ApoE4 reduction: An emerging and promising therapeutic strategy for Alzheimer's disease

May combine two claims.

Human iPSC-derived neurons and organoids confirm that apoE4 increases Aβ production and aggregation and decreases Aβ clearance.

“Studies with human iPSC-derived neurons and organoids confirm that apoE4 increases Aβ production and aggregation as well as decreases Aβ clearance”

• cites Lin et al 2018 sourcePartly supported

  The Results report increased Aβ42 secretion, but unchanged Aβ40 secretion, from APOE4 neurons; they do not establish an unqualified increase in Aβ production. The Results also show more Aβ aggregates in six-month-old APOE4 organoids and less Aβ42 clearance by APOE4 astrocytes. The Discussion describes increased neuronal Aβ generation as a possible contributor, rather than a confirmed mechanism. (LLM, conf=0.84)

  Experimental — accuracy not yet measured
• cites Wang et al 2018 sourcePartly supported

  The Results section, “Human apoE4/4 neurons produce more Aβ than human apoE3/3 neurons” (page unavailable), reports that human iPSC-derived apoE4/4 neurons secreted more than twice as much Aβ40 and Aβ42 as apoE3/3 neurons. It does not report organoid experiments or show increased Aβ aggregation or decreased clearance in those neurons. The reduced-clearance finding is described there and in the Discussion as a finding from mouse studies, not this paper’s human-neuron experiments. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites Zhao et al 2020 sourceDisputed

  The Results section (‘Increased Aβ amounts in cerebral organoids from AD-iPSCs’; page not provided) says Aβ increases in AD organoids were independent of APOE4, APP processing was unaffected, and insoluble Aβ was undetectable. The Discussion likewise says neither APOE4 nor apoE amounts influenced Aβ levels in these organoids; it raises impaired clearance as a possibility for AD organoids, not as an established effect of APOE4. (LLM, conf=0.88)

  Checked by a reasoning model — may be wrong.

  Experimental — accuracy not yet measured

May combine two claims.

Overexpression of a functional LRP1 minireceptor resulted in a 25% reduction of brain apoE levels but an age-dependent increase of soluble Aβ in the brain of PDAPP transgenic mice.

“overexpression of a functional LRP1 minireceptor resulted in a 25% reduction of brain apoE levels, there was an age-dependent increase of soluble Aβ in the brain of PDAPP transgenic mice”

• cites Zerbinatti et al 2004 sourceDisputed

  The Results and Discussion report an age-dependent increase in soluble brain Aβ in PDAPP mice overexpressing the LRP minireceptor. But the Discussion explicitly says apoE levels were unchanged by mLRP2 overexpression, contrary to the claimed 25% reduction. Page numbers are not available in the supplied passages. (LLM, conf=0.90)

  Checked by a reasoning model — may be wrong.

  Experimental — accuracy not yet measured

Probably not a substantial claim: may not pass S3 (load-bearing).

The FDA has approved four siRNA-based therapeutics including inclisiran which targets PCSK9 for hypercholesterolaemia.

“The FDA has approved four siRNA-based therapeutics including the recently approved drug inclisiran which targets PCSK9 for the treatment of hypercholesterolaemia”

• cites FDA 2021Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

• cites Zhang et al 2021 sourceDisputed

  The Abstract identifies three approved siRNA drugs and lists inclisiran among Phase 3 candidates, not approved drugs. The Inclisiran section says FDA approval was expected in the future. The paper does support that inclisiran targets PCSK9 for hypercholesterolemia, but contradicts the claimed FDA approval and count of four. (LLM, conf=0.94)

  Checked by a reasoning model — may be wrong.

  Experimental — accuracy not yet measured

May combine two claims.

Human iPSC-derived neurons and cerebral organoids demonstrate that apoE4 enhances tau phosphorylation and exacerbates synapse loss and neurodegeneration.

“Studies with human iPSC-derived neurons and cerebral organoids demonstrate that apoE4 enhances tau phosphorylation and exacerbates synapse loss and neurodegeneration”

• cites Lin et al 2018 sourcePartly supported

  The Results section on APOE4 organoids reports increased tau phosphorylation in six-month-old APOE4 organoids compared with APOE3 organoids (page unavailable). But the Results section on iPSC-derived neurons reports increased synapse numbers, not synapse loss, and the paper does not show that APOE4 exacerbates neurodegeneration in these models. (LLM, conf=0.90)

  Experimental — accuracy not yet measured
• cites Wang et al 2018 sourcePartly supported

  The Results sections on phosphorylated tau and GABAergic neuron loss report higher p-tau levels and degeneration in human iPSC-derived apoE4 neurons. The passages do not establish synapse loss or findings from cerebral organoids; the reported experiments used neuronal cultures. Page numbers were not provided in our copy. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites Zhao et al 2020 sourceSupported

May combine two claims.

ApoE reduction or depletion attenuates neuroinflammation and alleviates pathological changes in various mouse models of amyloid and tau pathology.

“apoE reduction or depletion attenuates neuroinflammation and alleviates pathological changes in various mouse models of amyloid and tau pathology”

• cites Kim et al 2011 sourcePartly supported

  The Results section, “APOE dosage-dependent modulation of neuroinflammatory response” (page unavailable), reports markedly reduced microgliosis with APOE haploinsufficiency; the Discussion also reports less Aβ accumulation and amyloid deposition. The study examines APOE3 and APOE4 dosage in an APPPS1-21 amyloid model, but does not establish the claimed effects in tau-pathology models or across various distinct mouse models. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites Krasemann et al 2017 sourcePartly supported

  The Results section reports that Apoe deletion reduced neuronal loss after facial nerve axotomy and cites reduced neuroinflammation and disease after Apoe targeting in EAE. The Discussion links APOE to amyloid pathology, but our copy does not show that ApoE reduction alleviates neuroinflammation or pathological changes in mouse models of both amyloid and tau pathology. No page numbers are available in the indexed passages. (LLM, conf=0.83)

  Experimental — accuracy not yet measured
• cites Shi et al 2017aNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

May combine two claims.

ApoE4 exacerbates amyloid pathology by promoting Aβ production and aggregation, and inhibiting Aβ clearance and degradation.

“apoE4 exacerbates amyloid pathology by promoting Aβ production and aggregation, and inhibiting Aβ clearance and degradation”

• cites Koutsodendris et al 2021 sourceNot checked — no full text of the source
• cites Yamazaki et al 2019 sourcePartly supported

  The Aβ clearance section reports less efficient clearance and degradation with APOE4, and the Formation of Aβ fibrils section reports enhanced initial seeding. The Aβ production section reports increased production in human-derived neurons but conflicting mouse findings; it does not establish the claim’s unqualified production effect. Page numbers were not available in our copy. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

May combine two claims.

ApoE4 aggravates tau pathology via promoting tau phosphorylation, aggregation, propagation, and tau-mediated neurodegeneration.

“apoE4 aggravates the tau pathology via promoting tau phosphorylation, aggregation, propagation, and tau-mediated neurodegeneration”

• cites Koutsodendris et al 2021 sourceNot checked — no full text of the source
• cites Yamazaki et al 2019 sourcePartly supported

  The section “Tau, α-synuclein and TDP43 proteinopathies” (page unavailable) reports increased tau phosphorylation with APOE4 and greater tau-mediated brain atrophy in one mouse model. It also reports more tau aggregates in APOE4 homozygotes only when Aβ pathology is present, and describes a different mouse model with more severe tau pathology under APOE2. The copy does not establish that APOE4 promotes tau propagation, so the unqualified list of effects overstates the source. (LLM, conf=0.87)

  Experimental — accuracy not yet measured

May combine two claims.

There is a strong positive correlation between the APOE ε4 allele and Aβ pathology in human AD brains, with the highest Aβ burden in homozygous APOE ε4 carriers.

“there is a strong positive correlation between the APOE ε4 allele and Aβ pathology in human AD brains with the highest Aβ burden found in homozygous APOE ε4 carriers”

• cites Bertram et al 2007 sourceNot checked — no full text of the source
• cites Mishra et al 2018 sourcePartly supported

  The Results report earlier and greater rates of amyloid-β accumulation in APOE ε4 homozygotes than heterozygotes, supporting a genotype-related difference. But the Discussion describes the homozygote analysis as exploratory and based on a very small sample; the study examined cognitively normal adults, not brains of people with diagnosed AD. Greater accumulation rates do not establish the claim that homozygotes had the highest Aβ burden. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites Polvikoski et al 1995 sourceNot checked — no full text of the source

May combine two claims.

The risk for AD is 3-4-fold higher in individuals carrying one APOE ε4 allele and about 10-15-fold higher in those carrying two APOE ε4 alleles.

“The risk for AD is 3–4-fold higher in individuals carrying one APOE ε4 allele and about 10–15-fold higher in those carrying two APOE ε4 alleles”

• cites Corder et al 1993 sourceNot checked — no full text of the source
• cites Saunders et al 1993 sourcePartly supported

  The Statistical analysis table reports higher APOE ε4 allele frequencies in late-onset and sporadic AD groups than in controls, and the discussion calls ε4 a possible risk factor. The paper does not report AD risk separately for people carrying one versus two ε4 alleles, so it does not support the stated 3–4-fold and 10–15-fold estimates. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites Sims et al 2020 sourceSupported

May combine two claims.

Overexpression of LDLR in PS19 tauopathy mice results in a significant reduction of brain apoE levels and inhibition of tau phosphorylation, which strongly correlate with one another, and consequent amelioration of tau pathology and neurodegeneration.

“overexpression of LDLR in PS19 tauopathy mice also results in a significant reduction of brain apoE levels and inhibition of tau phosphorylation, which strongly correlate with one another, and consequent amelioration of tau pathology and neurodegeneration”

• cites Shi et al 2021 sourceSupported

May combine two claims.

Brain apoE is primarily produced by glial cells and plays a critical role in lipid transport for neuronal maintenance and repair.

“Brain apoE is primarily produced by glial cells and plays a critical role in lipid transport for neuronal maintenance and repair”

• cites Lanfranco et al 2020 sourceSupported

May combine two claims.

Using an ASO to reduce IDOL expression in the brains of APP/PS1 male mice, IDOL reduction led to a significant increase of brain LDLR levels, decrease of apoE levels, and alleviation of amyloid pathology and cognitive decline.

“Using an antisense oligonucleotide (ASO) to reduce IDOL expression in the brains of APP/PS1 male mice, it was demonstrated that IDOL reduction led to a significant increase of brain LDLR levels, decrease of apoE levels, and alleviation of amyloid pathology and cognitive decline”

• cites Gao et al 2020 sourcePartly supported

  The Results (pp. 3, 6) report reduced ApoE and amyloid pathology and improved spatial learning and memory after IDOL-ASO treatment in male APP/PS1 mice. The Results (p. 3) also report increased brain LDLR protein, but the corresponding Western blot is identified as using wild-type mice (Fig. 1D, p. 4), not APP/PS1 mice; the copy does not establish that this increase was significant. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

May combine two claims.

PCSK9 is expressed at a low level in adult brain but its expression is greatly upregulated in neurological disorders.

“PCSK9 is expressed at a low level in adult brain but its expression is greatly upregulated in neurological disorders”

• cites O’Connell & Lohoff 2020 sourceSupported

May combine two claims.

ApoE is enriched in amyloid plaques as a major constituent and promotes Aβ aggregation.

“apoE is enriched in amyloid plaques as a major constituent and promotes Aβ aggregation”

• cites Huynh et al 2017 sourcePartly supported

  The Introduction (page unavailable) says apoE co-localizes with amyloid plaques and promotes Aβ aggregation; the Discussion (page unavailable) also describes its role in initial plaque formation. But co-localization does not establish that apoE is enriched in plaques or is a major constituent, and the paper says plaques consist mostly of aggregated Aβ. (LLM, conf=0.87)

  Experimental — accuracy not yet measured
• cites Liu et al 2017 sourcePartly supported

  The Discussion (page unavailable) calls apoE a component of cerebral amyloid deposits, but does not establish that it is enriched in plaques or a major constituent. It reports that apoE4 can enhance Aβ fibrillogenesis and may promote amyloid seeding; the claim extends that finding to apoE generally and states it without the paper’s qualification. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites Ma et al 1994Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

May combine two claims.

ApoE4 proteins are poorly lipidated and display an impaired capacity in lipid transport when compared to apoE3 proteins.

“apoE4 proteins are poorly lipidated and display an impaired capacity in lipid transport when compared to apoE3 proteins”

• cites Gong et al 2002 sourceSupported
• cites Hu et al 2015Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

May combine two claims.

ApoE4-expressing 5xFAD mice display higher levels of glial activation and IL-1β as well as larger and more intensely stained Aβ plaques than apoE3-expressing 5xFAD mice.

“apoE4-expressing 5xFAD mice display higher levels of glial activation and the proinflammatory cytokine interleukin-1β (IL-1β) as well as larger and more intensely stained Aβ plaques than apoE3-expressing 5xFAD mice”

• cites Rodriguez et al 2014 sourceSupported

May combine two claims.

2-fold LDLR protein overexpression is sufficient to reduce more than 50% of brain apoE levels and Aβ accumulation.

“2-fold LDLR protein overexpression is sufficient to reduce more than 50% of brain apoE levels and Aβ accumulation”

• cites Kim et al 2009 sourcePartly supported

  The Results (Generation and Characterization of LDLR Transgenic Mice; page unavailable) report that twofold LDLR overexpression reduced brain apoE by approximately 50%, not clearly more than 50%. The Results (Two-fold Overexpression of LDLR is Sufficient to Inhibit Amyloid Formation; page unavailable) report a 50–55% reduction in fibrillar plaque load in female APP/PS1 mice, but smaller reductions in some Aβ measures and no significant effect in males. The claim overstates both the magnitude and the generality of the Aβ finding. (LLM, conf=0.90)

  Experimental — accuracy not yet measured

May combine two claims.

Peripheral apoE, produced primarily from the liver, is a key player in cholesterol metabolism and has prominent effects on cardiovascular disease.

“peripheral apoE, which is produced primarily from the liver, is a key player in cholesterol metabolism and has prominent effects on cardiovascular disease”

• cites Belloy et al 2019 sourceSupported

May combine two claims.

ApoE4 can greatly inhibit the recycling of apoER2 to the cell surface and thereby severely impair Reelin signaling in neurons.

“apoE4 can greatly inhibit the recycling of apoER2 to the cell surface and thereby severely impair Reelin signaling in neurons”

• cites Chen et al 2010 sourceSupported
• cites Feng et al 2020 sourceNot checked — no full text of the source
• cites Xian et al 2018 sourceSupported

May combine two claims.

The phenotype of disease-associated microglia is dependent on the TREM2-apoE pathway, and deletion of apoE might prevent DAM development.

“The phenotype of disease-associated microglia (DAM) is dependent on the TREM2-apoE pathway, and deletion of apoE might prevent DAM development”

• cites Krasemann et al 2017 sourceSupported

May combine two claims.

Reduction of apoE4 protein levels by ~50% in the P301S/ApoE4 mouse model resulted in significant protection against tau pathology and associated neurodegeneration as well as inhibition of neuroinflammation.

“reduction of apoE4 protein levels by ~50% in the P301S/ApoE4 mouse model resulted in significant protection against tau pathology and associated neurodegeneration as well as inhibition of neuroinflammation”

• cites Litvinchuk et al 2021 sourceSupported

May combine two claims.

PCSK9 is a negative regulator of LDLR that binds to the extracellular domain of LDLR and induces LDLR degradation in endosomes/lysosomes.

“Proprotein convertase subtilisin/kexin type 9 (PCSK9) is another negative regulator of LDLR. PCSK9 binds to the extracellular domain of LDLR and thereby induces LDLR degradation in endosomes/lysosomes”

• cites O’Connell & Lohoff 2020 sourceSupported

May combine two claims. The quote only partly states this claim.

ApoE antibodies can suppress amyloidosis progression, alleviate amyloid pathology and improve cognitive function through multiple mechanisms including modification of glia responses, regulation of proinflammatory cytokines, amendment of apoE4-induced apoER2 reduction, and improvement of cerebrovascular function.

“ApoE antibodies can suppress amyloidosis progression, alleviate amyloid pathology and improve cognitive function through multiple mechanisms including modification of glia responses”

• cites Kim et al 2012 sourcePartly supported

  Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  Experimental — accuracy not yet measured
• cites Liao et al 2014 sourcePartly supported

  Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  Experimental — accuracy not yet measured
• cites Liao et al 2018 sourcePartly supported

  The Discussion (pp. 7–8) reports that anti-apoE antibodies reduced amyloid accumulation in mice and that the effect appeared to require a microglial response. It does not establish improved cognitive function. The longer supplied claim also attributes effects on cytokines, apoER2, and cerebrovascular function that this paper does not report. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

May combine two claims.

Pretreatment with PCSK9 inhibitor Pep2-8 reduces Aβ42 levels and attenuates neuroinflammation and brain damage induced by cardiac ischemia/reperfusion injury in rats.

“pretreatment with PCSK9 inhibitor Pep2–8 (a small peptide) reduces Aβ42 levels and attenuates neuroinflammation and brain damage induced by cardiac ischemia/reperfusion injury in rats”

• cites Apaijai et al 2019 sourcePartly supported

  The Methods (Animals; page unavailable) describe pretreatment of rats with a PCSK9 inhibitor before cardiac ischemia/reperfusion. The Results (PCSK9 Inhibition Reduced the Expression of Aβ; page unavailable) report reduced brain Aβ, and the Discussion and Conclusion report reduced glial activation and brain damage. The paper measures Aβ generally, however, and does not establish that the reduced Aβ was specifically Aβ42. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

May combine two claims.

Neuroinflammation is a major pathological feature strongly correlated with Aβ plaque and NFT pathologies and modulates AD progression.

“Neuroinflammation is another major pathological feature that is strongly corelated with the Aβ plaque and NFT pathologies and modulates AD progression”

• cites Kloske & Wilcock 2020 sourcePartly supported

  The Introduction and “Inflammation in Alzheimer’s Disease” sections describe neuroinflammation as important to AD progression, while the microglia and “ApoE and Tau” sections link inflammatory responses to Aβ plaques and tau pathology (page numbers unavailable). The paper does not establish the claimed strong correlation with both plaque and NFT pathology. (LLM, conf=0.82)

  Experimental — accuracy not yet measured
• cites Shi & Holtzman 2018aNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

May combine two claims.

LRP1 mediates tau endocytosis and promotes tau propagation between neurons.

“LRP1 mediates tau endocytosis and promotes tau propagation between neurons”

• cites Rauch et al 2020 sourceSupported

May combine two claims.

Using ASOs to reduce human apoE expression in the brains of APP/PS1-21 mice homozygous for human APOE ε2, ε3 or ε4 allele, apoE4 reduction prior to plaque deposition led to a significant decrease in Aβ pathology, and lowering apoE4 after Aβ seeding resulted in a reduction in plaque-associated neuritic dystrophy.

“apoE4 reduction prior to plaque deposition led to a significant decrease in Aβ pathology, and that lowering apoE4 after Aβ seeding resulted in a reduction in plaque-associated neuritic dystrophy”

• cites Huynh et al 2017 sourcePartly supported

  Split into 3 atoms — 2 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  Experimental — accuracy not yet measured

May combine two claims.

IDOL plays a primary role in regulating brain LDLR protein and has a limited effect on hepatic LDLR levels in mice.

“IDOL plays a primary role in regulating brain LDLR protein and has a limited effect on hepatic LDLR levels in mice”

• cites Choi et al 2015 sourceSupported
• cites Hong et al 2014 sourcePartly supported

  The Introduction and Results report that hepatic LDLR protein in mice is relatively resistant to loss of IDOL activity, with only a subtle increase after a prolonged high-cholesterol diet. The Results identify effects in heart, spleen, macrophages, and other peripheral tissues, but our copy does not establish a primary role for IDOL in regulating brain LDLR protein (searched: brain and brain tissue LDLR). (LLM, conf=0.87)

  Experimental — accuracy not yet measured

May combine two claims.

ApoE is a ligand of TREM2 and can trigger TREM2 signaling, thereby regulating microglia function and neuroinflammation.

“apoE is a ligand of TREM2 and can trigger TREM2 signaling, thereby regulating microglia function and neuroinflammation”

• cites Atagi et al 2015 sourcePartly supported

  The Discussion (page not provided) identifies apoE as a high-affinity TREM2 ligand and reports increased TREM2-mediated phagocytosis by microglia. The paper describes TREM2 signaling generally, but does not show that apoE directly triggers that signaling; it suggests, rather than demonstrates, that the apoE–TREM2 interaction contributes to neuroinflammation. (LLM, conf=0.87)

  Experimental — accuracy not yet measured
• cites Bailey et al 2015 sourceNot checked — no full text of the source
• cites Jendresen et al 2017 sourcePartly supported

  The Results (page unavailable) show that ApoE acts as a TREM2 agonist and triggers dose-dependent signaling in reporter cells. The Discussion (page unavailable) says ApoE could potentially regulate microglial responses to neuroinflammatory stimuli, but does not establish that it regulates microglial function or neuroinflammation as the claim states. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

Probably not a substantial claim: may not pass S3 (load-bearing).

ASO targeting MAPT (Tau) for AD treatment is under Phase 1/2 clinical trial.

“Currently, ASO targeting MAPT (Tau) for AD treatment is under Phase 1/2 clinical trial”

• cites Bennett et al 2021 sourceSupported

May combine two claims.

ApoE4 accelerates AD pathogenesis by inducing dysregulation of microglia and astrocytes and provoking neuroinflammation.

“Therefore, apoE4 accelerates AD pathogenesis by inducing dysregulation of microglia and astrocytes and provoking neuroinflammation”

• cites Shi et al 2021 sourcePartly supported

  The Introduction says APOE4 increases late-onset AD risk and exacerbates neurodegeneration relative to APOE2 and APOE3 in a tauopathy mouse model. The Results link apoE to microglial activation and show less reactive astrocyte activation when apoE is reduced. These findings support parts of the proposed mechanism, but this paper does not establish that apoE4 specifically causes dysregulation of both cell types and neuroinflammation in AD. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites Shi et al 2017bNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

• AssumptionRests on an assumption: Findings from mouse models and human cell/organoid studies of apoE4 and apoE reduction are predictive of outcomes in human AD patients.

May combine two claims.

IDOL deficiency resulted in a significant reduction of apoE levels, induction of Aβ clearance, decrease of amyloid plaque burden, and amelioration of neuroinflammation in APP/PS1 mice.

“IDOL deficiency resulted in a significant reduction of apoE levels, induction of Aβ clearance, decrease of amyloid plaque burden, and amelioration of neuroinflammation in APP/PS1 mice”

• cites Choi et al 2015 sourcePartly supported

  The Results sections on amyloid burden, neuroinflammation, and ApoE report lower brain ApoE and Aβ levels, reduced plaques, and decreased neuroinflammation in APP/PS1 mice lacking Idol (pages not provided). The section on ApoE and Aβ uptake and clearance shows increased Aβ uptake in cultured cells, but only suggests enhanced clearance as the mechanism in the mice; it does not directly establish induced Aβ clearance in vivo. (LLM, conf=0.84)

  Experimental — accuracy not yet measured

May combine two claims.

The FDA has approved eight ASO drugs since 2016, and the approval of nusinersen provides a strong basis for using ASO technology to develop novel therapies for neurodegenerative diseases.

“The FDA has approved eight ASO drugs since 2016, and the approval of the ASO-based drug nusinersen provides a strong basis for using this technology to develop novel and effective therapies for neurodegenerative diseases”

• cites Bennett et al 2021 sourcePartly supported

  Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  Experimental — accuracy not yet measured
• cites Leavitt & Tabrizi 2020 sourcePartly supported

  Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  Experimental — accuracy not yet measured

May combine two claims.

ApoE4 knock-in mice exhibit an age-dependent loss of hilar GABAergic interneurons and deficits in learning and memory, which is more profound when the mice express neurotoxic apoE fragments.

“apoE4 knock-in (KI) mice exhibit an age-dependent loss of hilar GABAergic interneurons and deficits in learning and memory, which is more profound when the mice express neurotoxic apoE fragments”

• cites Andrews-Zwilling et al 2010 sourcePartly supported

  The Discussion reports age-dependent hilar GABAergic interneuron loss and learning and memory deficits in female apoE4 knock-in mice. It says interneuron loss was more pronounced in a separate neurotoxic apoE4-fragment transgenic model, but does not say that the learning and memory deficits were more profound or that those mice were knock-in mice. (LLM, conf=0.84)

  Experimental — accuracy not yet measured

May combine two claims.

Overexpression of LDLR in the brain of APP/PS1 transgenic mice results in a 50-90% reduction of brain apoE levels, correlated with marked attenuation of Aβ aggregation, induction of Aβ clearance and suppression of plaque-associated neuroinflammatory responses.

“overexpression of LDLR in the brain of APP/PS1 transgenic mice result in a 50–90% reduction of brain apoE levels, which is correlated with marked attenuation of Aβ aggregation, induction of Aβ clearance and suppression of plaque-associated neuroinflammatory responses”

• cites Kim et al 2009 sourceSupported

May combine two claims.

IDOL is an E3 ubiquitin ligase that binds to LDLR cytoplasmic tail and triggers LDLR ubiquitination and degradation.

“Inducible degrader of the LDLR (IDOL) is an E3 ubiquitin ligase that binds to LDLR cytoplasmic tail and thereby triggers LDLR ubiquitination and degradation”

• cites Zhang et al 2011 sourcePartly supported

  The Discussion reports that IDOL acts with UBE2D to ubiquitinate LDLR and that disrupting this complex inhibits LDLR degradation. Our copy does not establish that IDOL binds specifically to the LDLR cytoplasmic tail; it notes that studying the IDOL–LDLR interaction is challenging. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

May combine two claims.

APOE4 is the strongest genetic risk factor for AD with high prevalence.

“In conclusion, APOE4 is the strongest genetic risk factor for AD with high prevalence (Saunders et al 1993, Sims et al 2020).”

• cites Saunders et al 1993 sourcePartly supported

  The Statistical analysis section reports significantly higher APOE4 allele frequencies in late-onset familial and sporadic AD groups than in controls (0.36–0.42 versus 0.16), supporting its association with AD and its frequency in those patient groups. It does not establish APOE4 as the strongest genetic risk factor for AD overall; the same section reports no significant association in the combined early-onset familial AD group. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites Sims et al 2020 sourcePartly supported

  The ‘Late-onset AD Genetics: Common Variation’ section (p. 3) calls APOE the strongest genetic risk factor and says the ε4 allele increases AD risk. It does not establish that APOE4 has high prevalence; the reference to common forms of late-onset AD describes the disease, not the allele’s prevalence. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

May combine two claims.

IDOL plays a critical role in the regulation of neuronal VLDLR expression and systemic energy balance.

“In addition, IDOL plays a critical role in the regulation of neuronal VLDLR expression and systemic energy balance (Lee et al 2019).”

• cites Lee et al 2019 sourceSupported

May combine two claims.

A patient carrying a mutation associated with complete absence of apoE exhibited normal cognitive, neurological, and retinal function, and had no significant symptoms of cardiovascular disease.

“a patient carrying a mutation associated with complete absence of apoE exhibited normal cognitive, neurological, and retinal function, and had no significant symptoms of cardiovascular disease”

• cites Mak et al 2014 sourceSupported

May combine two claims.

Over 60% of symptomatic AD patients carry at least one APOE ε4 allele, while about 20% of the population carries APOE ε4.

“Although there is only about 20% of the population carrying the APOE ε4, this isoform is vastly enriched in AD patients with over 60% of symptomatic AD patients carrying at least one APOE ε4 allele”

• cites Corder et al 1993 sourceNot checked — no full text of the source
• cites Farrer et al 1997 sourceNot checked — no full text of the source

May combine two claims.

ApoE-deficient APP transgenic mice display virtually no fibrillar Aβ deposits nor neuritic degeneration.

“apoE-deficient APP transgenic mice display virtually no fibrillar Aβ deposits nor neuritic degeneration”

• cites Bales et al 1999 sourceNot checked — no full text of the source
• cites Bales et al 1997 sourceNot checked — no full text of the source
• cites Holtzman et al 2000aNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

May combine two claims.

Tissue-specific apoE siRNAs completely silenced apoE expression in the brain, had no effects on systemic cholesterol and greatly inhibited amyloid plaque formation in APP/PS1 transgenic mice.

“tissue-specific apoE siRNAs completely silenced apoE expression in the brain, had no effects on systemic cholesterol and greatly inhibited amyloid plaque formation in APP/PS1 transgenic mice”

• cites Ferguson 2021 sourceNot checked yet

  Checked before — its earlier verdict is held back until a new check runs.

• cites Khvorova et al 2020Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

May combine two claims.

ApoE primarily binds to LDLR and LRP1 in the brain, and both mediate endocytosis and clearance of apoE lipoproteins.

“ApoE primarily binds to LDLR and LDLR-related protein 1 (LRP1) in the brain, and both LDLR and LRP1 belong to the LDLR family and are metabolic receptors that mediate the endocytosis and clearance of apoE lipoproteins”

• cites Holtzman et al 2012 sourceNot checked — no full text of the source

May combine two claims.

PCSK9 loss-of-function mutations are associated with a marked increase of hepatic LDLR levels and a significant decrease of plasma LDL cholesterol levels.

“loss-of-function (LOF) mutations of PCSK9 are associated with a marked increase of hepatic LDLR levels and a significant decrease of plasma LDL cholesterol levels”

• cites Cohen et al 2005 sourceNot checked — no full text of the source
• cites Mayne et al 2011 sourceNot checked — no full text of the source

May combine two claims.

ASO-mediated apoE4 reduction can alleviate not only amyloid pathology but also tau pathology and tau-mediated neurodegeneration.

“Therefore, ASO-mediated apoE4 reduction can alleviate not only amyloid pathology but also tau pathology and tau-mediated neurodegeneration.”

• AssumptionRests on an assumption: Findings from mouse models and human cell/organoid studies of apoE4 and apoE reduction are predictive of outcomes in human AD patients.

May combine two claims.

ApoE4 reduction could have both prophylactic and therapeutic applications.

“thus, apoE4 reduction could have both prophylactic and therapeutic applications.”

• AssumptionRests on an assumption: Findings from mouse models and human cell/organoid studies of apoE4 and apoE reduction are predictive of outcomes in human AD patients.

May combine two claims.

Up-regulation of LDLR can lead to reduction of apoE and alleviation of AD pathologies.

“Together, these studies demonstrate that up-regulation of LDLR can lead to reduction of apoE and alleviation of AD pathologies.”

• AssumptionRests on an assumption: Findings from mouse models and human cell/organoid studies of apoE4 and apoE reduction are predictive of outcomes in human AD patients.

Probably not a substantial claim: may not pass S3 (load-bearing).

The siRNA-based PCSK9 inhibitor inclisiran has been recently approved for the treatment of hypercholesterolemia.

“The siRNA-based PCSK9 inhibitor inclisiran, which increases LDLR in hepatocytes, has been recently approved for the treatment of hypercholesterolemia (FDA 2021).”

• cites FDA 2021Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Classified as probably not a substantial claim.

Specific apoE ASOs and siRNAs are attractive therapeutic approaches to directly reduce apoE levels for AD patients carrying APOE ε4 allele.

“While specific apoE ASOs and siRNAs are attractive therapeutic approaches to directly reduce apoE levels for AD patients carrying APOE ε4 allele”

• AssumptionRests on an assumption: Findings from mouse models and human cell/organoid studies of apoE4 and apoE reduction are predictive of outcomes in human AD patients.

Probably not a substantial claim: may not pass S3 (load-bearing).

The siRNA-based PCSK9 inhibitor inclisiran increases LDLR in hepatocytes.

“The siRNA-based PCSK9 inhibitor inclisiran, which increases LDLR in hepatocytes, has been recently approved for the treatment of hypercholesterolemia (FDA 2021).”

• cites FDA 2021Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Probably not a substantial claim: may not pass S2 (checkable), S4 (based).

Developing novel and CNS-specific small molecules to reduce apoE4 levels is another promising therapeutic strategy.

“developing novel and CNS-specific small molecules to reduce apoE4 levels is another promising therapeutic strategy”

• AssumptionRests on an assumption: Findings from mouse models and human cell/organoid studies of apoE4 and apoE reduction are predictive of outcomes in human AD patients.

Classified as probably not a substantial claim.

ApoE4 reduction therapies are likely to be evaluated on safety and efficacy in clinical trials in the near future.

“With the recent advances in technologies for increasing bioavailability and stability and minimizing toxicity of ASOs and siRNAs, apoE4 reduction therapies are likely to be evaluated on safety and efficacy in clinical trials in the near future.”

Probably not a substantial claim: may not pass S2 (checkable), S4 (based).

Small molecules that reduce apoE4 levels in brain, particularly those targeting apoE and LDLR, could represent novel therapeutic tools in AD.

“Small molecules that reduce apoE4 levels in brain, particularly those targeting apoE and LDLR, could represent novel therapeutic tools in AD.”

• AssumptionRests on an assumption: Findings from mouse models and human cell/organoid studies of apoE4 and apoE reduction are predictive of outcomes in human AD patients.