Effects of APOE4 allelic dosage on lipidomic signatures in the entorhinal cortex of aged mice
Open accessAbstract
Apolipoprotein E ε4 ( APOE4 ) is the primary genetic risk factor for the late-onset form of Alzheimer’s disease (AD). Although the reason for this association is not completely understood, researchers have uncovered numerous effects of APOE4 expression on AD-relevant brain processes, including amyloid beta (Aβ) accumulation, lipid metabolism, endosomal-lysosomal trafficking, and bioenergetics. In this study, we aimed to determine the effect of APOE4 allelic dosage on regional brain lipid composition in aged mice, as well as in cultured neurons. We performed a targeted lipidomic analysis on an AD-vulnerable brain region (entorhinal cortex; EC) and an AD-resistant brain region (primary visual cortex; PVC) from 14–15 month-old APOE3/3 , APOE3/4 , and APOE4/4 targeted replacement mice, as well as on neurons cultured with conditioned media from APOE3/3 or APOE4/4 astrocytes. Our results reveal that the EC possesses increased susceptibility to APOE4 -associated lipid alterations compared to the PVC. In the EC, APOE4 expression showed a dominant effect in decreasing diacylglycerol (DAG) levels, and a semi-dominant, additive effect in the upregulation of multiple ceramide, glycosylated sphingolipid, and bis(monoacylglycerol)phosphate (BMP) species, lipids known to accumulate as a result of endosomal-lysosomal dysfunction. Neurons treated with conditioned media from APOE4/4 vs. APOE3/3 astrocytes showed similar alterations of DAG and BMP species to those observed in the mouse EC. Our results suggest that APOE4 expression differentially modulates regional neuronal lipid signatures, which may underlie the increased susceptibility of EC-localized neurons to AD pathology.
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Lipids are central to AD pathogenesis, as suggested by studies showing cholesterol dysregulation in a range of AD models and patients' brains.
“Together with studies showing cholesterol dysregulation in a range of AD models and patients’ brains, these studies suggest lipids are central to AD pathogenesis14–18.”
From Decreased lipidated ApoE‐receptor interactions confer protection against pathogenicity of ApoE and its lipid cargoes in lysosomes (2025) · cites this paper as [18]
The Introduction reports altered brain cholesterol in APOE mouse models and altered lipids in post-mortem brains of AD patients. The patient finding concerns glycerophospholipids, however, not cholesterol; the copy therefore does not establish the claimed cholesterol dysregulation in patients’ brains. The Discussion supports the broader suggestion that lipid dysregulation is implicated in AD. (LLM, conf=0.83)
Experimental — accuracy not yet measuredPrior lipidomic, metabolomic, and magnetic resonance spectroscopy studies in mouse models show that APOE genetic variation modifies brain metabolite levels.
“Prior lipidomic, metabolomic, and magnetic resonance spectroscopy (MRS) studies in mouse models show that genetic variation in APOE modify brain metabolite levels [20][21][22][23] .”
From APOE4-drives brain bioenergetic shifts independent of Alzheimer’s disease pathology (2026) · cites this paper as [23]
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“Also, we previously reported increased expression of several V-type ATPase subunits [33], possibly in response to altered lysosomal pH and membrane composition [68, 69].”
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“Also, PC is converted to PA by phospholipase D1 (PLD1) or PLD2 isoenzymes [83], both of which have been implicated in AD [84] and shown to signal downstream of Aβ [85, 86] and APOE [87].”
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“activation recapitulates prodromal features of AD, including endosomal enlargement and synaptic dysfunction [64], Rab7b granules are found in the EC of Lewy Body dementia patients [65], and altered Rab7 colocalizes with Aβ in apoE treated microglia [66]; that said, altered Rab GTPase levels are thus far correlative in…”
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Aβ-independent roles of apolipoprotein E4 in the pathogenesis of Alzheimer's disease
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ApoE4 upregulates the activity of mitochondria‐associated ER membranes
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“Interestingly, lipid droplet number and volume have previously been shown to increase in neurons treated with APOE4 vs APOE3 ACM as a result of both increased lipid droplet synthesis and decreased mobilization [73, 74].”
BackgroundAPOE4 exacerbates α-synuclein pathology and related toxicity independent of amyloid
Zhao, N., Attrebi, O. N., Ren, Y., Qiao, W., Sonustun, B., Martens, Y. A., Meneses, A. D., Li, F., Shue, F., Zheng, J., et al. (2020) · Science Translational Medicine · doi:10.1126/scitranslmed.aay1809 · Cited by 156 · cited 1× · see citing works
“Since APOE4 also increases the risk for dementia in pure synucleinopathies and specifically exacerbates α-synuclein pathology [59, 60], we propose the disruption of lysosomal metabolism of glycosphingolipids as a common contributing factor in both forms of dementia.”
BackgroundHuang, Y.-W. A., Zhou, B., Nabet, A. M., Wernig, M., & Südhof, T. C. (2019) · The Journal of Neuroscience · doi:10.1523/jneurosci.2994-18.2019 · Cited by 152 · cited 1× · see citing works
“, downstream of neuronal receptor signaling) [80].”
Self-citationTajima, Y., Ishikawa, M., Maekawa, K., Murayama, M., Senoo, Y., Nishimaki‐Mogami, T., Nakanishi, H., Ikeda, K., Arita, M., Taguchi, R., et al. (2013) · Lipids in Health and Disease · doi:10.1186/1476-511x-12-68 · Cited by 146 · cited 1× · see citing works
“This sample size was chosen based on similar lipidomics studies in mice [37, 38], and our own metabolomics study in APOE mice [32].”
MethodThe endosomal-lysosomal pathway is dysregulated by APOE4 expression in vivo
Nuriel, T., Peng, K. Y., Ashok, A., Dillman, A. A., Figueroa, H. Y., Apuzzo, J., Ambat, J., Levy, E., Cookson, M. R., Mathews, P. M., et al. (2017) · Frontiers in Neuroscience · doi:10.3389/fnins.2017.00702 · Cited by 140 · cited 6× · see citing works
“This suggests that while some effects of APOE4 expression may be regionally restricted, others are common throughout the brain, including previously described effects of APOE4 expression on endosomal-lysosomal trafficking [33, 53].”
BackgroundInfluentialSelf-citationMorikawa, M., Fryer, J. D., Sullivan, P. M., Christopher, E., Schindler, S. E., Demattos, R. B., Odell, M., Fagan, A. M., Lashuel, H. A., Walz, T., et al. (2005) · Neurobiology of Disease · doi:10.1016/j.nbd.2004.11.005 · Cited by 136 · cited 2× · see citing works
“David Holtzman) that were originally generated from primary astrocytes from P1-2 pups of APOE targeted replacement mice [41].”
Ginsberg, S. D., Mufson, E. J., Alldred, M. J., Counts, S., Wuu, J., Nixon, R. A., & Che, S. (2011) · Journal of Chemical Neuroanatomy · doi:10.1016/j.jchemneu.2011.05.012 · Cited by 133 · cited 1× · see citing works
“In keeping with a prominent effect of APOE4 in endosomallysosomal trafficking, we previously showed increased expression levels of Rab GTPase genes, such as Rab5b, Rab7 and Rab9, in the EC of aged APOE4mice [33], similar to that observed in cholinergic basal forebrain neurons in MCI and AD [63].”
BackgroundFitz, N. F., Nam, K. N., Wolfe, C. M., Letronne, F., Playso, B. E., Iordanova, B. E., Kozai, T. D. Y., Biedrzycki, R. J., Kagan, V. E., Tyurina, Y. Y., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-23762-0 · Cited by 129 · cited 1× · see citing works
“showed that APOE particles in ACM from APOE4 targeted replacement mouse primary astrocytes presented overall decreased levels of most GPL classes compared to APOE3 particles [92].”
Novel Role for Apolipoprotein E in the Central Nervous System
Han, X., Cheng, H., Fryer, J. D., Fagan, A. M., & Holtzman, D. M. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m212340200 · Cited by 126 · see citing works
Pensalfini, A., Kim, S., Subbanna, S., Bleiwas, C., Goulbourne, C. N., Stavrides, P. H., Jiang, Y., Lee, J., Darji, S., Pawlik, M., et al. (2020) · Cell Reports · doi:10.1016/j.celrep.2020.108420 · Cited by 125 · see citing works
Marked regional differences of brain human apolipoprotein e expression in targeted replacement mice
Sullivan, P. M., Mace, B. E., Maeda, N., & Schmechel, D. E. (2004) · Neuroscience · doi:10.1016/j.neuroscience.2003.10.011 · Cited by 113 · cited 1× · see citing works
“[35, 36] and were acquired from Taconic Biosciences or directly from Dr.”
MethodGryglewski, G., Seiger, R., James, G. M., Godbersen, G. M., Komorowski, A., Unterholzner, J., Michenthaler, P., Hahn, A., Wadsak, W., Mitterhauser, M., et al. (2018) · NeuroImage · doi:10.1016/j.neuroimage.2018.04.068 · Cited by 111 · cited 2× · see citing works
“These observations support a reduced effect of APOE4 on the lipid composition of the PVC as compared to the EC, which may be due to the fact that APOE displays increased gene expression in the medial temporal lobe compared to other brain regions [49, 50].”
BackgroundApolipoprotein E4 genotype compromises brain exosome production
Peng, K. Y., Pérez-González, R., Alldred, M. J., Goulbourne, C. N., Morales-Corraliza, J., Saito, M., Saito, M., Ginsberg, S. D., Mathews, P. M., & Levy, E. (2019) · Brain · doi:10.1093/brain/awy289 · Cited by 109 · cited 1× · see citing works
“Since neurons upregulate the secretion of exosomes to mitigate lysosomal lipid and cargo burden [56], the inhibitory effect of APOE4 expression in exosomes release [70] may also contribute to neuronal vulnerability.”
BackgroundJeong, W., Lee, H. G., Cho, S., & Seo, J. (2019) · PubMed Central · doi:10.14348/molcells.2019.0200 · Cited by 104 · see citing works
Phospholipase D in brain function and Alzheimer's disease
Oliveira, T. G., & Paolo, G. D. (2010) · Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids · doi:10.1016/j.bbalip.2010.04.004 · Cited by 97 · cited 1× · see citing works
“Also, PC is converted to PA by phospholipase D1 (PLD1) or PLD2 isoenzymes [83], both of which have been implicated in AD [84] and shown to signal downstream of Aβ [85, 86] and APOE [87].”
BackgroundSelf-citationAltered cholesterol metabolism in human apolipoprotein E4 knock-in mice
Hamanaka, H. (2000) · Human Molecular Genetics · doi:10.1093/hmg/9.3.353 · Cited by 96 · see citing works
Effect of lysosomal storage on bis(monoacylglycero)phosphate
Meikle, P. J., Duplock, S. K., Blacklock, D., Whitfield, P. D., MacIntosh, G. L., Hopwood, J. J., & Fuller, M. (2008) · Biochemical Journal · doi:10.1042/bj20071043 · Cited by 94 · cited 1× · see citing works
“In fact, these effects of APOE4 are reminiscent of that observed in lysosomal storage disorders [54, 55].”
BackgroundThe role of APOE4 in Alzheimer’s disease: strategies for future therapeutic interventions
Hunsberger, H. C., Pinky, P. D., Smith, W., Suppiramaniam, V., & Reed, M. N. (2019) · Neuronal Signaling · doi:10.1042/ns20180203 · Cited by 94 · see citing works
Liu, N., Tengstrand, E., Chourb, L. S., & Hsieh, F. Y. (2014) · Toxicology and Applied Pharmacology · doi:10.1016/j.taap.2014.06.014 · Cited by 76 · cited 1× · see citing works
“In fact, these effects of APOE4 are reminiscent of that observed in lysosomal storage disorders [54, 55].”
BackgroundAPOE2 orchestrated differences in transcriptomic and lipidomic profiles of postmortem AD brain
Lefterov, I., Wolfe, C. M., Fitz, N. F., Nam, K. N., Letronne, F., Biedrzycki, R. J., Kofler, J., Han, X., Wang, J., Schug, J., et al. (2019) · Alzheimer's Research & Therapy · doi:10.1186/s13195-019-0558-0 · Cited by 74 · cited 1× · 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].”
BackgroundThe role of apolipoprotein E in lipid metabolism in the central nervous system
Han, X.-L. (2004) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-004-4009-z · Cited by 70 · see citing works
Kariv-Inbal, Z., Yacobson, S., Berkecz, R., Péter, M., Janáky, T., Lütjohann, D., Broersen, L., Hartmann, T., & Michaelson, D. (2012) · Journal of Alzheimer's Disease · doi:10.3233/jad-2011-111265 · Cited by 70 · cited 1× · see citing works
“The results from these studies include observations that APOE4 expression increased the levels of triacylglycerol (TAG) and decreased the levels of lysophosphatidylcholine (LPC), phosphatidylserine (PS), cholesterol, and 14-demethylanosterol (a cholesterol derivative) in the brains of APOE targeted replacement mice [2…”
BackgroundUntargeted lipidomics reveals progression of early Alzheimer’s disease in APP/PS1 transgenic mice
Zhang, X., Liu, W., Zan, J., Wu, C., & Tan, W. (2020) · Scientific Reports · doi:10.1038/s41598-020-71510-z · Cited by 68 · cited 1× · see citing works
“This sample size was chosen based on similar lipidomics studies in mice [37, 38], and our own metabolomics study in APOE mice [32].”
MethodChouinard‐Watkins, R., & Plourde, M. (2014) · Nutrients · doi:10.3390/nu6104452 · Cited by 67 · see citing works
Higashi, S., Moore, D. J., Minegishi, M., Kasanuki, K., Fujishiro, H., Kabuta, T., Togo, T., Katsuse, O., Uchikado, H., Furukawa, Y., et al. (2011) · Journal of Neuropathology & Experimental Neurology · doi:10.1097/nen.0b013e318211c86a · Cited by 61 · cited 1× · see citing works
“activation recapitulates prodromal features of AD, including endosomal enlargement and synaptic dysfunction [64], Rab7b granules are found in the EC of Lewy Body dementia patients [65], and altered Rab7 colocalizes with Aβ in apoE treated microglia [66]; that said, altered Rab GTPase levels are thus far correlative in…”
BackgroundThe APOEε3/ε4 Genotype Drives Distinct Gene Signatures in the Cortex of Young Mice
Foley, K. E., Hewes, A. A., Garceau, D. T., Kotredes, K. P., Carter, G. W., Sasner, M., & Howell, G. R. (2022) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2022.838436 · Cited by 57 · cited 1× · see citing works
“While several groups have addressed APOE isoform-related lipid alterations in plasma and serum [24, 25], relatively few studies have reported the use of lipidomic analysis to investigate the lipid alterations that occur specifically in the brain [26–31].”
BackgroundCholesterol-Independent SREBP-1 Maturation Is Linked to ARF1 Inactivation
Smulan, L. J., Ding, W., Freinkman, E., Gujja, S., Edwards, Y. J. K., & Walker, A. K. (2016) · Cell Reports · doi:10.1016/j.celrep.2016.05.086 · Cited by 56 · cited 1× · see citing works
“PA is tightly linked to DAG metabolism via synthesis and catalysis by DAG kinase and lipin/PA phosphatase [81] and has been implicated in synaptic vesicle recycling and in neuronal plasticity mechanisms [82], which may underlie neuronal hyperactivity in aged APOE4 mice [32].”
BackgroundLarramona-Arcas, R., González-Arias, C., Perea, G., Gutiérrez, A., Vitorica, J., García-Barrera, T., Gómez-Ariza, J. L., Pascua-Maestro, R., Ganfornina, M. D., Kara, E., et al. (2020) · Molecular Neurodegeneration · doi:10.1186/s13024-020-00382-8 · Cited by 56 · cited 1× · see citing works
“Also, we previously reported increased expression of several V-type ATPase subunits [33], possibly in response to altered lysosomal pH and membrane composition [68, 69].”
BackgroundApolipoprotein E as a β-amyloid-independent factor in Alzheimer’s disease
Wolf, A. B., Valla, J., Bu, G., Kim, J., LaDu, M., Reiman, E. M., & Caselli, R. J. (2013) · Alzheimer's Research & Therapy · doi:10.1186/alzrt204 · Cited by 55 · see citing works
Area-Gomez, E., Larrea, D., Pera, M., Agrawal, R. R., Guilfoyle, D. N., Pirhaji, L., Shannon, K., Arain, H. A., Ashok, A., Chen, Q., et al. (2020) · Scientific Reports · doi:10.1038/s41598-020-61142-8 · Cited by 55 · cited 2× · see citing works
“While we have previously reported an effect at the level of free fatty acids in the EC of APOE4 mice, including an increase in docosahexaenoic acid (22:6) in the EC [34], our results do not support a preferential acyl chain enrichment in the molecular signature of DAG/GPL and SL.”
BackgroundResultSelf-citationDifferential lipid composition and regulation along the hippocampal longitudinal axis
Miranda, A. M., Bravo, F. V., Chan, R., Sousa, N., Paolo, G. D., & Oliveira, T. G. (2019) · Translational Psychiatry · doi:10.1038/s41398-019-0478-6 · Cited by 54 · cited 2× · see citing works
“Additionally, we observed a neuron-specific decrease in multiple PCe lipid species, which is also observed in the prefrontal cortex [45] and ventral hippocampus [44] of rodents exposed to chronic stress, a known risk factor for AD [90].”
BackgroundMethodSelf-citationThe Relationship between Apolipoprotein E4 and Lipid Metabolism Is Impaired in Alzheimer’s Disease
Dupuy, A., Mas, E., Ritchie, K. A., Descomps, B., Badiou, S., Cristol, J., & Touchon, J. (2001) · Gerontology · doi:10.1159/000052801 · Cited by 50 · see citing works
den Heijer, J. M., Kruithof, A. C., van Amerongen, G., de Kam, M. L., Thijssen, E., Grievink, H. W., Moerland, M., Walker, M., Been, K., Skerlj, R. T., et al. (2021) · British Journal of Clinical Pharmacology · doi:10.1111/bcp.14772 · Cited by 47 · cited 1× · see citing works
“This association bears great therapeutical potential, as allosteric activators of glucocerebrosidase restore lysosomal function [61] and have recently been proven safe in humans [62], underscoring the possibility of extending their application to management of AD in APOE4 carriers.”
BackgroundRegulation of beta-amyloid production in neurons by astrocyte-derived cholesterolPreprint
Wang, H., Kulas, J. A., Ferris, H. A., & Hansen, S. B. (2020) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2020.06.18.159632 · Cited by 43 · see citing works
Diacylglycerol, phosphatidic acid, and their metabolic enzymes in synaptic vesicle recycling
Tu‐Sekine, B., Goldschmidt, H. L., & Raben, D. M. (2014) · Advances in Biological Regulation · doi:10.1016/j.jbior.2014.09.010 · Cited by 40 · cited 1× · see citing works
“PA is tightly linked to DAG metabolism via synthesis and catalysis by DAG kinase and lipin/PA phosphatase [81] and has been implicated in synaptic vesicle recycling and in neuronal plasticity mechanisms [82], which may underlie neuronal hyperactivity in aged APOE4 mice [32].”
BackgroundSharman, M. J., Shui, G., Fernandis, A. Z., Lim, W. L. F., Berger, T., Hone, E., Taddei, K., Martins, I. J., Ghiso, J., Buxbaum, J. D., et al. (2010) · Journal of Alzheimer's Disease · doi:10.3233/jad-2010-1348 · Cited by 35 · cited 1× · see citing works
“While our findings corroborate previous observations reporting that differential APOE isoform expression does not profoundly alter lipid composition in the brain [26, 27], significant effects were observed in the levels of less abundant and bioactive lipid species in both brain regions.”
ResultLim, W. L. F., Lam, S. M., Shui, G., Mondal, A., Ong, D., Duan, X., Creegan, R., Martins, I. J., Sharman, M. J., Taddei, K., et al. (2013) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2013.03.012 · Cited by 34 · see citing works
Granger, M. W., Liu, H., Fowler, C., Blanchard, A. P., Taylor, M. W., Sherman, S., Xu, H., Le, W., & Bennett, S. A. L. (2018) · Journal of Neurochemistry · doi:10.1111/jnc.14560 · Cited by 31 · cited 1× · see citing works
“Since PC can similarly be converted to LPC through the action of phospholipase A2 (PLA2), the inverse relationship between PC and LPC levels upon exposure to APOE4/ 4 ACM suggests upregulation of this pathway, also observed in several transgenic AD models [88, 89].”
BackgroundJenner, A. M., Lim, W. L. F., Ng, M. P.-E., Wenk, M. R., Shui, G., Sharman, M. J., Gandy, S., & Martins, R. N. (2010) · Neuroscience · doi:10.1016/j.neuroscience.2010.04.026 · Cited by 30 · cited 1× · see citing works
“While our findings corroborate previous observations reporting that differential APOE isoform expression does not profoundly alter lipid composition in the brain [26, 27], significant effects were observed in the levels of less abundant and bioactive lipid species in both brain regions.”
Cholesterol and matrisome pathways dysregulated in human APOE ε4 gliaPreprint
Julia, T. C. W., Liang, S., Lü, Q., Pipalia, N. H., Chao, M. J., Shi, Y., Bertelsen, S. E., Kapoor, M., Marcora, E. M., Sikora, E., et al. (2019) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/713362 · Cited by 28 · see citing works
Phospholipase D1 Ablation Disrupts Mouse Longitudinal Hippocampal Axis Organization and Functioning
Marinha, L. S., Castanho, I., Silva, R. R., Bravo, F. V., Miranda, A. M., Meira, T., Morais‐Ribeiro, R., Marques, F., Xu, Y., du Jour, K. P., et al. (2019) · Cell Reports · doi:10.1016/j.celrep.2020.02.102 · Cited by 23 · cited 1× · see citing works
“Also, PC is converted to PA by phospholipase D1 (PLD1) or PLD2 isoenzymes [83], both of which have been implicated in AD [84] and shown to signal downstream of Aβ [85, 86] and APOE [87].”
BackgroundSelf-citationBravo, F. V., Silva, J. D. D., Chan, R., Paolo, G. D., Teixeira‐Castro, A., & Oliveira, T. G. (2018) · Scientific Reports · doi:10.1038/s41598-018-21918-5 · Cited by 20 · cited 1× · see citing works
“Also, PC is converted to PA by phospholipase D1 (PLD1) or PLD2 isoenzymes [83], both of which have been implicated in AD [84] and shown to signal downstream of Aβ [85, 86] and APOE [87].”
BackgroundSelf-citation
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Apolipoprotein E in lipid metabolism and neurodegenerative disease
Yang, L. G., March, Z. M., Stephenson, R. A., & Narayan, P. S. (2023) · Trends in Endocrinology & Metabolism · doi:10.1016/j.tem.2023.05.002 · Cited by 286 · see citing works
Fernández-Calle, R., Konings, S. C., Frontiñán-Rubio, J., García-Revilla, J., Camprubí-Ferrer, L., Svensson, M., Martinson, I., Boza-Serrano, A., Venero, J. L., Nielsen, H. M., et al. (2022) · Molecular Neurodegeneration · doi:10.1186/s13024-022-00566-4 · Cited by 278 · 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
“A handful of previous studies have examined the role of human APOE on the mouse brain transcriptome and metabolome, 28-32 and a recent study inferred strong, glial-driven APOE genotype effects from whole-tissue bulk RNA-seq of postmortem human brains.”
Litvinchuk, A., Suh, J. H., Guo, J. L., Lin, K., Davis, S. S., Bien-Ly, N., Tycksen, E., Tabor, G. T., Remolina Serrano, J., Manis, M., et al. (2024) · Neuron · doi:10.1016/j.neuron.2023.10.023 · Cited by 161 · see citing works
Guo, J. L., Braun, D., Fitzgerald, G. A., Hsieh, Y.-T., Rougé, L., Litvinchuk, A., Steffek, M., Propson, N. E., Heffner, C. M., Discenza, C., et al. (2025) · Cell · doi:10.1016/j.cell.2024.10.027 · Cited by 91 · see citing works
“8,9 18 However, the precise molecular mechanisms underlying ApoE isoform-dependent lipid dyshomeostasis in LOAD are poorly understood.”
The Batten disease gene product CLN5 is the lysosomal bis(monoacylglycero)phosphate synthase
Medoh, U. N., Hims, A., Chen, J. Y., Ghoochani, A., Nyame, K., Dong, W., & Abu-Remaileh, M. (2023) · Science · doi:10.1126/science.adg9288 · Cited by 87 · see citing works
The Bis(monoacylglycero)-phosphate Hypothesis: From Lysosomal Function to Therapeutic Avenues
Medoh, U. N., & Abu-Remaileh, M. (2024) · Annual Review of Biochemistry · doi:10.1146/annurev-biochem-092823-113814 · Cited by 58 · see citing works
RNA nanotherapeutics with fibrosis overexpression and retention for MASH treatment
Shan, X., Zhao, Z., Lai, P., Liu, Y., Li, B., Ke, Y., Jiang, H., Zhou, Y., Li, W., Wang, Q., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-51571-8 · Cited by 44 · see citing works
Chen, Y., Jin, H., Chen, J., Li, J., Găman, M., & Zou, Z. (2025) · Cell Death Discovery · doi:10.1038/s41420-025-02600-y · Cited by 52 · see citing works
“This has been suggested as a potential mechanism underlying the hyperactivity of ApoE4 neurons [125].”
Neuronal ApoE4 in Alzheimer’s disease and potential therapeutic targets
Zhang, L., Xia, Y., & Gui, Y. (2023) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2023.1199434 · Cited by 41 · see citing works
“In addition, CSF Aβ42 levels and PiB imaging in ApoE4 carriers, both of which suggest cerebrospinal fluid amyloid deposition (Miranda et al., 2022).”
BackgroundImpact of apolipoprotein E isoforms on sporadic Alzheimer’s disease
Lozupone, M., & Panza, F. (2023) · Neural Regeneration Research · doi:10.4103/1673-5374.375316 · Cited by 37 · see citing works
Systematic review of brain and blood lipidomics in Alzheimer's disease mouse models
Ferré‐González, L., Lloret, A., & Cháfer‐Pericás, C. (2023) · Progress in Lipid Research · doi:10.1016/j.plipres.2023.101223 · Cited by 29 · see citing works
Leikin-Frenkel, A. I., Beeri, M. S., & Cooper, I. (2022) · Nutrients · doi:10.3390/nu14235091 · Cited by 29 · see citing works
Bulfon, D., Breithofer, J., Grabner, G. F., Fawzy, N., Pirchheim, A., Wolinski, H., Kolb, D., Hartig, L., Tischitz, M., Zitta, C., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-54213-1 · Cited by 28 · see citing works
“Furthermore, altered BMP levels are lipidomic signatures of common neurodegenerative diseases such as Parkinson ’ s 16 and Alzheimer ’ s disease 17,18 .”
Kalkman, H. O., & Smigielski, L. (2025) · Molecular Neurobiology · doi:10.1007/s12035-025-04989-0 · Cited by 29 · see citing works
“Further studies in mice indicate that APOE ε4, compared to APOE ε3, increases the expression of multiple ceramide species in the cerebral cortex [57].”
Xu, Z., Shabestari, S. K., Barannikov, S., Bieniek, K. F., Blurton-Jones, M. M., Palavicini, J. P., & Han, X. (2025) · Nature Communications · doi:10.1038/s41467-025-64161-z · Cited by 28 · see citing works
Protective ApoE variants support neuronal function by effluxing oxidized phospholipids
Ralhan, I., Do, A. D., Bae, J.-Y., Feringa, F. M., Cai, W., Chang, J., Chik, K., Lee, N. Y. J., Gerry, C. J., van der Kant, R., et al. (2026) · Neuron · doi:10.1016/j.neuron.2025.10.040 · Cited by 23 · see citing works
Menopause and Alzheimer’s disease susceptibility: Exploring the potential mechanisms
Breeze, B., Connell, E., Wileman, T., Müller, M. M., Vauzour, D., & Pontifex, M. G. (2024) · Brain Research · doi:10.1016/j.brainres.2024.149170 · Cited by 22 · see citing works
Gręda, A., Gomes, J. P., Schmidt, V., Żurawska-Płaksej, E., Fritsche‐Guenther, R., Rudolph, I., Telugu, N. S., Cömert, C., Kirwan, J., Kunz, S., et al. (2025) · Nature Metabolism · doi:10.1038/s42255-025-01389-5 · Cited by 21 · see citing works
“Also, prior work reported differences in lipid-loading comparing apoE variants 65,66 .”
A metabolomic signature of the APOE2 allele
Sebastiani, P., Song, Z., Ellis, D., Tian, Q., Schwaiger-Haber, M., Stancliffe, E., Lustgarten, M. S., Funk, C. C., Baloni, P., Yao, C.-H., et al. (2022) · GeroScience · doi:10.1007/s11357-022-00646-9 · Cited by 16 · see citing works
“[52] found lower levels of some diglycerol lipids in brain tissues of e4 carriers compared to e3 homozygotes.”
BackgroundAPOE genotype dictates lipidomic signatures in primary human hepatocytes
Almeida, F., Patra, K., Giannisis, A., Niesnerova, A., Nandakumar, R., Ellis, E. C. S., Oliveira, T. G., & Nielsen, H. M. (2024) · Journal of Lipid Research · doi:10.1016/j.jlr.2024.100498 · Cited by 14 · see citing works
Self-citationIsoform- and cell-state-specific APOE homeostasis and function
Lindner, K., & Gavin, A.-C. (2024) · Neural Regeneration Research · doi:10.4103/nrr.nrr-d-23-01470 · Cited by 13 · see citing works
Lipids and α-Synuclein: adding further variables to the equation
Schepers, J., Löser, T., & Behl, C. (2024) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2024.1455817 · Cited by 13 · see citing works
Bhattarai, P., Yılmaz, E., Cakir, E. Ö., Yüceer, H., Lee, A., Ma, Y., Çelikkaya, H., Coşacak, M. İ., Haage, V. C., Wang, X., et al. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.01.24.634732 · Cited by 12 · see citing works
Self-citationToledano‐Díaz, A., Álvarez, M., & Tolédano, A. (2022) · Journal of Central Nervous System Disease · doi:10.1177/11795735221128703 · Cited by 11 · see citing works
Detecting amyloid‐β positivity using regions of interest from structural magnetic resonance imaging
Hwang, J., Park, H. K., Yoon, H., Jeong, J. H., Lee, H., & Initiative, A. D. N. (2023) · European Journal of Neurology · doi:10.1111/ene.15775 · Cited by 10 · see citing works
“A recent study has shown that APOE4 expression affects the regulation of lipid metabolism in the ERC, implying that APOE4 increases the susceptibility of neurons in the ERC to AD pathogenesis [41].”
BackgroundWeerakkody, T. N., Sabelström, H., Andrews, S. V., Chadarevian, J. P., Chin, M. Y., Tatarakis, D., Propson, N. E., Kim, D. J., Theolis, R., Parico, G. C. G., et al. (2025) · Science Translational Medicine · doi:10.1126/scitranslmed.adw7428 · Cited by 11 · see citing works
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Brain areas lipidomics in female transgenic mouse model of Alzheimer's disease
Ferré‐González, L., Balaguer, Á., Roca, M., Ftara, A., Lloret, A., & Cháfer‐Pericás, C. (2024) · Scientific Reports · doi:10.1038/s41598-024-51463-3 · Cited by 9 · see citing works
“…GLs (DAG and TAG), a decrease was observed in the AD compared to the WT group, while other studies carried out in other areas showed increasing levels 47–49 , decreasing levels 50,51 and no significant differences between groups using the same AD murine model, but in a more advanced AD stage 52 .”
ResultEffects of obesogenic diet and 17β-estradiol in female mice with APOE 3/3, 3/4, and 4/4 genotypes
Christensen, A., McGill, C. J., Qian, W., & Pike, C. J. (2024) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2024.1415072 · Cited by 7 · see citing works
“A recent targeted brain lipidome analysis in middle-aged male APOE knock-in mice reported differences across APOE3/3 , APOE3/4, and APOE4/4 genotypes with APOE3/4 often positioned between the two homozygous groups (Miranda et al., 2022).”
BackgroundLysaker, C. R., Johnson, C. N., Csikós, V., Franczak, E., Benson, M. N., Gilmore, C. A., Birky, C. J., Davis, X. C., McCoin, C. S., Smith, K. P., et al. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.06.15.659811 · Cited by 8 · see citing works
PGRN as an emerging regulator of lipid metabolism in neurodegenerative diseases
Shi, Y., Hou, W., Li, B., & Zhu, C. (2025) · Communications Biology · doi:10.1038/s42003-025-08272-9 · Cited by 8 · see citing works
Recent advances in Alzheimer’s disease: From molecular mechanisms to therapeutic strategies
Rudman, M. D., Ulrich, J. D., & Holtzman, D. M. (2026) · Cell · doi:10.1016/j.cell.2026.06.006 · Cited by 10 · see citing works
Lysophosphatidylcholines are associated with P-tau181 levels in early stages of Alzheimer’s DiseasePreprint
Kalia, V., Reyes‐Dumeyer, D., Dubey, S., Nandakumar, R., Lee, A., Lantigua, R., Medrano, M. Z., Rivera, D., Honig, L. S., Mayeux, R. P., et al. (2023) · medRxiv · doi:10.1101/2023.08.24.23294581 · Cited by 7 · see citing works
Lysophosphatidylcholines are associated with amyloidosis in early stages of Alzheimer’s disease
Kalia, V., Reyes‐Dumeyer, D., Dubey, S., Udhani, H. H., Nandakumar, R., Lee, A., Lantigua, R., Medrano, M. Z., Rivera, D., Honig, L. S., et al. (2025) · Nature Aging · doi:10.1038/s43587-025-01025-7 · Cited by 6 · see citing works
“APOE ε4 carriers tend to exhibit higher levels of specific lysoPC species, including DHA and AHA in CSF, plasma and brain tissue compared to noncarriers 72–75 .”
Microglia-derived APOE2 improves remyelination even in the presence of endogenous APOE4
Nolt, G. L., Golden, L. R., Thorpe, S. P., Funnell, J. L., Stephens, I. O., Hernandez, G., MacLean, S. M., Lucido, C. C., Brock, C. R., Pallerla, A. V., et al. (2025) · Journal of Neuroinflammation · doi:10.1186/s12974-025-03639-5 · Cited by 5 · see citing works
“Studies have profiled the lipi-domic alterations between ApoE isoforms in humans and mice, revealing several lipid species that are differentially regulated in E4s in a region-dependent manner compared to E3s and E2s [23, 52, 64, 65].”
de Moraes, R. C. M., Roth, J. R., Mao, H., Crawley, S. R., Xu, B. P., Watson, J. C., & Melkani, G. C. (2024) · Genes · doi:10.3390/genes15111376 · Cited by 5 · see citing works
Astrocytic spermidine insufficiency contributes to enhanced pain sensitivity associated with ApoE4
Yu, K., Zhou, X., Li, B., Sun, J., Yang, T., Li, W., Wang, N., Gu, X., Cui, S., & Cao, R. (2025) · The Journal of Headache and Pain · doi:10.1186/s10194-025-02054-8 · Cited by 4 · see citing works
McGill, C. J., Christensen, A., Qian, W., Thorwald, M. A., Godoy-Lugo, J. A., Namvari, S., White, O. S., Finch, C. E., Benayoun, B. A., & Pike, C. J. (2025) · Communications Medicine · doi:10.1038/s43856-025-00942-3 · Cited by 4 · see citing works
“Sphingomyelin dysregulation is associated with APOE4 and AD 63,65,69 .”
Richards, S. E. V., Yang, M., Deik, A. A., & Ricq, E. L. (2025) · Neurochemical Research · doi:10.1007/s11064-025-04463-2 · Cited by 3 · see citing works
“Finally, we sought to profile the brain lipidome of young humanized APOE targeted replacement (TR) mice, as previous reports have not examined the APOE2 genotype nor captured individual cholesteryl ester species (SI Table 2) [47–49].”
Delivanoglou, N., Todd, K. T., Almeida, F., Rego, S., Changavi, A., Spajer, M., Ayuso, V. E., Pinho-Correia, L. M., Sánchez, G., das Neves, S. P., et al. (2026) · Neuron · doi:10.1016/j.neuron.2026.02.030 · Cited by 4 · see citing works
Self-citationAPOE genotype and biological age impact inter-omic associations related to bioenergetics
Ellis, D., Watanabe, K., Wilmanski, T. M., Lustgarten, M. S., Korat, A. V. A., Glusman, G., Hadlock, J., Fiehn, O., Paola Sebastiani, B., Price, N. D., et al. (2025) · Aging · doi:10.18632/aging.206243 · Cited by 5 · see citing works
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“Furthermore, altered BMP levels are lipidomic signatures of common neurodegenerative diseases such as Parkinson's 16 and Alzheimer's disease 17,18 .”
BackgroundWang, M., Niu, D.-C., Zhang, Q., Tang, Y.-Q., Zhao, Y., & Chen, F. (2026) · International Journal of Biological Macromolecules · doi:10.1016/j.ijbiomac.2026.151352 · Cited by 1 · see citing works
Radiomics features of FDG PET images predict ApoE4
Rasi, R., & Güveniş, A. (2025) · European Journal of Radiology Artificial Intelligence · doi:10.1016/j.ejrai.2025.100009 · Cited by 2 · see citing works
McGill, C. J., Christensen, A., Qian, W., Thorwald, M. A., Lugo, J. G., Namvari, S., White, O. S., Finch, C. E., Benayoun, B. A., & Pike, C. J. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.03.12.584678 · Cited by 2 · see citing works
APOE Genotype and Biological Age Impact Inter-Omic Associations Related to BioenergeticsPreprint
Ellis, D., Watanabe, K., Wilmanski, T. M., Lustgarten, M. S., Korat, A. V. A., Glusman, G., Hadlock, J., Fiehn, O., Paola Sebastiani, B., Price, N. D., et al. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.10.17.618322 · Cited by 2 · see citing works
“22 This discrepancy of APOE E4’s potential influence on DAG levels between the blood and brain may point to differences in DAG transport and sequestering as well as metabolism across APOE, or potentially highlight the limitations of mouse models to accurately reflect humans.”
Tamagno, W. A., Mendes, H. W., Stradtman, S. C., et al. (2026) · Environmental Research · doi:10.1016/j.envres.2026.125045 · Cited by 1 · see citing works
APOE4-drives brain bioenergetic shifts independent of Alzheimer’s disease pathology
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“Priorlipidomic, metabolomic, and magnetic resonance spectroscopy (MRS)studiesinmousemodelsshowthatgeneticvariationin APOE modify brain metabolite levels 20 – 23 .”
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“16 20-22 .”
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Aging, genomic mitochondrial, and regulatory changes
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“This is in line with previous research in mice, which also reported increased phospholipid levels associated with APOE4 expression [68].”
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“This enhancement is supported by phosphatidylcholine dynamics that may improve cholinergic neuron function and BMP enrichment that likely boosts endolysosomal activity (Miranda et al., 2022).”
CSF APOE Secondary Glycosylation Predicts Cognitive Decline in Mild Cognitive Impairment
Jiao, Y., Du, C., Ding, Y., Zhou, R., Zhao, A., Liu, J., Deng, Y., & Initiative, A. D. N. (2026) · Biomedicines · doi:10.3390/biomedicines14102206
- Authors
- 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., & Nuriel, T.
- Affiliations
- Centro Hospitalar de Vila Nova de Gaia (PT)
- Columbia University (US)
- UK Dementia Research Institute (GB)
- Hospital Braga (PT)
- Columbia University Irving Medical Center (US)
- Corresponding author
- Oliveira, Tiago Gil
- Nuriel, Tal
- ORCID
- Venue
- Translational Psychiatry
- Published
- 2022-03-29
- Volume
- 12
- Issue
- 1
- Pages
- 129-129
- ISSN
- 2158-3188 (ISSN-L)
- PMC
- PMC8964762
- OpenAlex
- W4220903838
- Semantic Scholar
- 90548caf93d1615d819a130b167be19d4b4acc76
- Cited by
- 60
- References
- 96
- Citations by year
- 2026: 10 · 2025: 18 · 2024: 17 · 2023: 11 · 2022: 4
- FWCI
- 7.73
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Translational Psychiatry (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Funders
- U.S. Department of Health & Human Services | NIH | National Institute on Aging (AG047797, AG061264, AG062271, AG047954, NS084328, AG048408)
- BrightFocus Foundation
- Alzheimer’s Association (AARG-19-619164)
- Cure Alzheimer’s Fund
- U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NS071836)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sphingolipid Metabolism and Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Lipid metabolism and biosynthesis
- Keywords
- APOE ε4, allelic dosage, Alzheimer's disease, entorhinal cortex, lipidomics, diacylglycerol, ceramide, bis(monoacylglycerol)phosphate, astrocyte-conditioned medium, aged mice, primary visual cortex
- MeSH terms
- Lipidomics, Animals, Amyloid beta-Peptides, Gene Dosage, Entorhinal Cortex, Mice, Apolipoprotein E3, Apolipoprotein E4
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