Yoon, J. H., Seo, Y., Jo, Y. S., Lee, S., Cho, E., Cazenave-Gassiot, A., Shin, Y.-S., Moon, M. H., An, H. J., Wenk, M. R., et al. (2022) · Science Advances · doi:10.1126/sciadv.adc9317 · Cited by 324 · see citing works
Mitophagy in Alzheimer’s disease: Molecular defects and therapeutic approaches
Mary, A., Eysert, F., Checler, F., & Chami, M. (2023) · Molecular Psychiatry · doi:10.1038/s41380-022-01631-6 · Cited by 244 · see citing works
Lee, S., Devanney, N. A., Golden, L. R., Smith, C. T., Schwartz, J. L., Walsh, A. E., Clarke, H. A., Goulding, D. S., Allenger, E. J., Morillo-Segovia, G., et al. (2023) · Cell Reports · doi:10.1016/j.celrep.2023.112196 · Cited by 203 · see citing works
<i>APOE3</i> -Jacksonville (V236E) variant reduces self-aggregation and risk of dementia
Liu, C.-C., Murray, M. E., Li, X., Zhao, N., Wang, N., Heckman, M. G., Shue, F., Martens, Y., Li, Y., Raulin, A.-C., et al. (2021) · Science Translational Medicine · doi:10.1126/scitranslmed.abc9375 · Cited by 108 · see citing works
Self-citationRen, F., Wei, J., Chen, Q., Hu, M., Yu, L., Mi, J., Zhou, X., Qin, D., Wu, J., & Wu, A. (2025) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2025.07.030 · Cited by 97 · see citing works
Trem2 deficiency differentially affects phenotype and transcriptome of human APOE3 and APOE4 mice
Fitz, N. F., Wolfe, C. M., Playso, B. E., Biedrzycki, R. J., Lu, Y., Nam, K. N., Lefterov, I., & Koldamova, R. (2020) · Molecular Neurodegeneration · doi:10.1186/s13024-020-00394-4 · Cited by 68 · see citing works
Self-citationEffects of APOE4 allelic dosage on lipidomic signatures in the entorhinal cortex of aged mice
Miranda, A. M., Ashok, A., Chan, R. B., Zhou, B., Xu, Y., McIntire, L. B., Area-Gomez, E., Di Paolo, G., Duff, K. E., Oliveira, T. G., et al. (2022) · Translational Psychiatry · doi:10.1038/s41398-022-01881-6 · Cited by 60 · see citing works
“In humans, a post-mortem lipidomic analysis of the inferior parietal lobule from AD patients showed that APOE4 carriers had decreased levels of glycerophospholipids, most notably in phosphatidic acid (PA) [29].”
BackgroundFitz, N. F., Wang, J., Kamboh, M. I., Koldamova, R., & Lefterov, I. (2021) · Neurobiology of Disease · doi:10.1016/j.nbd.2021.105481 · Cited by 49 · see citing works
“4) (Lefterov et al., 2019).”
InfluentialSelf-citationKloske, C. M., Belloy, M. E., Blue, E. E., Bowman, G. R., Carrillo, M. C., Chen, X., Chiba‐Falek, O., Davis, A. A., Paolo, G. D., Garretti, F., et al. (2024) · Alzheimer's & Dementia · doi:10.1002/alz.13877 · Cited by 33 · see citing works
Golden, L. R., Siano, D. S., Stephens, I. O., MacLean, S. M., Saito, K., Nolt, G. L., Funnell, J. L., Pallerla, A. V., Lee, S., Smith, C., et al. (2025) · Nature Neuroscience · doi:10.1038/s41593-025-02094-y · Cited by 18 · see citing works
Apolipoprotein E2 Stimulates Protein Synthesis and Promotes Melanoma Progression and Metastasis
Adaku, N., Ostendorf, B. N., Mei, W., & Tavazoie, S. F. (2023) · Cancer Research · doi:10.1158/0008-5472.can-23-1252 · Cited by 15 · see citing works
Yesiltepe, M., Yin, T., Tambini, M., Bao, H., Pan, M., d’Abramo, C., Giliberto, L., Han, X., & D’Adamio, L. (2024) · Cell Communication and Signaling · doi:10.1186/s12964-024-01832-2 · Cited by 10 · see citing works
“These observations are consistent with data showing that brain samples from APOE2 LOAD patients exhibit elevated levels of CAR, SM, PC, and LPE compared to APOE3 and APOE4 LOAD patients [86].”
MethodResultSelf-citationNolt, G. L., MacLean, S. M., Golden, L. R., Thorpe, S. P., Stephens, I. O., Funnell, J. L., Brock, C. R., Lucido, C. C., Smith, L., Hernandez, G., et al. (2027) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2026.08.005
- Authors
- Lefterov, I., Wolfe, C. M., Fitz, N. F., Nam, K. N., Letronne, F., Biedrzycki, R. J., Kofler, J., Han, X., Wang, J., Schug, J., & Koldamova, R.
- Affiliations
- University of Pittsburgh (US)
- The University of Texas at San Antonio Health Science Center (US)
- University of Pennsylvania (US)
- Corresponding author
- Lefterov, Iliya
- Koldamova, Radosveta
- ORCID
- Venue
- Alzheimer's Research & Therapy
- Published
- 2019-12
- Volume
- 11
- Issue
- 1
- Pages
- 113-113
- ISSN
- 1758-9193 (ISSN-L)
- PMC
- PMC6937981
- OpenAlex
- W2997916102
- Cited by
- 74
- References
- 86
- Citations by year
- 2026: 7 · 2025: 13 · 2024: 15 · 2023: 8 · 2022: 14 · 2021: 9 · 2020: 7 · 2018: 1
- FWCI
- 5.13
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Alzheimer s Research & Therapy (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Institute on Aging (AG037919, AG056371, AG057565, AG044490, NIA RF1 AG061872)
- National Institute of Environmental Health Sciences (ES024233)
- Alzheimer's Disease Association (AARF-16-443213)
- 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 ε2 allele, APOE ε4, APOE genotype, transcriptome, lipidome, postmortem brain, inferior parietal lobule, proteasomal degradation, autophagy, endoplasmic reticulum stress, unfolded protein response, mitochondrial function, small nucleolar RNA, phosphatidylethanolamine, phosphatidic acid
- MeSH terms
- Lipidomics, Aged, Aged, 80 and over, Alzheimer Disease, Brain, Female, Humans, Male, Apolipoprotein E2, Transcriptome
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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