ApoE in Alzheimer’s disease: pathophysiology and therapeutic strategies

Raulin, Ana-Caroline; Doss, Sydney V.; Trottier, Zachary A.; Ikezu, Tadafumi C.; Bu, Guojun; Liu, Chia-Chen

doi:10.1186/s13024-022-00574-4

Molecular Neurodegeneration

Table 1 APOE isoform effects in aging and AD: Insights from multi-omics and biomarker studies

From: ApoE in Alzheimer’s disease: pathophysiology and therapeutic strategies

Cohort	Findings	Source	DOI
Transcriptomics
Normal; AD	• APOE2/3 AD brains are enriched in complement pathway genes (C4A, C4B, and HSPA2) whose expressions are associated with an increase of pTau231/tTau [296]	Brain	https://doi.org/10.1038/s41380-021-01266-z
AD	• APOE2 is associated with genes involved in protein synthesis, folding and degradation, response to unfolded protein, autophagy, and mitochondrial function [139]	Brain	https://doi.org/10.1186/s13195-019-0558-0
Normal; AD	• APOE is one of the DAM-like signature genes that is significantly up-regulated in human AD brain assessed by single cell- or single nuclei-RNA Sequencing [64, 297,298,299]	Brain	https://doi.org/10.1038/s41467-020-19737-2 https://doi.org/10.1038/s41586-019-1195-2 https://doi.org/10.1007/s00401-020-02200-3 https://doi.org/10.1007/s00401-021-02263-w
Normal APOE mice	• APOE4 reduces energy expenditure in young females and decreases glucose oxidation by redirecting flux through aerobic glycolysis [300]	Brain Plasma	https://doi.org/10.1186/s13024-021-00483-y
APOE mice Amyloid mouse models	• APOE4 increases the expression of Serpina3 family genes, whereas APOE2 drives distinct blood metabolome profile [173] • DAM/MGnD/ARM exhibit conserved transcriptional signatures across different AD mouse models with Apoe being one of the central regulators [116, 118, 301]	Brain Plasma	https://doi.org/10.1016/j.neuron.2020.02.034 https://doi.org/10.1016/j.cell.2017.05.018 https://doi.org/10.1016/j.immuni.2017.08.008 https://doi.org/10.1016/j.celrep.2019.03.099
Normal	• Microglial gene expression modules associated with APOE4 and sex are also enriched with genes involved in cholesterol absorption and lipid digestion [302] • Microglial gene expression modules associated with APOE4 and age suggest perturbations in lipid and carbohydrate metabolism as well as microglial activation [302]	Brain	https://doi.org/10.1111/acel.13606
Normal; AD APOE mice	• APOE4 astrocytes and microglia demonstrate dysregulated lipid metabolism [179] • APOE4 alters the matrisome, ECM, and immune pathways in hiPSC-mixed cortical cultures and AD brains [179]	Brain hiPSC	https://doi.org/10.1016/j.cell.2022.05.017
Proteomics
Normal; AD	• AIF1, APP, GDI2, HSP90AA1, METAP2, NACA, NCK1, PRDX1, RPS27A, SFTPD and UFC1 are downregulated in AD versus control among APOE4 carriers. [303]	Plasma, brain	https://doi.org/10.18632/aging.202950
Normal	• APOE genotype is associated with levels of PSD95 in superior temporal cortex in AD (E4/ > E3/E3 > E2/) [59] • APOE2 is associated with significantly increased levels of PSD95 in superior temporal cortex [59]	Brain	https://doi.org/10.1016/j.neurobiolaging.2005.04.008
Control; AsymAD; AD	• The matrisome module (i.e., extracellular matrix associated proteins) is influenced by the APOE4 but is not associated with cognitive decline rate after adjustment for neuropathology [304].	Brain	https://doi.org/10.1038/s41593-021-00999-y
Lipidomics
Normal; AD	• APOE4 copy number is positively associated with LysoPE and acylcarnitine species [305] • APOE4 copy number is negatively associated with PE(O), PE(P), ceramides, and triglycerides versus APOE2 carriers [305]	Plasma	https://doi.org/10.3233/jad-191304
Normal; Aging	• LDL cholesterol levels are genotype dependent (E4/E4 > E4/E3 > E3/E3 > E2/E3 > E2/E2) [306] • APOE2 is associated with increased levels of most phospholipids (i.e., lysophosphatidylcholines and all PE subclasses) [306] • APOE4 is associated with reduced levels of phosphatidylinositol relative to APOE2 and APOE3 carriers [306]	Plasma	https://doi.org/10.3233/jad-190524
AD	• APOE4 is associated with reduced levels of CAR, LPC, LPE, PA, PC, PE, PI, PS, SM, and ST [139]	Brain	https://doi.org/10.1186/s13195-019-0558-0
Apoe-KO mice	• Both APOE3 and APOE4 treatment reduces hyperlipidemia in a dose-dependent manner, lowering both plasma cholesterol and lipoprotein levels [307] • Expression of APOE4 increases VLDL-cholesterol and reduces HDL-cholesterol levels relative to apoE3 [307]	Plasma	https://doi.org/10.1161/atvbaha.112.301193
Metabolomics
AD	• APOE4 is associated with reduced LysoPC(18:1), LysoPC(P-18:0), and Cardiolipin [308]	Plasma	https://doi.org/10.1016/j.jpba.2019.113088
Normal; Young	• APOE4 carriers show higher levels of cholesterol relative to APOE2 carriers [309] • APOE influences GlycA, isoleucine, LDL-TG, VLDL-TG, and M-VLDL (E2 < E3 < E4) [309] • APOE influences LDL particle diameter (E2 > E3 > E4) [309]	Serum	https://doi.org/10.1038/s41598-018-36450-9
Biomarkers
Normal	• APOE4 is associated with increased LDL, IGF-1, SHBG, bilirubin, triphosphate, ApoB, and total cholesterol, and reduced HDL, HbA1C, lipoprotein A, CRP, GGT, vitamin D, creatine, urate, and urea compared to APOE3 [310] • APOE2 is associated with increased HDL, CRP, vitamin D, CysC, ApoA, creatinine, and alkaline phosphatase; and reduced LDL, IGF-1, bilirubin, and ApoB, compared to APOE3 [310]	Serum blood	https://doi.org/10.3233/jad-200338
Normal; Aging	• APOE2 reduces total cholesterol, LDL, lipoprotein A, and ApoB and increases apoA1 compared to APOE3 [311]	blood	https://doi.org/10.18632/aging.103405
Normal	• APOE4 is associated with increased SNAP-25 in cognitively normal patients [312]	CSF	https://doi.org/10.1016/j.neurobiolaging.2021.02.008
Normal; Aging	• APOE2 carriers without dementia have reduced Aβ burden, with no differences in tau accumulation [313] • APOE4 carriers without dementia have increased Aβ burden and tau burden [313]	PET	https://doi.org/10.1007/s00259-021-05192-8
AD	• APOE4 carriers with preclinical AD have increased VILIP-1 [314]	CSF	https://doi.org/10.2147/ndt.s235395
AD	• APOE4 is associated with increased levels of CDH6 and HAGH in AD patients [315]	Plasma	https://doi.org/10.1038/s41598-020-65038-5
AD	• Levels of CRP are influenced by APOE (E2/E3 > E3/E3 > E3/E4 > E4/E4 > E2/E4) [316] • Levels of ApoB are influenced by APOE (E2/E3 < E2/E4 < E3/E3 < E3/E4 < E4/E4) [316] • Levels of IL-13 are influenced by APOE (E2/E3 < E2/E4 < E3/E3 < E3/E4 < E4/E4) [316] • Levels of CXCL9 are influenced by APOE (E3/E3 > E3/E4 > E4/E4) [316]	Plasma	https://doi.org/10.1001/archneurol.2012.1070
APOE mice	• APOE4 is associated with increased NP1 levels [317]	Plasma	https://doi.org/10.1016/j.nbd.2018.02.014

Abbreviations: pTau: phosphorylated Tau, tTau: total Tau, DAM: disease-associated microglia, MGnD: microglial neurodegenerative phenotype, ARM: activated response microglia, AIF1: Allograft inflammatory factor 1, APP: Amyloid precursor protein, GDI2: Guanosine Diphosphate Dissociation Inhibitor 2, HSP90AA1: Heat Shock Protein 90 Alpha Family Class A Member 1, METAP2: Methionyl Aminopeptidase 2, NACA: Nascent Polypeptide Associated Complex Subunit Alpha, NCK1: Non-catalytic region of tyrosine kinase adaptor protein 1, PRDX1: Peroxiredoxin 1, RPS27A: Ribosomal Protein S27a, SFTPD: Surfactant Protein D, UFC1: Ubiquitin-Fold Modifier Conjugating Enzyme 1, PSD95: Postsynaptic density protein 95, AsymAD: asymptomatic AD, LysoPE: Lysophosphatidylethanolamine, PE: Phosphatidylethanolamine, LDL: Low-density lipoprotein, CAR: Carnitine, LPC: Lysophosphatidylcholine, LPE: Lysophosphatidylethanolamine, PA: Phosphatidic acid, PC: Phosphatidylcholine, PI: Phosphatidylinositol, PS: Phosphatidylserine, SM: Sphingomyelin, ST: Sterol, VLDL: Very low-density lipoprotein, HDL: High-density lipoprotein, LysoPC: Lysophosphatidylcholine, GlycA: Glycoprotein acetylation, TG: Triglyceride, IGF-1: Insulin-like growth factor-1, SHBG: Sex hormone binding globulin, HbA1C: Hemoglobin A1C, CRP: C-reactive protein, GGT: Gamma-glutamyl transferase, CysC: Cystatin C, ApoA: Apolipoprotein A, ApoB: Apolipoprotein B, VILIP-1: Visinin-like protein 1, CDH6: Cadherin 6, HAGH: Hydroxyacylglutathione Hydrolase, IL-13: Interleukin-13, CXCL9: Chemokine ligand 9, NP1: Neuronal pentraxin 1

Back to article page

ISSN: 1750-1326

Contact us

Submission enquiries: Access here and click Contact Us
General enquiries: info@biomedcentral.com