Apoe4 and Alzheimer’s Disease Pathogenesis—Mitochondrial Deregulation and Targeted Therapeutic Strategies

iPSC-derived neurons from LOAD patients expressing ApoE4 secrete higher levels of Aβ compared to ApoE3-expressing neurons.

“induced pluripotent stem cells (iPSC)-derived neurons from LOAD patients expressing ApoE4 secrete higher levels of Aβ, when compared to ApoE3-expressing neurons”

• cites [39] Lin, 2018, APOE4 Causes Widespread Molecular and Cellular Alterations Associated with Alzheimer’s Disease Phenotypes in Human IPSC-Derived Brain Cell Types, Neuron sourceDisputed

  The Results section on sAD patient-derived iPSCs reports no significant difference in secreted Aβ42 or Aβ40 between APOE4 neurons and their APOE3-edited counterparts (page unavailable). The reported 20% increase in Aβ42 came from a separate comparison using isogenic lines generated from unaffected parental cells, not the patient-derived neurons specified in the claim. (LLM, conf=0.90)

  Checked by a reasoning model — may be wrong.

  Experimental — accuracy not yet measured

The APOE ε4 allele reduces the age of onset of Alzheimer's disease-associated cognitive impairment by 7 to 9 years per copy.

“The APOE ε4 allele also reduces the age of onset of AD-associated cognitive impairment by 7 to 9 years per copy [18].”

• cites [18] Simonovitch, 2019, The Effects of APOE4 on Mitochondrial Dynamics and Proteins in vivo, J. Alzheimer’s Dis. sourceSupported

Both the receptor-binding and lipid-binding regions are critical for ApoE4 fragment-related neurotoxicity and mitochondrial impairment, rather than full-length protein.

“Both regions are thought to be critical for ApoE4 fragment-related neurotoxicity and mitochondrial impairment, rather than full-length protein [29,31].”

• cites [29] Chang, 2005, Lipid- and Receptor-Binding Regions of Apolipoprotein E4 Fragments Act in Concert to Cause Mitochondrial Dysfunction and Neurotoxicity, Proc. Natl. Acad. Sci. USA sourceSupported
• cites [31] Liraz, 2013, ApoE4 Induces Aβ42, Tau, and Neuronal Pathology in the Hippocampus of Young Targeted Replacement ApoE4 Mice, Mol. Neurodegener. sourcePartly supported

  The Introduction (page unavailable) associates apoE4 with mitochondrial pathology, and the Results (page unavailable) report altered mitochondrial markers in apoE4 mice. But the paper does not establish that both receptor-binding and lipid-binding regions are critical, or that fragments rather than full-length apoE4 cause neurotoxicity and mitochondrial impairment; the Discussion says the mechanism of the observed effects is unknown. (LLM, conf=0.84)

  Experimental — accuracy not yet measured

Several proteases are suggested to be responsible for ApoE4 cleavage at different sites, including collagenase, MMP-9, neuron-specific α-chymotrypsin-like serine protease, cathepsin D, and HtrA1.

“Several proteases have been suggested to be responsible for ApoE4 cleavage at different sites, including collagenase, matrix metalloproteinas-9 (MMP-9) [25], neuron-specific α-chymotrypsin-like serine protease [26], cathepsin D (the only aspartic protease identified) [27] and high-temperature requirement serine protease A1 (HtrA1) [21].”

• cites [25] Rohn, 2017, Nuclear Localization of Apolipoprotein E4: A New Trick for an Old Protein, Int. J. Neurol. Neurother. sourceCould not verify

  Citation [21] is attached to the HtrA1 part of the sentence. The Nuclear Localization of ApoE4 and Mechanism of Nuclear Trafficking sections discuss cleavage by collagenase and MMP-9, but our copy yielded no passage identifying HtrA1 as an ApoE4-cleaving protease (searched: HtrA1 and its expanded name). (LLM, conf=0.74)

  Experimental — accuracy not yet measured
• cites [26] Mahley, 2006, Apolipoprotein E4: A Causative Factor and Therapeutic Target in Neuropathology, Including Alzheimer’s Disease, Proc. Natl. Acad. Sci. USA sourceSupported
• cites [27] Love, 2017, Nuclear Uptake of an Amino-Terminal Fragment of Apolipoprotein E4 Promotes Cell Death and Localizes within Microglia of the Alzheimer’s Disease Brain, Int. J. Physiol. Pathophysiol. Pharmacol.Not checked — no full text of the source

ApoE4 increases susceptibility to Alzheimer's disease rather than determining its development.

“Being a risk factor, ApoE4 rather increases the susceptibility to AD than determines its development [19].”

• cites [19] Tambini, 2016, ApoE4 Upregulates the Activity of Mitochondria-associated ER Membranes, EMBO Rep. sourceSupported

ApoE4 is associated with decreased total levels of ApoE.

“ApoE4 in particular is associated to decreased total levels of ApoE [34]”

• cites [34] Riddell, 2008, Impact of Apolipoprotein E (ApoE) Polymorphism on Brain ApoE Levels, J. Neurosci. sourceSupported

Astrocytes expressing ApoE4 are linked to reduced neurotrophic support.

“astrocytes expressing ApoE4 have been linked to reduced neurotrophic support [17].”

• cites [17] Das, 2021, APOE and Alzheimer’s Disease: Advances in Genetics, Pathophysiology, and Therapeutic Approaches, Lancet Neurol. sourceSupported

Carrying the ε4 allele of APOE is linked to an earlier and more extensive formation of senile plaques.

“carrying the ε4 allele of APOE gene is linked to an earlier and more extensive formation of senile plaques [25]”

• cites [25] Rohn, 2017, Nuclear Localization of Apolipoprotein E4: A New Trick for an Old Protein, Int. J. Neurol. Neurother. sourceSupported

ApoE4 fragments are found in higher levels in Alzheimer's disease patients carrying APOE ε4 than in age- and sex-matched controls.

“and in higher levels than in age- and sex-matched controls [29].”

• cites [29] Chang, 2005, Lipid- and Receptor-Binding Regions of Apolipoprotein E4 Fragments Act in Concert to Cause Mitochondrial Dysfunction and Neurotoxicity, Proc. Natl. Acad. Sci. USA sourcePartly supported

  The Abstract reports higher levels of apoE fragments in the brains of AD patients than in age- and sex-matched controls. It also says apoE4 is more susceptible to cleavage than apoE3, but does not specify that the patients in that comparison carried APOE ε4 or that the measured fragments were exclusively apoE4. (LLM, conf=0.84)

  Experimental — accuracy not yet measured

ApoE4 accelerates tau pathology spreading particularly when secreted by neurons.

“or accelerate tau pathology spreading particularly when secreted by neurons [50]”

• cites [50] Wadhwani, 2019, Neuronal Apolipoprotein E4 Increases Cell Death and Phosphorylated Tau Release in Alzheimer Disease, Ann. Neurol. sourcePartly supported

  The Abstract’s Interpretation and Discussion suggest that neuronal E4 increases phosphorylated-tau release and may accelerate the spread of tau pathology. But the Discussion says further experiments are needed to determine whether APOE secretion is involved; the paper does not establish that the effect occurs particularly when E4 itself is secreted by neurons. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

Carrying the ε4 allele of APOE is associated with lower levels of Aβ1-42 in cerebrospinal fluid.

“associated to lower levels of Aβ1–42 in cerebrospinal fluid (CSF) [2].”

• cites [2] Guo, 2020, Molecular and Cellular Mechanisms Underlying the Pathogenesis of Alzheimer’s Disease, Mol. Neurodegener. sourceSupported

ApoE in general reduces LRP1-mediated tau uptake by neurons and propagation.

“it has been observed that ApoE in general reduces LRP1-mediated tau uptake by neurons and propagation [52]”

• cites [52] Rauch, 2020, LRP1 Is a Master Regulator of Tau Uptake and Spread, Nature sourcePartly supported

  The Results report that ApoE-conditioned medium significantly reduced full-length tau uptake in H4 cells, and suggest that ApoE could inhibit tau–LRP1 interactions and suppress tau spread. The ApoE uptake experiment was not performed in neurons, and the paper does not report a direct test of ApoE's effect on tau propagation; those parts of the claim overstate the evidence. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

The APOE ε3 allele has no significant effect on Alzheimer's disease risk.

“APOE ε3 allele (ApoE3) is the most frequent one, being expressed by 60–90% of the world population [20], but has no significant effect on AD risk [18].”

• cites [18] Simonovitch, 2019, The Effects of APOE4 on Mitochondrial Dynamics and Proteins in vivo, J. Alzheimer’s Dis. sourceCould not verify

  The Introduction identifies APOE ε4 as increasing Alzheimer’s disease risk and ε2 as protective, but describes ε3 only as the most widespread isoform. The Methods include people with ε3/ε3 genotypes, but neither those passages nor the searched passages assess whether ε3 has a significant effect on disease risk. (LLM, conf=0.73)

  Experimental — accuracy not yet measured

ApoE4 is the strongest genetic risk factor for sporadic Alzheimer's disease.

“APOE ε4 allele (ApoE4) is the strongest genetic risk factor for sporadic AD [15]”

• cites [15] Zhao, 2020, APOE4 Exacerbates Synapse Loss and Neurodegeneration in Alzheimer’s Disease Patient IPSC-Derived Cerebral Organoids, Nat. Commun. sourceSupported

Carrying one copy of the APOE ε2 allele reduces the risk of developing Alzheimer's disease by about 40%.

“carrying one copy of the APOE ε2 allele (ApoE2) reduces the risk of developing AD by about 40% [17]”

• cites [17] Das, 2021, APOE and Alzheimer’s Disease: Advances in Genetics, Pathophysiology, and Therapeutic Approaches, Lancet Neurol. sourceSupported

Carrying one copy of the APOE ε4 allele increases the risk of developing Alzheimer's disease by about 3 to 7 times.

“Carrying one copy of this allele increases the risk of developing AD by about 3 to 7 times”

• cites [17] Das, 2021, APOE and Alzheimer’s Disease: Advances in Genetics, Pathophysiology, and Therapeutic Approaches, Lancet Neurol. sourcePartly supported

  Panel 1 (Apolipoprotein E basic facts; page not specified) says that, relative to APOE ε3/ε3, possessing one ε4 allele increases Alzheimer’s disease risk by approximately 3.7 times. That supports an increase of roughly three to four times, but the passage does not give a range extending to seven times for one copy. (LLM, conf=0.85)

  Experimental — accuracy not yet measured

P-tau is highly susceptible to aggregation, forming insoluble oligomers and NFTs.

“P-tau is highly susceptible to aggregation, forming insoluble oligomers and NFTs”

• cites [5] Long, 2019, Alzheimer Disease: An Update on Pathobiology and Treatment Strategies, Cell sourcePartly supported

  The Pathophysiology of AD > Tau section says aberrant phosphorylation is thought to promote tau aggregation and fibrillization. It also says tau can form oligomers and fibrils, and that NFTs contain insoluble tau fibrils. It does not describe phosphorylated tau as highly susceptible to aggregation or say that the oligomers are insoluble. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

ApoE4 is the least stable among the three ApoE isoforms.

“which makes this protein the least stable among the three ApoE isoforms [24].”

• cites [24] Kloske, 2020, The Important Interface Between Apolipoprotein E and Neuroinflammation in Alzheimer’s Disease, Front. Immunol. sourceSupported

ApoE4 is less efficient than ApoE3 in transporting brain cholesterol.

“ApoE4 was also suggested to be less efficient than ApoE3 in transporting brain cholesterol [33]”

• cites [33] Liu, 2013, Apolipoprotein e and Alzheimer Disease: Risk, Mechanisms and Therapy, Nat. Rev. Neurol. sourceSupported

ApoE4 assumes a pathological conformation due to an interaction between arginine-61 and glutamate-255 at the N-terminal and C-terminal domains.

“ApoE4 assumes a pathological conformation due to the interaction between arginine −61 and glutamate −255, at the N-terminal and the C-terminal domains, respectively [22].”

• cites [22] Chen, 2011, Apolipoprotein E4 Domain Interaction Mediates Detrimental Effects on Mitochondria and Is a Potential Therapeutic Target for Alzheimer Disease, J. Biol. Chem. sourceSupported

ApoE4 fragmentation occurs in a brain region-dependent way, preferentially in the neocortex and hippocampus of NSE-ApoE4 transgenic mice.

“ApoE4 fragmentation occurs in a brain region-dependent way, preferentially in the neocortex and hippocampus of neuron-specific enolase (NSE)-ApoE4 transgenic mice”

• cites [30] Brecht, 2004, Neuron-Specific Apolipoprotein E4 Proteolysis Is Associated with Increased Tau Phosphorylation in Brains of Transgenic Mice, J. Neurosci. sourceSupported

Carrying two copies of the APOE ε4 allele increases the risk of developing Alzheimer's disease up to 12 times.

“while carrying two copies increases the risk up to 12 times [17]”

• cites [17] Das, 2021, APOE and Alzheimer’s Disease: Advances in Genetics, Pathophysiology, and Therapeutic Approaches, Lancet Neurol. sourceSupported

ApoE4 directly interacts with promoter region of MADD, ADNP, COMMD6 and PPP2R5E genes, decreasing their expression.

“ApoE4 also directly interacts with the promoter region of MAPK activating death domain (MADD), activity dependent neuroprotector homeobox (ADNP), COMM domain containing 6 (COMMD6) and protein phosphatase 2, regulatory subunit B’, epsilon isoform (PPP2R5E) genes, decreasing their expression.”

• cites [37] Theendakara, 2016, Direct Transcriptional Effects of Apolipoprotein E, J. Neurosci. sourcePartly supported

  The Discussion says ChIP-seq found ApoE4 interactions with the MADD, ADNP, and COMMD6 promoters and reports reduced transcription of those genes. Table 3 lists PPP2R5E among genes associated with ApoE4 binding, but the paper does not report decreased PPP2R5E expression. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites [43] Theendakara, 2018, Transcriptional Effects of ApoE4: Relevance to Alzheimer’s Disease, Mol. Neurobiol. sourceNot checked — no full text of the source

Mutations in mtDNA are more common in brains of AD patients than in age-matched controls.

“Mutations in mitochondrial DNA (mtDNA) may be involved in mitochondrial dysfunction in AD, since they are more common in the brains of AD patients than in those of age-matched controls [22].”

• cites [22] Chen, 2011, Apolipoprotein E4 Domain Interaction Mediates Detrimental Effects on Mitochondria and Is a Potential Therapeutic Target for Alzheimer Disease, J. Biol. Chem. sourceSupported

Decrease in mitochondrial respiratory complex IV activity was observed in autopsy brains from young ApoE4 carriers.

“a decrease in mitochondrial respiratory complex IV activity was observed in autopsy brains from young ApoE4 carriers [74]”

• cites [74] Valla, 2010, Reduced Posterior Cingulate Mitochondrial Activity in Expired Young Adult Carriers of the APOE Ε4 Allele, the Major Late-Onset Alzheimer’s Susceptibility Gene, J. Alzheimer’s Dis. sourceSupported

Astrocytes expressing ApoE4 exhibit higher cytosolic levels of Ca2+, mainly through ER IP3R-mediated release.

“astrocytes expressing ApoE4 exhibit higher cytosolic levels of Ca2+, mainly through ER inositol 1,4,5-trisphosphate receptor (IP3R)-mediated release [57].”

• cites [57] Perea, 2020, Sex-Dependent Calcium Hyperactivity Due to Lysosomal-Related Dysfunction in Astrocytes from APOE4 versus APOE3 Gene Targeted Replacement Mice, Mol. Neurodegener. sourcePartly supported

  The Results report greater stimulus-evoked cytosolic Ca2+ responses in APOE4 than APOE3 astrocytes, but not generally higher resting levels; another Results passage reports lower basal Ca2+ in APOE4 cells. The proposed main mechanism is also wrong: the Results say ER release is only slightly increased and cannot alone explain the larger responses, while the Discussion identifies increased release from acidic stores as the key difference (pages not available in our copy). (LLM, conf=0.90)

  Experimental — accuracy not yet measured

ApoE4 is associated with decreased ability of astrocytes to control oxidative stress.

“and to control oxidative stress [56].”

• cites [56] Abramov, 2004, Calcium Signals Induced by Amyloid β Peptide and Their Consequences in Neurons and Astrocytes in Culture, Biochim. Biophys. Acta (BBA) Mol. Cell Res. sourcePartly supported

  Section 1.4 reports that amyloid-β increases oxidative stress in astrocytes and depletes glutathione; the paper also describes a resulting failure of antioxidant support. Those passages concern amyloid-β exposure, not ApoE4, so they do not support the claimed association with ApoE4. (LLM, conf=0.78)

  Experimental — accuracy not yet measured

Decreased total ApoE levels are possibly related to potentiation of tau pathology through enhanced LRP-1 mediated tau propagation.

“which is possibly related to the potentiation of tau pathology throw enhanced LRP-1 mediated tau propagation [52]”

• cites [52] Rauch, 2020, LRP1 Is a Master Regulator of Tau Uptake and Spread, Nature sourceSupported

ApoE4 potentiates inflammatory cascades.

“ApoE4 potentiates inflammatory cascades, modifies microglial phenotype towards a proinflammatory profile and promotes APP-mediated activation of microglia [17]”

• cites [17] Das, 2021, APOE and Alzheimer’s Disease: Advances in Genetics, Pathophysiology, and Therapeutic Approaches, Lancet Neurol. sourceSupported

ApoE4 promotes APP-mediated activation of microglia.

“ApoE4 potentiates inflammatory cascades, modifies microglial phenotype towards a proinflammatory profile and promotes APP-mediated activation of microglia [17]”

• cites [17] Das, 2021, APOE and Alzheimer’s Disease: Advances in Genetics, Pathophysiology, and Therapeutic Approaches, Lancet Neurol. sourcePartly supported

  The ‘Effects on glia’ section reports that APOE4 microglia are primed toward a proinflammatory phenotype and that APOE and TREM2 influence microglial responses to Aβ plaques. It does not establish that APOE4 promotes APP-mediated activation of microglia; it also reports no difference between APOE ε4 carriers and non-carriers in activated microglia per Aβ plaque in the post-mortem sections studied. Page numbers are unavailable in our copy. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

Mitochondrial depolarization was observed in neurons subjected to oligomeric Aβ1-42 direct exposure.

“mitochondrial depolarization was observed in neurons subjected to oligomeric Aβ1–42 direct exposure [63].”

• cites [63] Peng, 2020, Central and Peripheral Metabolic Defects Contribute to the Pathogenesis of Alzheimer’s Disease: Targeting Mitochondria for Diagnosis and Prevention, Antioxid. Redox Signal. sourcePartly supported

  The “Ab and mitochondria” section says Aβ can decrease mitochondrial membrane potential, supporting the depolarization mechanism. It does not specify an observation in neurons directly exposed to oligomeric Aβ1–42; the separate report of reduced membrane potential concerns transgenic APP mouse brains, not that exposure condition. Page numbers are unavailable in our copy. (LLM, conf=0.84)

  Experimental — accuracy not yet measured

ApoE4 (272-299 aa fragment) increases ROS levels in N2a cell line.

“ApoE4 (272–299 aa fragment) was demonstrated to increase ROS levels in N2a cell line [28,73]”

• cites [28] Liang, 2021, ApoE4 (Δ272–299) Induces Mitochondrial-associated Membrane Formation and Mitochondrial Impairment by Enhancing GRP75-Modulated Mitochondrial Calcium Overload in Neuron, Cell Biosci. sourcePartly supported

  The Results section, “ApoE4 (Δ272–299) changes mitochondrial morphology and function,” reports significantly increased ROS in N2a cells expressing apoE4 (Δ272–299). The Introduction identifies this as a C-terminally truncated apoE4 fragment produced by cleavage at residue 272, not a fragment consisting of amino acids 272–299. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites [73] Orr, 2019, Neuronal Apolipoprotein E4 Expression Results in Proteome-Wide Alterations and Compromises Bioenergetic Capacity by Disrupting Mitochondrial Function, J. Alzheimer’s Dis. sourcePartly supported

  The Results (Fig. 3B; page unavailable) report approximately twofold higher ROS levels in N2a cells expressing apoE4 than in cells expressing apoE3. But Materials and Methods (Cell lines; page unavailable) specifies full-length apoE4, not a 272–299 amino-acid fragment, so the fragment-specific claim is not supported. (LLM, conf=0.90)

  Experimental — accuracy not yet measured

ApoE4 is associated with decreased ability of astrocytes to maintain Ca2+ and K+ homeostasis.

“it has been proposed that ApoE4 is associated to a decreased ability of astrocytes to maintain Ca2+ and K+ homeostasis [24]”

• cites [24] Kloske, 2020, The Important Interface Between Apolipoprotein E and Neuroinflammation in Alzheimer’s Disease, Front. Immunol. sourcePartly supported

  The “Astrocytes in Neuroinflammation” section says that astrocytes in Alzheimer’s disease can lose their ability to maintain calcium levels and potassium homeostasis. It does not attribute that specific loss to ApoE4, so the ApoE4 association in the citing sentence is not supported by this passage. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

This increase in ROS levels correlates with increased ER stress and enhanced MAM formation by favoring mitochondria-ER direct interaction.

“which was shown to correlate with increased ER stress and enhanced MAM formation by favoring mitochondria-ER direct interaction [28].”

• cites [28] Liang, 2021, ApoE4 (Δ272–299) Induces Mitochondrial-associated Membrane Formation and Mitochondrial Impairment by Enhancing GRP75-Modulated Mitochondrial Calcium Overload in Neuron, Cell Biosci. sourceSupported

Association between ApoE4 expression and mitochondrial Ca2+ overload was observed in in vitro models, such as Neuro-2 A cells, stem-cell-derived forebrain excitatory neurons and rat hippocampal neurons.

“an association between ApoE4 expression and mitochondrial Ca2+ overload was observed in in vitro models, such as Neuro-2 A cells [28,73], stem-cell-derived forebrain excitatory neurons [50] and rat hippocampal neurons [30].”

• cites [28] Liang, 2021, ApoE4 (Δ272–299) Induces Mitochondrial-associated Membrane Formation and Mitochondrial Impairment by Enhancing GRP75-Modulated Mitochondrial Calcium Overload in Neuron, Cell Biosci. sourceSupported
• cites [73] Orr, 2019, Neuronal Apolipoprotein E4 Expression Results in Proteome-Wide Alterations and Compromises Bioenergetic Capacity by Disrupting Mitochondrial Function, J. Alzheimer’s Dis. sourceSupported
• cites [50] Wadhwani, 2019, Neuronal Apolipoprotein E4 Increases Cell Death and Phosphorylated Tau Release in Alzheimer Disease, Ann. Neurol. sourcePartly supported

  The Results (page unavailable) show that ApoE4-expressing stem-cell-derived forebrain excitatory neurons were more susceptible than isogenic E3 neurons to ionomycin-induced calcium dysregulation and cell death. The paper does not report mitochondrial Ca2+ overload in those neurons, so the mitochondrial-specific part attributed to this source is unsupported. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

In ApoE4-expressing N2a cells, decrease in respiration rates and ATP production, showing poorer ability to respond to high energy demands relative to ApoE3-expressing cells.

“in other studies performed in ApoE4-expressing N2a cells, the authors demonstrated a decrease in respiration rates and ATP production, showing a poorer ability to respond to high energy demands relative to ApoE3-expressing cells [73].”

• cites [73] Orr, 2019, Neuronal Apolipoprotein E4 Expression Results in Proteome-Wide Alterations and Compromises Bioenergetic Capacity by Disrupting Mitochondrial Function, J. Alzheimer’s Dis. sourceSupported

ApoE4 modifies microglial phenotype towards a proinflammatory profile.

“ApoE4 potentiates inflammatory cascades, modifies microglial phenotype towards a proinflammatory profile and promotes APP-mediated activation of microglia [17]”

• cites [17] Das, 2021, APOE and Alzheimer’s Disease: Advances in Genetics, Pathophysiology, and Therapeutic Approaches, Lancet Neurol. sourceSupported

Aberrant tau phosphorylation and aggregation promote neuronal and synaptic damage, leading to cognitive decline in AD, through alterations in mitochondrial localization, imbalance in fusion/fission, ATP synthesis, ROS production and mitochondrial depolarization.

“Through alterations in mitochondrial localization in neurons, imbalance in fusion and fission processes and in ATP synthesis, ROS production and mitochondrial depolarization, aberrant tau phosphorylation and aggregation promote neuronal and synaptic damage, leading to cognitive decline in AD [66].”

• cites [66] Cheng, 2018, The Association of Tau with Mitochondrial Dysfunction in Alzheimer’s Disease, Front. Neurosci. sourceSupported

Several models of AD have demonstrated altered mitochondrial dynamics, not only in neurons, but also in astrocytes.

“Several models of AD have demonstrated altered mitochondrial dynamics, not only in neurons, but also in astrocytes [71].”

• cites [71] Schmukler, 2020, Altered Mitochondrial Dynamics and Function in APOE4-Expressing Astrocytes, Cell Death Dis. sourcePartly supported

  The Discussion reports altered mitochondrial dynamics in APOE4-expressing astrocytes and cites other studies of impaired mitophagy in AD neurons. It does not establish that several AD models have demonstrated the finding in astrocytes; its own astrocyte result concerns the APOE4 model. (LLM, conf=0.85)

  Experimental — accuracy not yet measured

ApoE4 accelerates tau pathology propagation through a trans-synaptic prion-like mechanism.

“which supports the hypothesis that ApoE4 accelerates tau pathology propagation, through a trans-synaptic prion-like mechanisms [50].”

• cites [50] Wadhwani, 2019, Neuronal Apolipoprotein E4 Increases Cell Death and Phosphorylated Tau Release in Alzheimer Disease, Ann. Neurol. sourceSupported

ApoE4 is associated with decreased fission and parkin-mediated mitophagy in APOE4 astrocytes.

“decreased fission and parkin-mediated mitophagy in APOE4 astrocytes [71].”

• cites [71] Schmukler, 2020, Altered Mitochondrial Dynamics and Function in APOE4-Expressing Astrocytes, Cell Death Dis. sourceSupported

Alterations in gene expression associated with ApoE4 potentiate apoptotic and inflammatory pathways.

“the referred alterations in gene expression associated to ApoE4 potentiate apoptotic and inflammatory pathways [37,43]”

• cites [37] Theendakara, 2016, Direct Transcriptional Effects of Apolipoprotein E, J. Neurosci. sourcePartly supported

  The Discussion (page not provided) reports ApoE4-associated repression of MADD, ADNP, and COMMD6, and the results report increased inflammatory cytokine expression. But the Discussion says these changes “could participate” in triggering inflammatory and apoptotic pathways; it does not establish that both pathways are potentiated as the claim states. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites [43] Theendakara, 2018, Transcriptional Effects of ApoE4: Relevance to Alzheimer’s Disease, Mol. Neurobiol. sourceNot checked — no full text of the source

Tau hyperphosphorylation and aggregation have been related to impairment of mitochondrial dynamics, namely axonal transport and bioenergetics.

“Tau hyperphosphorylation and aggregation have been related to the impairment of mitochondrial dynamics, namely axonal transport and bioenergetics.”

• cites [66] Cheng, 2018, The Association of Tau with Mitochondrial Dysfunction in Alzheimer’s Disease, Front. Neurosci. sourceSupported

Under some transfection conditions, ApoE4 has no effect on Δψm.

“other authors demonstrated that, under some transfection conditions, ApoE4 has no effect on Δψm [75].”

• cites [75] Nakamura, 2009, Apolipoprotein E4 (1-272) Fragment Is Associated with Mitochondrial Proteins and Affects Mitochondrial Function in Neuronal Cells, Mol. Neurodegener. sourceSupported

Characteristic glucose hypometabolism was observed in cognitively normal ApoE4 carriers.

“a characteristic glucose hypometabolism was observed in cognitively normal ApoE4 carriers [22].”

• cites [22] Chen, 2011, Apolipoprotein E4 Domain Interaction Mediates Detrimental Effects on Mitochondria and Is a Potential Therapeutic Target for Alzheimer Disease, J. Biol. Chem. sourceSupported

Other studies demonstrated association between ApoE4 and fission activation and fusion inhibition.

“other studies demonstrated an association between ApoE4 and fission activation and fusion inhibition [28]”

• cites [28] Liang, 2021, ApoE4 (Δ272–299) Induces Mitochondrial-associated Membrane Formation and Mitochondrial Impairment by Enhancing GRP75-Modulated Mitochondrial Calcium Overload in Neuron, Cell Biosci. sourcePartly supported

  The Results section reports that overexpression of ApoE4 (Δ272–299) increased pro-fission activity and decreased pro-fusion activity in transgenic mouse hippocampus and N2a cells. The citing sentence omits the Δ272–299 truncation and presents the finding as applying to ApoE4 generally; this paper's reported experiment does not establish that broader claim. (LLM, conf=0.85)

  Experimental — accuracy not yet measured

These alterations in N2a cells matched decrease in mitochondrial total respiratory capacity, through lower OCR after CCCP in Seahorse experiments, relative to ApoE3 expression.

“These alterations in N2a cells matched the decrease in mitochondrial total respiratory capacity, through a lower OCR (oxygen consumption rate) after stimulation with CCCP (Carboxyl cyanide m-chlorophenyl hydrazone), a mitochondrial uncoupler, in Seahorse experiments, relatively to ApoE3 expression [22].”

• cites [22] Chen, 2011, Apolipoprotein E4 Domain Interaction Mediates Detrimental Effects on Mitochondria and Is a Potential Therapeutic Target for Alzheimer Disease, J. Biol. Chem. sourceSupported

ApoE4-expressing astrocytes show morphological alterations, with fewer and shorter processes and elongated cell bodies.

“ApoE4-expressing astrocytes also show morphological alterations, with fewer and shorter processes and elongated cell bodies [55]”

• cites [55] Keable, A., O’Neill, R., MacGregor Sharp, M., Gatherer, M., Yuen, H.M., Johnston, D.A., Weller, R.O., and Carare, R.O. (2020). ApoE4 Astrocytes Secrete Basement Membranes Rich in Fibronectin and Poor in Laminin Compared to ApoE3 Astrocytes. IJMS, 21. sourceSupported

ApoE4 is associated with increased levels of neurotoxic and inflammatory cytokines (TNFα, IL-6, IL-1β) and nitric oxide released by microglia and astrocytes in different models of AD.

“Different studies have showed an association between this ApoE isoform and increased levels of neurotoxic and inflammatory cytokines, such as tumor necrosis factor α (TNFα), Interleukin-6 (IL-6), Interleukin-1β (IL-1β) and nitric oxide released by microglia and astrocytes, in different models of AD [24].”

• cites [24] Kloske, 2020, The Important Interface Between Apolipoprotein E and Neuroinflammation in Alzheimer’s Disease, Front. Immunol. sourcePartly supported

  In “Early Investigations of ApoE Isoforms’ Role on Inflammation” (page unavailable), the review reports higher brain TNFα and IL-6 in ApoE4 mice and greater nitric oxide release from ApoE4 microglia. “ApoE and Aβ” reports increased glial activity measured by IL-1β in an AD mouse model. The cited passages do not establish that astrocytes release the listed substances, and the TNFα/IL-6 finding comes from LPS-treated mice rather than an identified AD model. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

Overexpression of some MAM proteins in N2a cells expressing ApoE4, including VDAC1 and IP3R, in agreement with higher and faster Ca2+ flux from ER to mitochondria, comparing to ApoE3 expression.

“Other studies have also shown an overexpression of some MAM proteins in N2a cells expressing ApoE4, including voltage-dependent anion-selective channel 1 (VDAC1) and inositol 1,4,5-trisphosphate receptor (IP3R), in agreement with a higher and faster Ca2+ flux from the ER to mitochondria, comparing to ApoE3 expression [73].”

• cites [73] Orr, 2019, Neuronal Apolipoprotein E4 Expression Results in Proteome-Wide Alterations and Compromises Bioenergetic Capacity by Disrupting Mitochondrial Function, J. Alzheimer’s Dis. sourceSupported

ApoE4 activates LRP1 and subsequent intracellular signaling pathways, namely Wnt3/β-catenin/GSK3β pathway, that ultimately potentiates GSK3β-mediated tau hyperphosphorylation.

“ApoE4 activates LRP1 and subsequent intracellular signaling pathways, namely Wnt3/β-cathenin/GSK3β pathway, that ultimately potentiates GSK3β-mediated tau hyperphosphorylation [53,54]”

• cites [53] Hamdan, A.M.E., Alharthi, F.H.J., Alanazi, A.H., El-Emam, S.Z., Zaghlool, S.S., Metwally, K., Albalawi, S.A., Abdu, Y.S., Mansour, R.E.-S., and Salem, H.A. (2022). Neuroprotective Effects of Phytochemicals against Aluminum Chloride-Induced Alzheimer’s Disease through ApoE4/LRP1, Wnt3/β-Catenin/GSK3β, and TLR4/NLRP3 Pathways with Physical and Mental Activities in a Rat Model. Pharmaceuticals, 15. sourcePartly supported

  The Introduction links GSK3β overactivation to tau phosphorylation, supporting that part of the claim. But the Discussion says ApoE4 binding inhibits LRP1-mediated tau uptake and Aβ clearance, not that ApoE4 activates LRP1; it also says Wnt3/β-catenin activation inhibits tau hyperphosphorylation. Neither section establishes the claimed ApoE4-to-LRP1-to-Wnt signaling cascade. Page numbers are unavailable in our copy. (LLM, conf=0.87)

  Experimental — accuracy not yet measured
• cites [54] Leroy, 2010, Spectroscopic Studies of GSK3β Phosphorylation of the Neuronal Tau Protein and Its Interaction with the N-Terminal Domain of Apolipoprotein E, J. Biol. Chem. sourcePartly supported

  In “GSK3β Phospho-Tau and Apolipoprotein E” (page unavailable), the paper reports that GSK3β phosphorylates Tau and that the resulting phosphorylation pattern permits interaction with an apoE3 fragment. It does not show that apoE4 activates LRP1 or Wnt3/β-catenin signaling, or that apoE4 potentiates Tau hyperphosphorylation; it says the mechanism linking apoE4 to disease remains controversial. (LLM, conf=0.84)

  Experimental — accuracy not yet measured

Decrease in Δψm has been observed in several in vitro and in vivo AD models.

“A decrease in Δψm (or mitochondrial depolarization) has been observed in several in vitro and in vivo AD models [65,66]”

• cites [65] Onyango, 2016, Mitochondrial Dysfunction in Alzheimer’s Disease and the Rationale for Bioenergetics Based Therapies, Aging Dis. sourcePartly supported

  The Mitochondrial Membrane Potential section (page unavailable) reports decreased Δψm in AD animal models and human cortical neurons studied ex vivo. This supports the animal-model finding, but the paper describes the neuronal evidence as ex vivo, not as a finding in several in vitro AD models. (LLM, conf=0.83)

  Experimental — accuracy not yet measured
• cites [66] Cheng, 2018, The Association of Tau with Mitochondrial Dysfunction in Alzheimer’s Disease, Front. Neurosci. sourcePartly supported

  The ‘Tau pathology and mitochondrial dysfunction in AD’ section reports depolarized mitochondrial membrane potential in a triple-transgenic AD mouse model and impaired membrane potential associated with truncated tau. It also discusses cell-culture studies, but does not clearly establish decreased membrane potential across several in vitro and in vivo AD models. No page number is available in our copy. (LLM, conf=0.84)

  Experimental — accuracy not yet measured

Administration of ApoE-targeted ASO in an ApoE4-expressing mouse model of tauopathy protected against tau-associated neurodegeneration and other neuropathological features, namely synaptic disruption and neuroinflammation.

“The administration of ApoE-targeted ASO in an ApoE4-expressing mouse model of tauopathy, which is defined by the tau pathology common to AD, was also demonstrated to protect against tau-associated neurodegeneration and other neuropathological features of this disease, namely synaptic disruption and neuroinflammation [83].”

• cites [83] Litvinchuk, 2021, Apolipoprotein E4 Reduction with Antisense Oligonucleotides Decreases Neurodegeneration in a Tauopathy Model, Ann. Neurol. sourceSupported

Genome editing has not yet revealed effective results in animal models.

“Despite its promising results in vitro, genome editing has not yet revealed effective results in animal models [45] and its translation to clinics might be challenging.”

• cites [45] Safieh, 2019, ApoE4: An Emerging Therapeutic Target for Alzheimer’s Disease, BMC Med. sourcePartly supported

  The “Gene editing of APOE4 by CRISPR” section reports successful cell-culture editing but says successful in vivo application to apoE4 mice had not yet been reported. This supports the claim for APOE4-targeted CRISPR, not its unqualified wording about genome editing in animal models generally. (LLM, conf=0.84)

  Experimental — accuracy not yet measured

ABCA1 agonists decreased ApoE and ABCA1 aggregation in the hippocampus of ApoE4-targeted replacement mice.

“ABCA1 agonists also rescued impaired Aβ degradation in ApoE4 cells and further decreased ApoE and ABCA1 aggregation in the hippocampus of ApoE4-targeted replacement mice [88].”

• cites [88] Rawat, 2019, ApoE4 Alters ABCA1 Membrane Trafficking in Astrocytes, J. Neurosci. sourceSupported

Treating ApoE4-expressing iPSC-derived neurons with PH002 ameliorated the toxic effects induced by ApoE4.

“Additionally, treating ApoE4-expressing iPSC-derived neurons with PH002, another structure corrector, was able to ameliorate the toxic effects induced by this isoform of ApoE, by reducing ApoE4 detrimental effect on neurite outgrowth in Neuro-2a cells and dendritic spine development in primary neurons [85], increasing the number of GABAergic neurons and reducing P-tau, Aβ40 and Aβ42 levels [86].”

• cites [85] Brodbeck, 2011, Structure-dependent impairment of intracellular apolipoprotein E4 trafficking and its detrimental effects are rescued by small-molecule structure correctors, J. Biol. Chem. sourceSupported
• cites [86] Wang, 2018, Gain of Toxic Apolipoprotein E4 Effects in Human IPSC-Derived Neurons Is Ameliorated by a Small-Molecule Structure Corrector, Nat. Med. sourceSupported

Collagenase, MMP-9, neuron-specific α-chymotrypsin-like serine protease, cathepsin D and HtrA1 are proteases able to cleave ApoE4 into neurotoxic fragments.

“Nevertheless, as previously mentioned in this review, some authors identified collagenase, MMP-9, neuron-specific α-chymotrypsin-like serine protease, cathepsin D and HtrA1 as some of the proteases that are able to cleave ApoE4 into neurotoxic fragments.”

• cites [11] Huang, 2012, Alzheimer Mechanisms and Therapeutic Strategies, Cell sourcePartly supported

  The ApoE4 section reports that proteolytic cleavage of neuronal apoE4 produces neurotoxic fragments. However, the paper does not identify collagenase, MMP-9, neuron-specific α-chymotrypsin-like serine protease, cathepsin D, or HtrA1 as the enzymes responsible. The “Targeting ApoE4” section instead proposes identifying the protease that cleaves apoE4. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites [21] Vecchio, 2022, Are Apolipoprotein E Fragments a Promising New Therapeutic Target for Alzheimer’s Disease?, Ther. Adv. Chronic Dis. sourcePartly supported

  The ‘ApoE-cutting enzymes’ section identifies cathepsin D, α-chymotrypsin-like serine protease and HtrA1 as ApoE-cutting enzymes, and says MMP-9 probably mediates fragmentation. It also says ApoE4 cleavage produces more neurotoxic fragments than ApoE3 cleavage. The copy does not identify collagenase as an ApoE-cutting enzyme or establish that each listed protease produces neurotoxic fragments. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites [45] Safieh, 2019, ApoE4: An Emerging Therapeutic Target for Alzheimer’s Disease, BMC Med. sourcePartly supported

  The “ApoE degradation” section (page unavailable) says that distinct proteases can generate neurotoxic ApoE4 fragments. It does not identify collagenase, MMP-9, neuron-specific α-chymotrypsin-like serine protease, cathepsin D, or HtrA1 as those proteases. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

Recent study showed upregulation of molecular pathways related to cellular and ER stress, namely chaperone-mediated protein folding and unfolded protein response, in distinct cell types of human post-mortem brain tissue.

“a recent study showed the upregulation of molecular pathways related to cellular and ER stress, namely in chaperone-mediated protein folding and unfolded protein response, in distinct cell types of human post-mortem brain tissue [36].”

• cites [36] Blanchard, 2022, APOE4 Impairs Myelination via Cholesterol Dysregulation in Oligodendrocytes, Nature sourceSupported

ABCA1 agonists rescued impaired Aβ degradation in ApoE4 cells.

“ABCA1 agonists also rescued impaired Aβ degradation in ApoE4 cells and further decreased ApoE and ABCA1 aggregation in the hippocampus of ApoE4-targeted replacement mice [88].”

• cites [88] Rawat, 2019, ApoE4 Alters ABCA1 Membrane Trafficking in Astrocytes, J. Neurosci. sourceSupported

ApoE4 is associated with deregulation in mRNA levels of genes encoding for subunits of mitochondrial respiratory complexes, encoded by nuclear and mitochondrial DNA.

“Other studies demonstrated that ApoE4 is associated to a deregulation in mRNA levels of genes encoding for subunits of mitochondrial respiratory complexes (Figure 1), encoded by nuclear and mitochondrial DNA [22]”

• cites [22] Chen, 2011, Apolipoprotein E4 Domain Interaction Mediates Detrimental Effects on Mitochondria and Is a Potential Therapeutic Target for Alzheimer Disease, J. Biol. Chem. sourceSupported

GIND25, by blocking ApoE4 domain interaction, modifies the ApoE4 protein tertiary structure into an ApoE3-like conformation.

“By blocking ApoE4 domain interaction, GIND25 was then able to modify the protein tertiary structure into an ApoE3-like conformation, which is proposed to underly the ablation of its neurotoxic effects [85].”

• cites [85] Brodbeck, 2011, Structure-dependent impairment of intracellular apolipoprotein E4 trafficking and its detrimental effects are rescued by small-molecule structure correctors, J. Biol. Chem. sourceSupported

By affecting NRF1 transcriptional role, ApoE4 influences expression of its target genes, potentially involved in mitochondrial dynamics and Ca2+ handling.

“By affecting NRF1 transcriptional role, ApoE4 then influences the expression of its target genes, potentially involved in mitochondrial dynamics and Ca2+ handling [37].”

• cites [37] Theendakara, 2016, Direct Transcriptional Effects of Apolipoprotein E, J. Neurosci. sourcePartly supported

  The Discussion reports that ApoE4 binds gene promoters and reduces transcription of SirT1, MADD, ADNP, and COMMD6. But our copy does not identify NRF1 as the mediator or establish that changes to NRF1 target genes affect mitochondrial dynamics or Ca2+ handling (searched: NRF1, mitochondrial dynamics, calcium handling). (LLM, conf=0.86)

  Experimental — accuracy not yet measured

ApoE3 and ApoE2 proteins are less susceptible to proteolytical cleavage than ApoE4 due to their structural properties.

“To genetically convert ApoE4 into ApoE3 or ApoE2 proteins would be also hypothetically effective in reducing ApoE fragments since their structural properties make these proteins less susceptible to proteolytical cleavage; this would also protect against AD-related phenotypical alterations that have been extensively attributed to ApoE4 [17].”

• cites [17] Das, 2021, APOE and Alzheimer’s Disease: Advances in Genetics, Pathophysiology, and Therapeutic Approaches, Lancet Neurol. sourcePartly supported

  In “Effects on Aβ” (page not provided), the paper says APOE4’s conformation could increase its propensity for enzymatic cleavage relative to APOE3 and APOE2, producing more C-terminal fragments. The citing sentence presents that proposed structural mechanism as an established cause of lower cleavage susceptibility in APOE3 and APOE2. (LLM, conf=0.85)

  Experimental — accuracy not yet measured

CRISPR/Cas9 conversion of APOE ε4 into APOE ε3 in neuronal, astrocytic and microglial cells from iPSCs derived from LOAD patients led to attenuation of some AD-related pathologies, namely Aβ glial uptake.

“CRISPR/Cas9 technology, which allow precise genetic modifications, was used to convert APOE ε4 into APOE ε3 in neuronal, astrocytic and microglial cells types from iPSCs derived from LOAD patients, which led to the attenuation of some AD-related pathologies, namely Aβ glial uptake [39].”

• cites [39] Lin, 2018, APOE4 Causes Widespread Molecular and Cellular Alterations Associated with Alzheimer’s Disease Phenotypes in Human IPSC-Derived Brain Cell Types, Neuron sourcePartly supported

  The Results section ('Converting APOE4 to APOE3 attenuates AD-related phenotypes') reports CRISPR/Cas9 editing of patient-derived iPSCs, followed by differentiation into neurons, astrocytes and microglia-like cells. It says the conversion enhanced Aβ uptake by astrocytes and microglia-like cells—not that Aβ glial uptake itself was attenuated. No page number is supplied in our copy. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

ApoE4 is associated with altered cholesterol and other lipids metabolic pathways in distinct cell types, through modified transcriptomics.

“these authors demonstrated that ApoE4 is associated to altered cholesterol and other lipids metabolic pathways in distinct cell types, through modified transcriptomics [36].”

• cites [36] Blanchard, 2022, APOE4 Impairs Myelination via Cholesterol Dysregulation in Oligodendrocytes, Nature sourceSupported

In ApoE4-expressing N2a cells, pharmacological treatment with GIND25 reverted some AD-related mitochondrial alterations, restoring Cx IV levels.

“In this respect, ApoE4-expressing N2a cells pharmacologically treated with GIND25, a small molecule that is able to disrupt ApoE4 domain interaction, reverted some AD-related mitochondrial alterations, namely by restoring Cx IV levels [22].”

• cites [22] Chen, 2011, Apolipoprotein E4 Domain Interaction Mediates Detrimental Effects on Mitochondria and Is a Potential Therapeutic Target for Alzheimer Disease, J. Biol. Chem. sourceSupported

Pharmacological treatment of ApoE4-TR mice with cyclodextrin improved learning and memory function.

“Pharmacological treatment of ApoE4-TR mice with this molecule was also able to improve learning and memory function [36].”

• cites [36] Blanchard, 2022, APOE4 Impairs Myelination via Cholesterol Dysregulation in Oligodendrocytes, Nature sourceSupported

Administration of ASOs lowered ApoE levels in APOE ε4 homozygous mice, which prevented Aβ plaque formation or related toxicity in an age-dependent way.

“a previous study in APP/PS1 mice showed that administration of ASOs lowered ApoE levels in APOE ε4 homozygous mice, which prevented Aβ plaque formation or related toxicity in an age-dependent way [82].”

• cites [82] Huynh, 2017, Age-Dependent Effects of ApoE Reduction Using Antisense Oligonucleotides in a Model of β-Amyloidosis, Neuron sourcePartly supported

  The Results report that ASOs lowered apoE in APOE4/4 mice and that treatment begun at birth reduced Aβ plaque area by about 50%. Treatment begun at six weeks did not significantly reduce overall plaque load, although it reduced plaque-associated dystrophic neurites. The paper supports age-dependent reductions in pathology, not prevention of plaque formation or related toxicity. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

ApoE4 interacts directly with NFTs in AD brains.

“ApoE4 has been demonstrated to interact directly with NFTs in AD brains”

• cites [51] Huang, 2001, Apolipoprotein E Fragments Present in Alzheimer’s Disease Brains Induce Neurofibrillary Tangle-like Intracellular Inclusions in Neurons, Proc. Natl. Acad. Sci. USA sourceNot checked — no full text of the source

ApoE4 prevents Aβ enzymatic degradation through blockade of astrocytic NEP and MMP-9, or the extracellular insulin-degrading enzyme (IDE).

“ApoE4 also prevents Aβ enzymatic degradation, through the blockade of astrocytic NEP and MMP-9, or the extracellular insulin-degrading enzyme (IDE).”

• cites [43] Theendakara, 2018, Transcriptional Effects of ApoE4: Relevance to Alzheimer’s Disease, Mol. Neurobiol. sourceNot checked — no full text of the source

Aβ accumulation and increased levels of extracellular senile plaques may be justified by defective clearance and astrogliosis.

“Apart from the direct interaction between ApoE4 and Aβ species, Aβ accumulation and increased levels of extracellular senile plaques may be justified by defective clearance and astrogliosis.”

LOAD patients carrying the ApoE4 allele, as opposed to ApoE3 carriers, show a decrease by about 50% in the levels of hippocampal IDE protein.

“LOAD patients carrying the ApoE4 allele, as opposed to ApoE3 carriers, show a decrease by about 50% in the levels of hippocampal IDE protein”

• cites [43] Theendakara, 2018, Transcriptional Effects of ApoE4: Relevance to Alzheimer’s Disease, Mol. Neurobiol. sourceNot checked — no full text of the source

ApoE4 is associated with a greater accumulation of Aβ peptide compared to other ApoE genetic variations.

“Primary studies showed that ApoE4 is associated with a greater accumulation of Aβ peptide, comparing to other ApoE genetic variations.”

ApoE4 fragments are suggested to play an essential role in ApoE4 neurotoxicity.

“the resulting fragments are suggested to play an essential role in ApoE4 neurotoxicity [23].”

• cites [23] Saul, 2017, Endogenous Apolipoprotein E (ApoE) Fragmentation Is Linked to Amyloid Pathology in Transgenic Mouse Models of Alzheimer’s Disease, Mol. Neurobiol. sourceNot checked — no full text of the source

Contradictory ApoE4 data may be accounted for by the differential effects exerted by each one of its fragments.

“Based on these observations, contradictory ApoE4 data may be accounted for by the differential effects exerted by each one of its fragments.”

ApoE4 is more susceptible to proteolytical cleavage than ApoE2 and ApoE3.

“Due to this structural property, ApoE4 is more susceptible to proteolytical cleavage than ApoE2 and ApoE3 [23].”

• cites [23] Saul, 2017, Endogenous Apolipoprotein E (ApoE) Fragmentation Is Linked to Amyloid Pathology in Transgenic Mouse Models of Alzheimer’s Disease, Mol. Neurobiol. sourceNot checked — no full text of the source

ApoE4 fragments with 14 to 20 kDa have been found in the brain of Alzheimer's disease patients carrying the APOE ε4 allele.

“Fragments with 14 to 20 kDa have been found in the brain of AD patients carrying the APOE ε4 allele [27]”

• cites [27] Love, 2017, Nuclear Uptake of an Amino-Terminal Fragment of Apolipoprotein E4 Promotes Cell Death and Localizes within Microglia of the Alzheimer’s Disease Brain, Int. J. Physiol. Pathophysiol. Pharmacol.Not checked — no full text of the source

ApoE4 is related to tau protein.

“ApoE4 is not only related to Aβ, but also to tau protein.”

ApoE4 potentiates the aggregation of P-tau into NFT-like inclusions in transfected primary neurons.

“this ApoE isoform potentiates the aggregation of P-tau into NFT-like inclusions in transfected primary neurons [51]”

• cites [51] Huang, 2001, Apolipoprotein E Fragments Present in Alzheimer’s Disease Brains Induce Neurofibrillary Tangle-like Intracellular Inclusions in Neurons, Proc. Natl. Acad. Sci. USA sourceNot checked — no full text of the source

These findings suggest that an imbalance in mitochondrial dynamics rather than a defined effect may underlie ApoE4-mediated mitochondrial dysfunction.

“these findings suggest that an imbalance in mitochondrial dynamics rather than a defined effect may underlie ApoE4-mediated mitochondrial dysfunction.”

ApoE4 has a negative effect on the protective anti-inflammatory role of glial cells compared to other isoforms.

“ApoE4 per se has a negative effect on this role of glial cells compared to other isoforms.”

ApoE4 induces neuroinflammation.

“which induces neuroinflammation.”

Relationship between ApoE4, AD and mitochondrial function and dynamics is connected to ApoE4 role as transcription factor.

“the relationship between ApoE4, AD and mitochondrial function and dynamics is straightforwardly connected to ApoE4 role as a transcription factor.”

Direct intracerebroventricular injection of mAb 9D11 prevented ApoE4-mediated accumulation of Aβ in hippocampal neurons by inhibiting neprilysin, an Aβ-degrading enzyme.

“Direct intracerebroventricular injection of mAb 9D11 prevented ApoE4-mediated accumulation of Aβ in hippocampal neurons by inhibiting neprilysin, an Aβ-degrading enzyme.”

• cites [84] Luz, 2016, An Anti-apoE4 Specific Monoclonal Antibody Counteracts the Pathological Effects of apoE4 In Vivo, Curr. Alzheimer Res. sourceNot checked — no full text of the source

ABCA1 agonists reduce ApoE4-mediated Aβ42 accumulation and tau hyperphosphorylation in hippocampal neurons.

“Thus, using ABCA1 agonists allows ApoE4 lipidation and was shown to reduce ApoE4-mediated Aβ42 accumulation and tau hyperphosphorylation in hippocampal neurons, as well as rescue synaptic impairments and cognitive deficits in ApoE4-targeted replacement mice [87].”

• cites [87] Bar, 2016, ABCA1 Agonist Reverses the ApoE4-Driven Cognitive and Brain Pathologies, J. Alzheimers Dis. sourceNot checked — no full text of the source

Administration of anti-ApoE4 antibodies attenuates Aβ pathology, neurodegeneration and cognitive impairments in ApoE4-expressing mouse models of AD.

“Thus, administration of anti-ApoE4 antibodies attenuates Aβ pathology, neurodegeneration and cognitive impairments in ApoE4-expressing mouse models of AD [84].”

• cites [84] Luz, 2016, An Anti-apoE4 Specific Monoclonal Antibody Counteracts the Pathological Effects of apoE4 In Vivo, Curr. Alzheimer Res. sourceNot checked — no full text of the source

By activating MAPK cascade, ApoE4 promotes APP expression and Aβ production.

“By activating a MAPK cascade, ApoE4 also promotes APP expression and Aβ production, proposing a clear impact on AD progression [43].”

• cites [43] Theendakara, 2018, Transcriptional Effects of ApoE4: Relevance to Alzheimer’s Disease, Mol. Neurobiol. sourceNot checked — no full text of the source

These data suggest a safe and effective AD gene therapy using surface-modified liposomes for brain-targeted delivery of APOE2 gene.

“These data suggest a safe and effective AD gene therapy using surface-modified liposomes for brain-targeted delivery of APOE2 gene.”

Using ABCA1 agonists allows ApoE4 lipidation.

“Thus, using ABCA1 agonists allows ApoE4 lipidation and was shown to reduce ApoE4-mediated Aβ42 accumulation and tau hyperphosphorylation in hippocampal neurons, as well as rescue synaptic impairments and cognitive deficits in ApoE4-targeted replacement mice [87].”

• cites [87] Bar, 2016, ABCA1 Agonist Reverses the ApoE4-Driven Cognitive and Brain Pathologies, J. Alzheimers Dis. sourceNot checked — no full text of the source

ApoE4 is hypolipidated compared to other ApoE isoforms.

“Comparing to the other ApoE isoforms, ApoE4 is hypolipidated, which prevents its binding to soluble and fibrillar forms of Aβ and enhances its accumulation.”