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Cited by 77Alzheimer's disease research and treatmentsPluripotent Stem Cells ResearchDementia and Cognitive Impairment Research

Modeling late-onset Alzheimer’s disease neuropathology via direct neuronal reprogramming

Open access
Sun, Zhao, Kwon, Ji-Sun, Ren, Yudong, Chen, Shawei, Walker, Courtney K., Lu, Xinguo, Cates, Kitra, Karahan, Hande +13 more·2024·Science
DOI 10.1126/science.adl2992PMC PMC11787906

Published version of a preprint

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Abstract

Late-onset Alzheimer’s disease (LOAD) is the most common form of Alzheimer’s disease (AD). However, modeling sporadic LOAD that endogenously captures hallmark neuronal pathologies such as amyloid-β (Aβ) deposition, tau tangles, and neuronal loss remains an unmet need. We demonstrate that neurons generated by microRNA (miRNA)–based direct reprogramming of fibroblasts from individuals affected by autosomal dominant AD (ADAD) and LOAD in a three-dimensional environment effectively recapitulate key neuropathological features of AD. Reprogrammed LOAD neurons exhibit Aβ-dependent neurodegeneration, and treatment with β- or γ-secretase inhibitors before (but not subsequent to) Aβ deposit formation mitigated neuronal death. Moreover inhibiting age-associated retrotransposable elements in LOAD neurons reduced both Aβ deposition and neurodegeneration. Our study underscores the efficacy of modeling late-onset neuropathology of LOAD through high-efficiency miRNA-based neuronal reprogramming.

AI snapshot

Written from the paper’s full text.

TL;DR

MicroRNA-based direct reprogramming of patient fibroblasts into 3D cortical neurons and spheroids recapitulates Aβ deposition, tau pathology, and neurodegeneration in both autosomal dominant AD (ADAD) and late-onset AD (LOAD). LOAD neurons show Aβ-dependent degeneration, and inhibiting retrotransposable elements with lamivudine (3TC) reduces Aβ, tau pathology, DNA damage, and neuronal death.

Key findings

  • ADAD and LOAD reprogrammed neurons/spheroids develop extracellular Aβ deposits: ADAD 3D-CNs showed 10–50 μm deposits and a threefold increase in total Aβ volume versus healthy controls; LOAD 3D-CNs and spheroids had higher Aβ than age-matched controls (p < 0.05 for spheroids).
  • Both ADAD and LOAD neurons showed tau dysregulation, including elevated AT8/PHF1 p-tau, MC1 misfolded tau, K63-ubiquitin+ p-tau in beaded dystrophic neurites, seed-competent tau by FRET, and approximately equal 3R/4R tau isoform ratios.
  • Neurodegeneration was spontaneous and selective: ADAD spheroids shrank ~50% from PID17 to PID33 versus ~10% for HC; LOAD spheroids showed ~50% size reduction versus ~10–20% for HC, with increased TUNEL, neurite retraction, and impaired synapse formation.
  • β- or γ-secretase inhibition before Aβ deposit formation (PID16) reduced LOAD spheroid Aβ by 80–90%, lowered p-tau, and reduced neuronal death by ~50%; treatment after deposits formed (PID22) was absent or only modest (~30% with DAPT) and did not reduce death. 3TC reduced ssDNA by ~50% and decreased neuronal death, Aβ deposition, p-tau, K63-ubiquitin+ tau, and DNA damage.

Methods

  • Human fibroblasts from 10 individuals with AD (4 ADAD, 6 LOAD) and 17 age-/sex-matched healthy controls were reprogrammed with miR-9/9*–124 plus NEUROD2 and MYT1L toward cortical neurons.
  • Two 3D formats were used: thin-gel culture (~0.1×10^6 cells/well) and high-density spheroids (~0.5×10^6 cells), followed by 2–3 weeks of reprogramming.
  • Analyses included immunostaining, RNA-seq, qPCR, FRET tau seeding assays, TEM, Sytox-Green/TUNEL cell-death assays, and drug treatments with β-/γ-secretase inhibitors or 3TC; RNA-seq comparisons used separate ADAD (4 vs 4 HC), LOAD (5 vs 5 HC), and 3TC-treated LOAD (4 individuals) groups.

Limitations

  • Stated: the mechanism by which 3TC reduces Aβ formation remains unclear; why LOAD neurons are selectively vulnerable to RTE dysregulation while old healthy-control neurons tolerate it is unresolved; future whole-genome sequencing and chromatin profiling are needed to identify genetic/epigenetic changes underlying LOAD neuron degeneration.
  • Stated: the study focuses on neurons and does not model interactions with other brain cell types; robust direct reprogramming methods for aged astrocytes and microglia are still needed to study neuron-glia interactions in age-associated disease progression.
  • Evident from the text: sample sizes are small (e.g., 4 ADAD, 6 LOAD, and corresponding control lines), and the model relies on patient-derived fibroblasts rather than direct human brain tissue, though transcriptomic comparisons to postmortem AD datasets are reported.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1126/science.adl2992

Cites

113 of 113 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

114 of 127 cited sources checked · 57 supported · 4 flagged · accuracy not yet measured

  • Premisecitation

    Late-stage neuropathological features, such as formation of insoluble tau and neurodegeneration, have not been reported in iPSC-derived neurons from individuals with AD.

    “but late-stage neuropathological features, such as formation of insoluble tau and neurodegeneration have not been reported.”
    Quote in the paperSubstantial claim6 of 6 sources checked
    • cites [12] Israel MA, Probing sporadic and familial Alzheimer’s disease using induced pluripotent stem cells. Nature 482, 216– 220 (2012). 22278060 PMC3338985 source

      The paper’s discussion of early pathogenesis reports elevated phosphorylated tau, but treats neurofibrillary tangles and cell death as downstream questions rather than observed features in its iPSC-derived neurons (section labelled Abstract; page unavailable). It does not report insoluble tau or neurodegeneration in its cultures, but it does not establish the broader claim that these features had not been reported in any AD iPSC-derived neurons. (LLM, conf=0.79)

      Experimental — accuracy not yet measured
    • cites [13] Kondo T., Modeling Alzheimer’s disease with iPSCs reveals stress phenotypes associated with intracellular Abeta and differential drug responsiveness. Cell Stem Cell 12, 487– 496 (2013). 23434393 source

      The Results (page unavailable) report that AD(APP-E693Δ) iPSC-derived neurons had a lower survival rate than control neurons under neurotrophic-factor-depleted culture conditions, contrary to the unqualified statement that neurodegeneration had not been reported. The paper does not address whether insoluble tau had been reported in these neurons. (LLM, conf=0.76)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured
    • cites [14] Lomoio S., 3D bioengineered neural tissue generated from patient-derived iPSCs mimics time-dependent phenotypes and transcriptional features of Alzheimer’s disease. Mol Psychiatry, (2023). PMC11164539 37365240 source

      The Background says iPSC-derived neural cultures reproduce some AD phenotypes, and the Discussion reports amyloid deposition in the authors’ 3D cultures. Neither section says whether insoluble tau or neurodegeneration had been reported in AD patient-derived iPSC neurons. Searches for those terms and late-stage hallmarks found no passage establishing the claimed absence. (LLM, conf=0.70)

      Experimental — accuracy not yet measured
    • cites [15] Ochalek A., Neurons derived from sporadic Alzheimer’s disease iPSCs reveal elevated TAU hyperphosphorylation, increased amyloid levels, and GSK3B activation. Alzheimers Res Ther 9, 90 (2017). 29191219 PMC5709977 source

      The Discussion reports TAU hyperphosphorylation in AD iPSC-derived neurons but does not say whether insoluble TAU or late-stage neurodegeneration has been reported in such models. The Results report cell death after externally applied Aβ oligomers, which does not establish spontaneous late-stage neurodegeneration. Searches for insoluble TAU and late-stage neurodegeneration found no passage resolving the claim. (LLM, conf=0.70)

      Experimental — accuracy not yet measured
    • cites [16] Raja WK, Self-Organizing 3D Human Neural Tissue Derived from Induced Pluripotent Stem Cells Recapitulate Alzheimer’s Disease Phenotypes. PLoS One 11, e0161969 (2016). 27622770 PMC5021368 source

      The Introduction (page unavailable) says iPSC-derived neural cells have been used to model aspects of AD, while the Discussion describes tau pathology and neuronal loss in mouse models. Neither passage says whether insoluble tau or neurodegeneration had been reported in AD patient-derived iPSC neurons. Searches for those specific late-stage features did not find a passage addressing that claim. (LLM, conf=0.70)

      Experimental — accuracy not yet measured
    • cites [17] Wang C., Gain of toxic apolipoprotein E4 effects in human iPSC-derived neurons is ameliorated by a small-molecule structure corrector. Nat Med 24, 647– 657 (2018). 29632371 PMC5948154 source

      The Results section, “ApoE4 causes GABAergic neuron degeneration/loss in hiPSC-derived neuronal culture” (page unavailable), reports degeneration and apoptotic death in human iPSC-derived GABAergic neurons—contrary to the claim that neurodegeneration has not been reported. The passages report phosphorylated tau, but do not establish formation of insoluble tau. (LLM, conf=0.90)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured
  • Findingown data

    PI16 and ADAMDEC1, whose expression is strongly suppressed by inflammatory response, were increased in 3TC-treated spheroids.

    “Both PI16 and ADAMDEC1, whose expression is strongly suppressed by inflammatory response (91, 92), were increased in 3TC-treated spheroids (Fig. 7F).”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [91] Hazell GG, PI16 is a shear stress and inflammation-regulated inhibitor of MMP2. Sci Rep 6, 39553 (2016). 27996045 PMC5171773 source
    • cites [92] O’Shea NR, Critical Role of the Disintegrin Metalloprotease ADAM-like Decysin-1 [ADAMDEC1] for Intestinal Immunity and Inflammation. J Crohns Colitis 10, 1417– 1427 (2016). 27226416 PMC5174729 source

      The Results (§3.4; page unavailable) report that Adamdec1 was significantly upregulated during DSS-induced colitis, not suppressed by the inflammatory response. The Discussion likewise says that under-expression reported in Crohn’s disease is unlikely to be due to bowel inflammation itself. This source does not address the citing authors’ 3TC-treated spheroids; that finding is attributed to their Figure 7F, not to this paper. (LLM, conf=0.89)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured
  • Premisecitation

    Modeling these pathological hallmarks has largely relied on transgenic cellular and animal models harboring genetic mutations linked to ADAD.

    “Modeling these pathological hallmarks has largely relied on transgenic cellular and animal models harboring genetic mutations linked to ADAD (3–5).”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites [3] Choi SH, A three-dimensional human neural cell culture model of Alzheimer’s disease. Nature 515, 274– 278 (2014). 25307057 PMC4366007 source
    • cites [4] Yokoyama M, Kobayashi H, Tatsumi L, Tomita T, Mouse Models of Alzheimer’s Disease. Front Mol Neurosci 15, 912995 (2022). 35799899 PMC9254908 source

      The section “Aβ Deposited Mouse Models Based on APP Mutations” says widely used mouse models carry familial AD-linked APP mutations. The paper does not establish the claim about cellular models, and its “Tauopathy Mouse Models” section says tau models use mutations linked to frontotemporal dementia, not familial AD. No page numbers are available in our copy. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [5] Zetterberg H, Mattsson N, Understanding the cause of sporadic Alzheimer’s disease. Expert Rev Neurother 14, 621– 630 (2014). 24852227 source
  • Premisecitation

    Ultra-structural analyses of tau filaments in brains from individuals with AD have shown that tau tangles contain both 3-repeat (3R)-tau and 4-repeat (4R)-tau isoforms.

    “ultra-structural analyses of tau filaments in brains from individuals with AD have shown that tau tangles contain both 3-repeat (3R)-tau and 4-repeat (4R)-tau isoforms (18)”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [18] Fitzpatrick AWP, Cryo-EM structures of tau filaments from Alzheimer’s disease. Nature 547, 185– 190 (2017). 28678775 PMC5552202 source
  • Premisecitation

    Fetal neurons and iPSCs-derived neurons primarily express 3R-tau.

    “However, fetal neurons and iPSCs-derived neurons primarily express 3R-tau (20, 21)”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [20] Capano LS, Recapitulation of endogenous 4R tau expression and formation of insoluble tau in directly reprogrammed human neurons. Cell Stem Cell 29, 918– 932 e918 (2022). 35659876 PMC9176216 source
    • cites [21] Sato C., Tau Kinetics in Neurons and the Human Central Nervous System. Neuron 97, 1284– 1298 e1287 (2018). 29566794 PMC6137722 source

      The Results state that iPSC-derived neurons express predominantly 3R tau, and the Discussion reports much less 4R than 3R tau in the cultures studied. The passages found do not address whether fetal neurons primarily express 3R tau, so that part of the claim is unsupported by this paper. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
  • Classified as probably not a substantial claim. 28
  • May combine two claims. 41

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    AD is the most prevalent of tauopathies and is considered a secondary tauopathy because tau aggregation is regarded as a response to other pathological proteins or events (Aβ), but it is not driven by tau mutations.

    “AD is the most prevalent of tauopathies and is considered a secondary tauopathy because tau aggregation is regarded as a response to other pathological proteins or events (Aβ), but it is not driven by tau mutations (19, 65).”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [19] Espinoza M, de Silva R, Dickson DW, Davies P, Differential incorporation of tau isoforms in Alzheimer’s disease. J Alzheimers Dis 14, 1– 16 (2008). 18525123 PMC2882247 source

      The Introduction (page unavailable) explicitly lists AD among the primary tauopathies, contrary to the claim that this paper considers it a secondary tauopathy. The Discussion (page unavailable) says there are no known tau-gene mutations in sporadic AD, but it does not establish that tau aggregation is a response to Aβ or that AD is the most prevalent tauopathy. (LLM, conf=0.88)

      Checked by a reasoning model — may be wrong.

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    • cites [65] Dugger BN, Dickson DW, Pathology of Neurodegenerative Diseases. Cold Spring Harb Perspect Biol 9, (2017). PMC5495060 28062563 source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    AD is the leading cause of dementia characterized by key neuronal hallmarks: extracellular deposition of Aβ plaques, formation of intracellular neurofibrillary tangles, and neuronal loss.

    “AD is the leading cause of dementia characterized by key neuronal hallmarks: extracellular deposition of Aβ plaques, formation of intracellular neurofibrillary tangles, and neuronal loss (1, 2).”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [1] Serrano-Pozo A, Frosch MP, Masliah E, Hyman BT, Neuropathological alterations in Alzheimer disease. Cold Spring Harb Perspect Med 1, a006189 (2011). 22229116 PMC3234452 source
    • cites [2] Alzheimer A, Stelzmann RA, Schnitzlein HN, Murtagh FR, An English translation of Alzheimer’s 1907 paper, “Uber eine eigenartige Erkankung der Hirnrinde”. Clin Anat 8, 429– 431 (1995). 8713166 source

  • May combine two claims.

    Premisecitation

    iPSC-derived neurons from individuals with AD exhibit increased production of Aβ42, active GSK-3β, phosphorylated tau, endosomal abnormalities, and oxidative stress.

    “iPSC-derived neurons from individuals with AD exhibit increased production of Aβ42, active GSK-3β, phosphorylated tau, endosomal abnormalities, and oxidative stress (12–17)”
    Quote in the paperSubstantial claim6 of 6 sources checked
    • cites [12] Israel MA, Probing sporadic and familial Alzheimer’s disease using induced pluripotent stem cells. Nature 482, 216– 220 (2012). 22278060 PMC3338985 source

      The paper’s Abstract reports increased active GSK-3β, phosphorylated tau, amyloid-β(1–40), and enlarged early endosomes in neurons from two familial AD patients and one sporadic AD patient. It does not establish increased Aβ42: the Aβ(1–42) measurements were often below the assay’s detection range. The passages found also do not report oxidative stress in these AD-derived neurons. (LLM, conf=0.91)

      Experimental — accuracy not yet measured
    • cites [13] Kondo T., Modeling Alzheimer’s disease with iPSCs reveals stress phenotypes associated with intracellular Abeta and differential drug responsiveness. Cell Stem Cell 12, 487– 496 (2013). 23434393 source

      The Results and Discussion report oxidative stress in neurons from the APP-E693Δ case and one sporadic AD case. The Results find increased extracellular Aβ42 only in APP-V717L cells; Aβ42 was decreased in APP-E693Δ cells and unchanged extracellularly in the sporadic cases. Our copy does not report active GSK-3β, phosphorylated tau, or endosomal abnormalities in these neurons; it reports only that some Aβ-positive puncta stained for an endosomal marker. (LLM, conf=0.90)

      Experimental — accuracy not yet measured
    • cites [14] Lomoio S., 3D bioengineered neural tissue generated from patient-derived iPSCs mimics time-dependent phenotypes and transcriptional features of Alzheimer’s disease. Mol Psychiatry, (2023). PMC11164539 37365240 source

      The Results section, “Aβ42/40 ratio and extracellular Aβ42 deposition are elevated in FAD cultures” (page unavailable), reports an increased Aβ42/Aβ40 ratio in patient-derived familial AD cultures compared with controls; the Discussion also reports extracellular Aβ42 deposition. These findings support the amyloid component, though an increased ratio is not the same as increased Aβ42 production. Our copy does not report active GSK-3β, phosphorylated tau in the iPSC-derived neurons, endosomal abnormalities, or oxidative stress. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [15] Ochalek A., Neurons derived from sporadic Alzheimer’s disease iPSCs reveal elevated TAU hyperphosphorylation, increased amyloid levels, and GSK3B activation. Alzheimers Res Ther 9, 90 (2017). 29191219 PMC5709977 source

      The Results report higher Aβ1–42, phosphorylated tau, and active GSK-3β in AD-derived neurons. The Background reports enlarged early endosomes in AD neurons from an earlier study. But this paper demonstrates greater sensitivity to induced oxidative stress, not that its untreated AD-derived neurons exhibit elevated oxidative stress. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites [16] Raja WK, Self-Organizing 3D Human Neural Tissue Derived from Induced Pluripotent Stem Cells Recapitulate Alzheimer’s Disease Phenotypes. PLoS One 11, e0161969 (2016). 27622770 PMC5021368 source

      The Results section (“Alzheimer’s disease phenotypes in organoids”; page not provided) reports increased Aβ in familial-AD organoids, increased phosphorylated tau, and enlarged endosomes; it also notes an earlier finding of increased secreted Aβ42 in neurons from one patient-derived line. The paper does not establish increased active GSK-3β or oxidative stress, and its own experiments concern 3D organoids rather than isolated iPSC-derived neurons. (LLM, conf=0.90)

      Experimental — accuracy not yet measured
    • cites [17] Wang C., Gain of toxic apolipoprotein E4 effects in human iPSC-derived neurons is ameliorated by a small-molecule structure corrector. Nat Med 24, 647– 657 (2018). 29632371 PMC5948154 source

      The Results report increased Aβ42 secretion and phosphorylated tau in human iPSC-derived apoE4/4 neurons compared with apoE3/3 neurons. The paper does not report increased active GSK-3β, endosomal abnormalities, or oxidative stress in those neurons; its comparison is by apoE genotype, not broadly between individuals with and without AD. Page numbers are not available in our copy. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • Classified as probably not a substantial claim.

    Premisecitation

    Recent studies have directly induced neurons from individuals with AD through NGN2/ASCL1 overexpression.

    “Recent studies have directly induced neurons from individuals with AD through NGN2/ASCL1 overexpression.”
    Quote in the paperSubstantial claim3 of 3 sources checked
    • cites [11] Mertens J., Age-dependent instability of mature neuronal fate in induced neurons from Alzheimer’s patients. Cell Stem Cell 28, 1533– 1548 e1536 (2021). 33910058 PMC8423435 source
    • cites [24] Herdy JR, Increased post-mitotic senescence in aged human neurons is a pathological feature of Alzheimer’s disease. Cell Stem Cell 29, 1637– 1652 e1636 (2022). 36459967 PMC10093780 source
    • cites [25] Traxler L., Warburg-like metabolic transformation underlies neuronal degeneration in sporadic Alzheimer’s disease. Cell Metab 34, 1248– 1263 e1246 (2022). 35987203 PMC9458870 source

  • May combine two claims.

    Findingcitation

    The miRNA+TFs approach generated a highly enriched neuronal population as previously characterized by single cell and bulk RNA-seq and electrically active cells in 2D culture, showing inward and outward currents and multiple action potentials measured by whole-cell recording.

    “This miRNA+TFs approach generated a highly enriched neuronal population as previously characterized by single cell and bulk RNA-seq (20, 28, 29) and electrically active cells in 2D culture, showing inward and outward currents and multiple action potentials measured by whole-cell recording (Fig. S1A).”
    Quote in the paperSubstantial claim3 of 3 sources checked
    • cites [20] Capano LS, Recapitulation of endogenous 4R tau expression and formation of insoluble tau in directly reprogrammed human neurons. Cell Stem Cell 29, 918– 932 e918 (2022). 35659876 PMC9176216 source

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

      Experimental — accuracy not yet measured
    • cites [28] Abernathy DG, MicroRNAs Induce a Permissive Chromatin Environment that Enables Neuronal Subtype-Specific Reprogramming of Adult Human Fibroblasts. Cell Stem Cell 21, 332– 348 e339 (2017). 28886366 PMC5679239 source

      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 [29] Cates K., Deconstructing Stepwise Fate Conversion of Human Fibroblasts to Neurons by MicroRNAs. Cell Stem Cell 28, 127– 140 e129 (2021). 32961143 PMC7796891 source

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

      Experimental — accuracy not yet measured

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

    Premisecitation

    Downregulation of KCNIP3 in the brains of individuals with AD is associated with memory and learning.

    “Downregulation of KCNIP3 in the brains of individuals with AD is associated with memory and learning (63).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [63] Pereira AC, Age and Alzheimer’s disease gene expression profiles reversed by the glutamate modulator riluzole. Mol Psychiatry 22, 296– 305 (2017). 27021815 PMC5042881 source

      The Results section reports that several genes are diminished in AD tissue, and the Discussion links some of those genes to learning and memory. Neither section identifies KCNIP3 or addresses whether its downregulation is associated with learning and memory; searches for KCNIP3 and its alternative names found no matching passage in our copy. (LLM, conf=0.73)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    The expression of SST and KCNIP1 is reduced in the brains of individuals with AD, and downregulation of these two genes has been implicated in mediating the formation of Aβ oligomers.

    “The expression of SST (61) and KCNIP1 (62) is reduced in the brains of individuals with AD, and downregulation of these two genes has been implicated in mediating the formation of Aβ oligomers.”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [61] Saiz-Sanchez D., Somatostatin, Olfaction, and Neurodegeneration. Front Neurosci 14, 96 (2020). 32140092 PMC7042373 source

      The 'Somatostatin and Alzheimer’s Disease' section reports reduced SST in AD and says SST can encourage Aβ oligomer formation. It does not say that SST downregulation mediates oligomer formation. KCNIP1 is attached to a different citation in the citing sentence, so it is not assessed against this source. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [62] Miller JA, Woltjer RL, Goodenbour JM, Horvath S, Geschwind DH, Genes and pathways underlying regional and cell type changes in Alzheimer’s disease. Genome Med 5, 48 (2013). 23705665 PMC3706780 source

      Table 3 in the Results lists KCNIP1 as downregulated with AD in the CA1 hippocampal region (fold change −1.77), supporting the part of the sentence attached to this citation. The paper does not implicate KCNIP1 downregulation in Aβ oligomer formation; SST has a separate citation in the citing sentence. (LLM, conf=0.88)

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

    Premisecitation

    CCL20, CSF3 and IL10 are associated with the inflammatory response in AD.

    “CCL20 (55), CSF3 (56) and IL10 (57) are associated with the inflammatory response in AD.”
    Quote in the paperNot a substantial claim3 of 3 sources checked
    • cites [55] Wang Y., Interleukin-1beta induces blood-brain barrier disruption by downregulating Sonic hedgehog in astrocytes. PLoS One 9, e110024 (2014). 25313834 PMC4196962 source

      Citation 55 is attached to CCL20, so this verdict does not assess CSF3 or IL10. The Results section reports that IL-1β increased CCL20 in astrocytes and links these pro-inflammatory chemokines to neuroinflammation. The Discussion mentions Alzheimer’s disease among conditions associated with elevated IL-1β, but the paper does not directly establish a CCL20–inflammatory-response association in AD; no page number is available in our copy. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites [56] Zhang W, Zhang Y, Hu N, Wang A, Alzheimer’s disease-associated inflammatory pathways might contribute to osteoporosis through the interaction between PROK2 and CSF3. Front Neurol 13, 990779 (2022). 36203970 PMC9531648 source
    • cites [57] Guillot-Sestier MV, Il10 deficiency rebalances innate immunity to mitigate Alzheimerlike pathology. Neuron 85, 534– 548 (2015). 25619654 PMC4352138 source

  • May combine two claims.

    Premisecitation

    Neurons directly induced from individuals with AD through NGN2/ASCL1 overexpression exhibited age-associated dysregulations such as instability of mature neuronal fate, increased cellular senescence, and metabolic shifts.

    “These neurons exhibited several age-associated dysregulations such as instability of mature neuronal fate, increased cellular senescence, and metabolic shifts (11, 24, 25)”
    Quote in the paperSubstantial claim3 of 3 sources checked
    • cites [11] Mertens J., Age-dependent instability of mature neuronal fate in induced neurons from Alzheimer’s patients. Cell Stem Cell 28, 1533– 1548 e1536 (2021). 33910058 PMC8423435 source

      The Results sections on direct iN conversion and stress-related de-differentiation report Ngn2/Ascl1 conversion of AD patient fibroblasts, loss of mature neuronal identity, and changes in genes associated with energy metabolism. The Results section on immature transcriptional programs finds enrichment of senescence-related pathways, but does not establish increased cellular senescence in the neurons themselves; the epigenetic-aging analysis also reports no accelerated aging relative to controls. Page numbers are unavailable in our copy. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [24] Herdy JR, Increased post-mitotic senescence in aged human neurons is a pathological feature of Alzheimer’s disease. Cell Stem Cell 29, 1637– 1652 e1636 (2022). 36459967 PMC10093780 source
    • cites [25] Traxler L., Warburg-like metabolic transformation underlies neuronal degeneration in sporadic Alzheimer’s disease. Cell Metab 34, 1248– 1263 e1246 (2022). 35987203 PMC9458870 source

      The Results section describes generating AD-patient-derived neurons by overexpressing Ascl1 and Ngn2. The Introduction and Discussion describe loss of mature neuronal identity and a shift toward aerobic glycolysis. The passages do not establish increased cellular senescence in these neurons; preserving donors’ aging signatures is not the same finding. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

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

    Premisecitation

    A recent proteomic study identified HGF protein as one of the elevated proteins in the ADAD brain compared with cognitively normal individuals.

    “A recent proteomic study identified HGF protein as one of the elevated proteins in the ADAD brain compared with cognitively normal individuals (Fig. S5F) (58).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [58] Sung YJ, Proteomics of brain, CSF, and plasma identifies molecular signatures for distinguishing sporadic and genetic Alzheimer’s disease. Sci Transl Med 15, eabq5923 (2023). 37406134 PMC10803068 source

      The Results section on sporadic AD identifies HGF among proteins associated with AD in brain tissue. The ADAD Results section reports altered brain proteins relative to cognitively normal controls and says most sporadic-AD-associated proteins showed stronger alterations in ADAD, but our copy does not specifically say that HGF was elevated in ADAD brain. (LLM, conf=0.84)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Among the most upregulated DEGs, higher amounts of MMP3, IBSP, or TAGLN in the brain have been linked to increased risk of AD.

    “Among the most upregulated DEGs, higher amounts of MMP3 (52), IBSP (53), or TAGLN (54) in the brain have been linked to increased risk of AD.”
    Quote in the paperNot a substantial claim3 of 3 sources checked
    • cites [52] Pentz R., A new role for matrix metalloproteinase-3 in the NGF metabolic pathway: Proteolysis of mature NGF and sex-specific differences in the continuum of Alzheimer’s pathology. Neurobiol Dis 148, 105150 (2021). 33130223 PMC7856186 source

      The Results section, “Alterations of MMP-3 levels in the human cerebral cortex through the continuum of AD pathology” (page not supplied), reports higher brain MMP-3 in AD, MCI, and cognitively normal people with AD-like pathology. It also links higher MMP-3 to greater amyloid burden. These findings support an association with AD pathology, but the paper does not show that higher brain MMP-3 predicts an increased risk of developing AD. Citation (52) is attached to MMP3, not IBSP or TAGLN. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [53] Frick EA, Serum proteomics reveals APOE dependent and independent protein signatures in Alzheimer’s disease. medRxiv, (2023). source

      The Results section on Mendelian randomization reports that higher IBSP was associated with increased risk of late-onset AD in serum-based analyses. It does not establish that higher IBSP amounts in the brain are linked to that risk; the brain-proteome comparison does not identify IBSP as such a finding. No page number is available in our copy. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [54] Gonzalez-Rodriguez M., Human amygdala involvement in Alzheimer’s disease revealed by stereological and dia-PASEF analysis. Brain Pathol 33, e13180 (2023). 37331354 PMC10467039 source

      Table 2 in the Results lists TAGLN (transgelin) as an upregulated protein in AD amygdala samples, with a fold change of 1.82. The paper reports differential protein expression, not TAGLN as an upregulated DEG, and does not establish that higher TAGLN increases the risk of developing AD. Citation (54) is attached to TAGLN, so the MMP3 and IBSP claims are not assessed here. (LLM, conf=0.87)

      Experimental — accuracy not yet measured

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

    Premisecitation

    Several studies suggest that increased tau phosphorylation generally reflects brain aging.

    “Several studies suggest that increased tau phosphorylation generally reflects brain aging (67, 68).”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [67] Scholl M., PET Imaging of Tau Deposition in the Aging Human Brain. Neuron 89, 971– 982 (2016). 26938442 PMC4779187 source

      The Introduction and Discussion report that tau pathology occurs in healthy aging and that advancing age predicts greater medial temporal tau accumulation. But the Discussion distinguishes this age-related pattern from tau spread into other cortical regions, which it associates with amyloid burden. The paper therefore supports an aging association for tau pathology, not the unqualified claim that increased tau phosphorylation generally reflects brain aging. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [68] Sjogren M., Tau and Abeta42 in cerebrospinal fluid from healthy adults 21–93 years of age: establishment of reference values. Clin Chem 47, 1776– 1781 (2001). 11568086 source

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

    Premisecitation

    Other DEGs include DOC2A and FOXF1 that have been recently identified by a recent GWAS study as genes whose variants were linked to AD.

    “Other DEGs also include DOC2A and FOXF1 (Table S5) that have been recently identified by a recent GWAS study as genes whose variants were linked to AD (78).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [78] Bellenguez C., New insights into the genetic etiology of Alzheimer’s disease and related dementias. Nat Genet 54, 412– 436 (2022). 35379992 PMC9005347 source

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

    Premisecitation

    Depletion of piwi proteins was shown to increase transposable element (TE) transcription in a Drosophila model of tauopathy.

    “Depletion of piwi proteins was shown to increase transposable element (TE) transcription in a Drosophila model of tauopathy (77).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [77] Sun W, Samimi H, Gamez M, Zare H, Frost B, Pathogenic tau-induced piRNA depletion promotes neuronal death through transposable element dysregulation in neurodegenerative tauopathies. Nat Neurosci 21, 1038– 1048 (2018). 30038280 PMC6095477 source

      The Results section, “Piwi/piRNA depletion is a mechanistic driver of transposable element transcription in tauopathy,” reports that neuronal piwi knockdown elevated TE transcript levels in Drosophila. However, that knockdown experiment was performed without transgenic tau, so it does not directly show the effect of induced piwi depletion within tau-expressing flies. (LLM, conf=0.82)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    MMPs are known to be linked to extracellular protein degradation including Aβ, whereas MMPs upregulated in AD may also confer neuroinflammation, synaptic dysfunction, and neuronal death.

    “MMPs are known to be linked to extracellular protein degradation including Aβ (72), whereas MMPs upregulated in AD may also confer neuroinflammation, synaptic dysfunction, and neuronal death (73, 74).”
    Quote in the paperNot a substantial claim3 of 3 sources checked
    • cites [72] White AR, Degradation of the Alzheimer disease amyloid beta-peptide by metal-dependent up-regulation of metalloprotease activity. J Biol Chem 281, 17670– 17680 (2006). 16648635 source
    • cites [73] Hoogmartens J., Investigation of the role of matrix metalloproteinases in the genetic etiology of Alzheimer’s disease. Neurobiol Aging 104, 105 e101– 105 e106 (2021). 33892965 source
    • cites [74] Zipfel P, Rochais C, Baranger K, Rivera S, Dallemagne P, Matrix Metalloproteinases as New Targets in Alzheimer’s Disease: Opportunities and Challenges. J Med Chem 63, 10705– 10725 (2020). 32459966 source

      The 'General implication of MMPs in AD' section identifies MMPs as Aβ-degrading enzymes and discusses AD-associated MMPs in relation to neuroinflammation and neuronal death. It attributes synaptic deficits to Aβ accumulation, however, rather than stating that upregulated MMPs cause synaptic dysfunction. No page numbers are available in our copy. (LLM, conf=0.84)

      Experimental — accuracy not yet measured

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

    Premisecitation

    NPAS4 is a TF that protects against age-dependent accumulation of DNA damages and somatic mutations.

    “NPAS4, a TF that protects against age-dependent accumulation of DNA damages and somatic mutations (76)”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [76] Pollina EA, A NPAS4-NuA4 complex couples synaptic activity to DNA repair. Nature 614, 732– 741 (2023). 36792830 PMC9946837 source

      The ‘Age-dependent mutations at NPAS4 sites’ section reports that NPAS4–NuA4-bound sites in mouse hippocampal neurons were relatively protected from mutations accumulating with age. The ‘NPAS4–NuA4 disruption impairs DSB repair’ section also reports more DNA double-strand breaks after NPAS4 deletion. The claim is broader than these findings: the mutation result concerns specific bound sites, and the paper does not establish protection against age-dependent accumulation of DNA damage generally. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    SV2 is a marker for mature synaptic vesicles and regulates presynaptic release.

    “SV2, a marker for mature synaptic vesicles and regulates presynaptic release (70, 71)”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [70] Wen Z., Synaptic dysregulation in a human iPS cell model of mental disorders. Nature 515, 414– 418 (2014). 25132547 PMC4501856 source
    • cites [71] Chang WP, Sudhof TC, SV2 renders primed synaptic vesicles competent for Ca2+ -induced exocytosis. J Neurosci 29, 883– 897 (2009). 19176798 PMC2693337 source

      The Introduction (page not provided) identifies SV2 as a component of all vertebrate synaptic vesicles, and “The function of SV2” reports that deleting it substantially reduces release. The paper does not specifically identify SV2 as a marker for mature synaptic vesicles; its discussion of a vesicle maturation step does not establish that marker claim. (LLM, conf=0.84)

      Experimental — accuracy not yet measured

  • Classified as probably not a substantial claim.

    Premisecitation

    Methanol fixation has previously been used to remove soluble proteins, including tau.

    “Methanol fixation has previously been used to remove soluble proteins, including tau (20, 46).”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [20] Capano LS, Recapitulation of endogenous 4R tau expression and formation of insoluble tau in directly reprogrammed human neurons. Cell Stem Cell 29, 918– 932 e918 (2022). 35659876 PMC9176216 source
    • cites [46] Guo JL, Unique pathological tau conformers from Alzheimer’s brains transmit tau pathology in nontransgenic mice. J Exp Med 213, 2635– 2654 (2016). 27810929 PMC5110027 source

      The Immunocytochemistry methods state that neurons were fixed with methanol to remove soluble tau. This supports the tau example, but the passage does not say that methanol fixation was used to remove soluble proteins more generally. (LLM, conf=0.83)

      Experimental — accuracy not yet measured

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

    Premisecitation

    Pathogenic tau has been linked to synaptic dysfunction and loss.

    “Pathogenic tau has been linked to synaptic dysfunction and loss (69).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [69] Guerrero-Munoz MJ, Gerson J, Castillo-Carranza DL, Tau Oligomers: The Toxic Player at Synapses in Alzheimer’s Disease. Front Cell Neurosci 9, 464 (2015). 26696824 PMC4667007 source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    In AD, tau protein becomes hyperphosphorylated, resulting in tau dissociating from microtubules and forming insoluble tau aggregates in the neurites and cell bodies.

    “In AD, tau protein becomes hyperphosphorylated, resulting in tau dissociating from microtubules and forming insoluble tau aggregates in the neurites and cell bodies (3, 37).”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [3] Choi SH, A three-dimensional human neural cell culture model of Alzheimer’s disease. Nature 515, 274– 278 (2014). 25307057 PMC4366007 source

      The main text says tau is hyperphosphorylated in AD and reports insoluble p-tau aggregates in the cell bodies and neurite-like structures of its 3D culture model. It does not state that hyperphosphorylation causes tau to dissociate from microtubules, so that mechanistic step is unsupported by our copy. Page numbers are not provided. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [37] Trojanowski JQ, Lee VM, The role of tau in Alzheimer’s disease. Med Clin North Am 86, 615– 627 (2002). 12168561 source

  • May combine two claims.

    Premisecitation

    Tau FRET sensors composed of tau P301S-Ruby2 and -Clover reporters aggregate and transmit FRET signals in the presence of seed-competent tau species.

    “These reporter proteins aggregate and transmit FRET signals in the presence of seed-competent tau species (44, 45).”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [44] Hitt BD, Ultrasensitive tau biosensor cells detect no seeding in Alzheimer’s disease CSF. Acta Neuropathol Commun 9, 99 (2021). 34039426 PMC8152020 source

      The Results section (‘Construction of tau RD(P301S) v2H biosensor cells’; page not available) reports that the biosensors aggregate and produce FRET upon exposure to tau seeds. But the Methods section (‘Generation of biosensor cell lines’; page not available) identifies the reporters as tau RD(P301S) fused to mClover3 and mCerulean3, not Ruby2 and Clover. (LLM, conf=0.90)

      Experimental — accuracy not yet measured
    • cites [45] Lam AJ, Improving FRET dynamic range with bright green and red fluorescent proteins. Nat Methods 9, 1005– 1012 (2012). 22961245 PMC3461113 source

      The Results sections on mRuby2 and RhoA responses show that Clover–mRuby2 functions as a FRET pair in other reporters. Our copy does not address tau P301S reporters, aggregation, or responses to seed-competent tau species; searches for those terms found no supporting passage. (LLM, conf=0.76)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Findingown data

    Both 3R- and 4R-tau isoforms were detected with no noticeable difference in the 3R to 4R ratio between LOAD and HC 3D-CNs.

    “Both 3R- and 4R-tau isoforms were detected with no noticeable difference in the 3R to 4R ratio between LOAD and HC 3D-CNs, consistent with the concept that AD is a mixed 3R/4R tauopathy (65, 66) (Fig. 3D).”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [65] Dugger BN, Dickson DW, Pathology of Neurodegenerative Diseases. Cold Spring Harb Perspect Biol 9, (2017). PMC5495060 28062563 source
    • cites [66] Zhang Y, Wu KM, Yang L, Dong Q, Yu JT, Tauopathies: new perspectives and challenges. Mol Neurodegener 17, 28 (2022). 35392986 PMC8991707 source

  • Classified as probably not a substantial claim.

    Premisecitation

    Dysregulation of retrotransposon elements (RTEs) in aging may trigger inflammatory responses.

    “It was previously shown that dysregulation of retrotransposon elements (RTEs) in aging may trigger inflammatory responses (86–88)”
    Quote in the paperSubstantial claim3 of 3 sources checked
    • cites [86] De Cecco M., L1 drives IFN in senescent cells and promotes age-associated inflammation. Nature 566, 73– 78 (2019). 30728521 PMC6519963 source
    • cites [87] Gorbunova V., The role of retrotransposable elements in ageing and age-associated diseases. Nature 596, 43– 53 (2021). 34349292 PMC8600649 source
    • cites [88] Lopez-Otin C, Blasco MA, Partridge L, Serrano M, Kroemer G, Hallmarks of aging: An expanding universe. Cell 186, 243– 278 (2023). 36599349 source

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

    Premisecitation

    Counteracting aging pathways has been shown to lower age- and disease stage-dependent neurodegeneration in a patient-derived Huntington disease model.

    “Indeed, counteracting aging pathways has been shown to lower age- and disease stage-dependent neurodegeneration in a patient-derived Huntington disease model (32).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [32] Oh YM, Age-related Huntington’s disease progression modeled in directly reprogrammed patient-derived striatal neurons highlights impaired autophagy. Nat Neurosci 25, 1420– 1433 (2022). 36303071 PMC10162007 source

  • May combine two claims.

    Premisecitation

    Previous studies focused on overexpressing mutant APP and Presenilin in REN stem cells grown in a 3D culture, which differs from patient-specific LOAD model that relies on endogenous recapitulation of AD-associated phenotypes as provided in this study.

    “As for human neurons, previous studies focused on overexpressing mutant APP and Presenilin in REN stem cells grown in a 3D culture (3), which differs from patient-specific LOAD model that relies on the endogenous recapitulation of AD-associated phenotypes as provided in this study.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [3] Choi SH, A three-dimensional human neural cell culture model of Alzheimer’s disease. Nature 515, 274– 278 (2014). 25307057 PMC4366007 source

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

    Premisecitation

    Brain atrophy resulting from neuronal loss is a pathologic feature in LOAD.

    “Brain atrophy resulting from neuronal loss is a pathologic feature in LOAD (36).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [36] Knopman DS, Alzheimer disease. Nat Rev Dis Primers 7, 33 (2021). 33986301 PMC8574196 source

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

    Premisecitation

    AD is a neurodegenerative disorder marked by neuronal loss, especially in the hippocampus and cerebral cortex.

    “AD is a neurodegenerative disorder marked by neuronal loss, especially in the hippocampus and cerebral cortex (49, 50).”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [49] Golde TE, The therapeutic importance of understanding mechanisms of neuronal cell death in neurodegenerative disease. Mol Neurodegener 4, 8 (2009). 19193222 PMC2644308 source

      The Introduction identifies AD as a neurodegenerative disease, and the section on the natural history of neurodegenerative diseases describes neuronal loss as part of its progression (Figure 1). The passages do not identify the hippocampus or cerebral cortex as sites of especially marked loss, so that anatomical detail is unsupported by our copy. (LLM, conf=0.87)

      Experimental — accuracy not yet measured
    • cites [50] Gorman AM, Neuronal cell death in neurodegenerative diseases: recurring themes around protein handling. J Cell Mol Med 12, 2263– 2280 (2008). 18624755 PMC4514105 source

      The Introduction identifies AD as a neurodegenerative disease, and the Alzheimer’s disease section describes neuronal loss in hippocampal regions. The paper does not state that neuronal loss is especially prominent in the cerebral cortex generally, although its references mention loss of entorhinal cortex neurons. Page numbers are unavailable in our copy. (LLM, conf=0.84)

      Experimental — accuracy not yet measured

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

    Premisecitation

    Genes involved in APP metabolism were identified as AD risk genes.

    “Moreover, genes involved in APP metabolism were identified as AD risk genes (78).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [78] Bellenguez C., New insights into the genetic etiology of Alzheimer’s disease and related dementias. Nat Genet 54, 412– 436 (2022). 35379992 PMC9005347 source

  • May combine two claims.

    Premisecitation

    It typically requires additional expression of human tau harboring mutations associated with primary tauopathy or seeding mutant human APP knock-in mouse brain with human AD brain-derived tau to develop tau pathology in mouse models.

    “It typically requires additional expression of human tau harboring mutations associated with primary tauopathy (94–96) or seeding mutant human APP knock-in mouse brain with human AD brain-derived tau (97) to develop the tau pathology.”
    Quote in the paperSubstantial claim4 of 4 sources checked
    • cites [94] Dawson TM, Golde TE, Lagier-Tourenne C, Animal models of neurodegenerative diseases. Nat Neurosci 21, 1370– 1379 (2018). 30250265 PMC6615039 source

      The sections on genetic-based tau and amyloid models (page not provided) say that mice overexpressing human tau with FTD-linked mutations develop tau pathology, while amyloid models generally lack prominent tau accumulation unless seeded with AD tau. The copy does not specify that the seeded mice are mutant human APP knock-in mice or that the tau is derived from human AD brain. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites [95] King A, The search for better animal models of Alzheimer’s disease. Nature 559, S13– S15 (2018). 30046083 source

      In the section on mouse models (page not provided), the paper says that PD-APP mice do not develop tau tangles and that some models use tau mutations associated with frontotemporal dementia, sometimes alongside mutations that produce amyloid plaques. It does not describe seeding mutant APP knock-in mouse brains with human Alzheimer’s disease brain-derived tau. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [96] Reardon S, Frustrated Alzheimer’s researchers seek better lab mice. Nature 563, 611– 612 (2018). 30482928 source

      The cited portion of the sentence concerns seeding mutant human APP knock-in mouse brains with human Alzheimer’s disease brain-derived tau. The article discusses mice engineered to show amyloid plaques and tau tangles (p. 2), but does not describe that seeding method; searches for tau seeding and APP knock-in mice found no supporting passage. (LLM, conf=0.74)

      Experimental — accuracy not yet measured
    • cites [97] He Z., Amyloid-beta plaques enhance Alzheimer’s brain tau-seeded pathologies by facilitating neuritic plaque tau aggregation. Nat Med 24, 29– 38 (2018). 29200205 PMC5760353 source

  • May combine two claims.

    Premisecitation

    Mouse models overexpressing gene mutations associated with ADAD offer valuable insights into Aβ plaque formation but show no obvious tau pathology.

    “Although mouse models overexpressing gene mutations associated with ADAD offer valuable insights into Aβ plaque formation (93), they show no obvious tau pathology.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [93] Oakley H., Intraneuronal beta-amyloid aggregates, neurodegeneration, and neuron loss in transgenic mice with five familial Alzheimer’s disease mutations: potential factors in amyloid plaque formation. J Neurosci 26, 10129– 10140 (2006). 17021169 PMC6674618 source

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    Suppression of RTE reduces tau activation and tau-induced neurotoxicity in tau transgenic Drosophila.

    “suppression of RTE was shown to reduce tau activation and tau-induced neurotoxicity in tau transgenic Drosophila (77).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [77] Sun W, Samimi H, Gamez M, Zare H, Frost B, Pathogenic tau-induced piRNA depletion promotes neuronal death through transposable element dysregulation in neurodegenerative tauopathies. Nat Neurosci 21, 1038– 1048 (2018). 30038280 PMC6095477 source

      The Results section on dietary restriction and reverse-transcriptase inhibition reports that reducing transposable-element mobilization in tau-transgenic Drosophila also reduced tau-induced neuronal death. It does not report that these interventions reduced tau activation; the reduced reporter activation described there measures transposable-element mobilization, not tau activation. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • Classified as probably not a substantial claim.

    Premisecitation

    AD is also associated with progressive neurite degeneration.

    “Since AD is also associated with progressive neurite degeneration (51), we examined neurite outgrowth in spheroids.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [51] Siskova Z., Dendritic structural degeneration is functionally linked to cellular hyperexcitability in a mouse model of Alzheimer’s disease. Neuron 84, 1023– 1033 (2014). 25456500 source

  • Classified as probably not a substantial claim.

    Premisecitation

    Ectopic retrotransposon activation has been associated with DNA damage and genomic instability.

    “Since ectopic retrotransposon activation has been associated with DNA damage and genomic instability (87, 90)”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [87] Gorbunova V., The role of retrotransposable elements in ageing and age-associated diseases. Nature 596, 43– 53 (2021). 34349292 PMC8600649 source
    • cites [90] Gasior SL, Wakeman TP, Xu B, Deininger PL, The human LINE-1 retrotransposon creates DNA double-strand breaks. J Mol Biol 357, 1383– 1393 (2006). 16490214 PMC4136747 source

  • May combine two claims.

    Findingown data

    The 832 LOAD spheroid DEGs overlap with bulk RNA-seq datasets from various brain regions in individuals with AD, GO terms related to apoptosis/neurodegeneration, and AD risk genes from Alzgene database, with overlaps ranging from 8 to 135 genes.

    “We further compared 832 DEGs with bulk RNA-seq datasets from various brain regions in individuals with AD (80–84), gene members in GO terms related to apoptosis/neurodegeneration, and AD risk genes from Alzgene database, revealing distinct sets of DEGs with overlaps ranging from 8 to 135 genes (Table S7, page 2, 3 and 4).”
    Quote in the paperSubstantial claim4 of 5 sources checked
    • cites [80] Friedman BA, Diverse Brain Myeloid Expression Profiles Reveal Distinct Microglial Activation States and Aspects of Alzheimer’s Disease Not Evident in Mouse Models. Cell Rep 22, 832– 847 (2018). 29346778 source

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

    • cites [81] Guo W., Exploring the interaction between T-cell antigen receptor-related genes and MAPT or ACHE using integrated bioinformatics analysis. Front Neurol 14, 1129470 (2023). 37056359 PMC10086260 source
    • cites [82] Ivashko-Pachima Y., Discovery of autism/intellectual disability somatic mutations in Alzheimer’s brains: mutated ADNP cytoskeletal impairments and repair as a case study. Mol Psychiatry 26, 1619– 1633 (2021). 31664177 PMC8159740 source
    • cites [83] Nativio R., An integrated multi-omics approach identifies epigenetic alterations associated with Alzheimer’s disease. Nat Genet 52, 1024– 1035 (2020). 32989324 PMC8098004 source
    • cites [84] Srinivasan K., Alzheimer’s Patient Microglia Exhibit Enhanced Aging and Unique Transcriptional Activation. Cell Rep 31, 107843 (2020). 32610143 PMC7422733 source

  • Classified as probably not a substantial claim.

    Premisecitation

    Aging may impact the function of astrocytes and microglia.

    “as aging may impact the function of astrocytes (98, 99) and microglia (100)”
    Quote in the paperSubstantial claim3 of 3 sources checked
    • cites [98] Clarke LE, Normal aging induces A1-like astrocyte reactivity. Proc Natl Acad Sci U S A 115, E1896– E1905 (2018). 29437957 PMC5828643 source
    • cites [99] Cohen J, Torres C, Astrocyte senescence: Evidence and significance. Aging Cell 18, e12937 (2019). 30815970 PMC6516680 source
    • cites [100] Niraula A, Sheridan JF, Godbout JP, Microglia Priming with Aging and Stress. Neuropsychopharmacology 42, 318– 333 (2017). 27604565 PMC5143497 source

  • May combine two claims.

    Findingown data

    ADAD 3D-CNs showed a threefold increase in total volume of Aβ deposits and higher numbers of Aβ deposits with size of 10,000-100,000 μm3 compared to HC 3D-CNs.

    “Similar results were observed using a different Aβ antibody, 6E10: ADAD 3D-CNs showed a threefold increase in total volume of Aβ deposits and higher numbers of Aβ deposits with size of 10,000–100,000 μm3 compared to HC 3D-CNs (Fig. 1J and Fig. S3B).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    HC spheroids maintained neurite length from PID22 to PID28, ADAD spheroids showed significant retraction of neurite outgrowth at PID28.

    “Whereas HC spheroids maintained neurite length from PID22 to PID28, ADAD spheroids showed significant (p < 0.05 in distal and middle regions) retraction of neurite outgrowth at PID28 (Fig. 2G).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    ADAD-RFP spheroids exhibited a 50% reduction in RFP+ area at PID33, higher than the 10-20% reduction observed in HC spheroids.

    “Similar to co-culturing, ADAD-RFP spheroids exhibited a 50% reduction in RFP+ area at PID33, higher than the 10–20% reduction observed in HC spheroids (Fig. S5B).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    ADAD spheroids shrank by 50% in size from PID17 to PID33, whereas HC spheroids only decreased by 10% in the same environment.

    “First, ADAD spheroids (labeled by turboRFP) cultured adjacent to HC spheroids (labeled by eGFP) shrank by 50% in size from PID17 to PID33, whereas HC spheroids only decreased by 10% in the same environment (Fig. 2E, right).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    ADAD and HC cells showed minimal cell death until PID20, substantial cell death was detected in ADAD 3D-CNs at PID30 and PID35, compared to HCs.

    “Whereas ADAD and HC cells showed minimal cell death until PID20, substantial cell death was detected in ADAD 3D-CNs at PID30 and PID35, compared to HCs (Fig. S5A).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    HC spheroids displayed low Aβ42 expression, whereas ADAD spheroids contained substantial expression of Aβ42.

    “HC spheroids displayed low Aβ42 expression, whereas ADAD spheroids contained substantial expression of Aβ42 (Fig. 1K), consistent with effects of ADAD mutations on APP processing.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    ADAD 3D-CNs exhibited significantly increased FRET signals compared to HCs, suggesting that ADAD 3D-CNs contain more seed-competent tau.

    “As shown in Fig. 2D, ADAD 3D-CNs exhibited significantly (p < 0.05) increased FRET signals compared to HCs, suggesting that ADAD 3D-CNs contain more seed-competent tau.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Cryosections of PID28 ADAD spheroids immunostained with 6E10 or 82E1 Aβ antibody showed that Aβ deposits were formed in the extracellular space, in higher amounts compared to HC spheroids.

    “Cryosections of PID28 ADAD spheroids immunostained with 6E10 or 82E1 Aβ antibody showed that Aβ deposits were formed in the extracellular space (Fig. 1M and Fig. S3E), in higher amounts compared to HC spheroids (Fig. S3E).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Sections of PID28 spheroids showed over 90% of cells expressed neuronal markers NCAM1, MAP2, TAU and TUBBIII and more than 80% of cells expressed NEUN, whereas less than 1% of cells expressing fibroblast marker FSP1.

    “Sections of PID28 spheroids showed over 90% of cells expressed neuronal markers NCAM1, MAP2, TAU and TUBBIII and more than 80% of cells expressed NEUN, whereas less than 1% of cells expressing fibroblast marker FSP1 (Fig. S1F).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Spheroids at PID28 showed neurite projections radiating out from the core and gene expression patterns similar to 3D-CNs at PID30 including downregulation of fibroblast marker genes and increased expression of long genes and neuronal markers.

    “Spheroids at PID28 showed neurite projections radiating out from the core (Fig. 1F) and gene expression patterns similar to 3D-CNs at PID30 including downregulation of fibroblast marker genes and increased expression of long genes and neuronal markers as assessed by RNA-seq (Fig. 1G and 1H).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    LOAD and HC reprogramming cells did not display apparent cell death during the early phase of reprogramming (PID20), whereas PID30 and PID35 time points exhibited increased Sytox-Green signal in LOAD 3D-CNs compared to HC 3D-CNs.

    “Specifically, LOAD and HC reprogramming cells did not display apparent cell death during the early phase of reprogramming (PID20), whereas PID30 and PID35 time points exhibited increased Sytox-Green signal in LOAD 3D-CNs compared to HC 3D-CNs (Fig. 4A), consistent with live-cell tracking over time showing neuronal loss of cell bodies and neurite length in LOAD 3D-CNs compared to HC 3D-CNs (Fig. S9”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Treating β- or γ-secretase inhibitors started at PID16 lowered p-tau and K63-ubiquitin/p-tau colocalization, whereas no effects were seen when treatment started at PID22.

    “Furthermore, treating b- or gsecretase inhibitors started at PID16 lowered p-tau and K63-ubiquitin/p-tau colocalization, whereas no effects were seen when treatment started at PID22 (Fig. 5B).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Early PID intervention (β- or γ-secretase inhibitors at PID16) substantially decreased Aβ deposits in the LOAD spheroids by 80-90% and also reduced cleaved Aβ species in the media.

    “This early PID intervention substantially decreased Aβ deposits in the LOAD spheroids by 80–90% (Fig. 5A) and also reduced cleaved Aβ species in the media (Fig. S6D).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    β- or γ-secretase inhibitors treated at PID16 effectively lowered neuronal death in LOAD spheroids by approximately 50%, whereas no effects were observed when treatment started at PID22.

    “Lastly, β- or γ- secretase inhibitors treated at PID16 effectively lowered neuronal death in LOAD spheroids by approximately 50%, whereas no effects were observed when treatment started at PID22 (Fig. 5C).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    LOAD spheroids showed a ~50% reduction in size from PID17 to PID33, in contrast to ~10-20% reduction in size observed in the HC counterparts.

    “In both cases, we observed a ~ 50% reduction in the size of LOAD spheroids from PID17 to PID33, in contrast to ~10–20% reduction in size observed in the HC counterparts (Fig. 4B and Fig. S9B).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Fewer numbers of SYN1+PSD95+ synapses and a reduction in PSD95+ signal in SYN1+ puncta in LOAD neurites compared to HC.

    “Quantification showed fewer numbers of SYN1+PSD95+ synapses and a reduction in PSD95+ signal in SYN1+ puncta in LOAD neurites compared to HC.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    3TC decreased Aβ formation and tau pathologies in LOAD spheroids, as evidenced by reduction of Aβ deposition, p-tau, and K63-linked ubiquitin-positive tau.

    “3TC also decreased Aβ formation and tau pathologies, as evidenced by the reduction of Aβ deposition, p-tau, and K63-linked ubiquitin-positive tau (Fig. 7C and 7D).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    3983 common DEGs were identified between young vs old HC spheroids and young HC vs LOAD spheroids, associated with translation, cell adhesion, response to hypoxia, axon guidance, ion transmembrane transport, and inflammatory response.

    “3983 common DEGs were identified between these two datasets, which were associated with translation, cell adhesion, response to hypoxia, axon guidance, ion transmembrane transport, and inflammatory response (Fig. S12B and Table S9).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingnone given

    Inhibition of APP processing mitigated degeneration of LOAD neurons, but the effect was clear only when cells were treated before the formation of Aβ deposits, not after the onset.

    “Whereas the inhibition of APP processing mitigated degeneration of LOAD neurons, the effect was clear only when cells were treated before the formation of Ab deposits, not after the onset.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    AD neurons undergo Aβ-dependent tauopathy and neurodegeneration, yet mitigation of neurodegeneration depends on the presence or absence of preformed Aβ deposits.

    “These results suggest that AD neurons undergo Aβ-dependent tauopathy and neurodegeneration, yet mitigation of neurodegeneration depends on the presence or absence of preformed Aβ deposits.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    LEP has been linked to the sporadic form of AD.

    “Other upregulated DEGs included LEP, which encodes for Leptin, that has been linked to the sporadic form of AD (75).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [75] Folch J., The role of leptin in the sporadic form of Alzheimer’s disease. Interactions with the adipokines amylin, ghrelin and the pituitary hormone prolactin. Life Sci 140, 19– 28 (2015). 25998028 source

  • Classified as probably not a substantial claim.

    Premisecitation

    MC1 antibody detects conformationally misfolded tau.

    “MC1 antibody, which detects conformationally misfolded tau (40)”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [40] Jicha GA, Bowser R, Kazam IG, Davies P, Alz-50 and MC-1, a new monoclonal antibody raised to paired helical filaments, recognize conformational epitopes on recombinant tau. J Neurosci Res 48, 128– 132 (1997). 9130141 source

  • May combine two claims.

    Interpretationown data

    Although common DEGs exist, the LOAD spheroid transcriptome is characterized by the presence of age-associated pathways as well as unique DEGs that differ from ADAD spheroids.

    “Taken together, although common DEGs exist, LOAD spheroid transcriptome is characterized by the presence of age-associated pathways as well as unique DEGs that differ from ADAD spheroids.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Transcriptomic overlap between LOAD spheroids and postmortem AD brains indicates that the spheroid model recapitulates LOAD neurodegeneration.

  • May combine two claims.

    Study design and conductown data

    3TC-treated cells retained the expression of neuronal genes, indicating the protective effects of 3TC were not due to loss of neuronal identity.

    “We further confirmed these protective effects of 3TC were not due to the loss of neuronal identity, as 3TC-treated cells retained the expression of neuronal genes (Fig. S11E).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Age is the major risk factor for LOAD compared to ADAD, in which mutations associated with APP processing drive the disease onset.

    “This highlights the important role of age as the major risk factor for LOAD compared to ADAD, in which mutations associated APP processing drive the disease onset.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Results demonstrate the effectiveness and sufficiency of 3D directly reprogrammed patient neurons to capture adult-onset neuropathology of LOAD.

    “Overall, results in this study demonstrate the effectiveness and sufficiency of 3D directly reprogrammed patient neurons to capture adult-onset neuropathology of LOAD.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Transcriptomic overlap between LOAD spheroids and postmortem AD brains indicates that the spheroid model recapitulates LOAD neurodegeneration.
61 of 61

  • The paper relies on this without support.

    Modeling sporadic LOAD that endogenously captures hallmark neuronal pathologies, such as Aβ deposition, tau tangles, and neuronal loss, remains an unmet need.

    “However, modeling sporadic LOAD, that endogenously captures hallmark neuronal pathologies, such as amyloid-β (Aβ) deposition, tau tangles, and neuronal loss, remains an unmet need.”

  • The paper relies on this without support.

    Sporadic LOAD modeling remains underexplored.

    “In contrast, sporadic LOAD modeling remains underexplored although LOAD represents over 95% of AD cases”

  • The paper relies on this without support.

    A LOAD patient-specific model system that allows the investigation of adult-onset neuropathological features remains to be established.

    “and a LOAD patient-specific model system that allows the investigation of adult-onset neuropathological features remains to be established.”

  • The paper relies on this without support.

    Transcriptomic overlap between LOAD spheroids and postmortem AD brains indicates that the spheroid model recapitulates LOAD neurodegeneration.

    “To further assess how the gene signatures of neurodegeneration in LOAD spheroids are reminiscent of its counterpart in the patient brain, we compared these DEGs with previously published gene expression profiling datasets of postmortem brains with AD as well as GO terms related to neurodegeneration (Table S7).”
4 of 4

Cites

Flagged first, then by citations

Research works printed but not linked: 4

  1. 10.1146/annurev-genet-120417-031534 · DOI
  2. 10.1016/j.stem.2015.09.001 · DOI · Paper page
  3. 10.1016/j.stem.2015.09.001 · DOI · Paper page
  4. 10.1074/jbc.M602487200 · DOI · Paper page

Cited by

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Related

Authors
Sun, Z., Kwon, J.-S., Ren, Y., Chen, S., Walker, C. K., Lu, X., Cates, K., Karahan, H., Sviben, S., Fitzpatrick, J. A. J., Valdez, C., Houlden, H., Karch, C. M., Bateman, R. J., Sato, C., Mennerick, S. J., Diamond, M. I., Kim, J., Tanzi, R. E., Holtzman, D. M., & Yoo, A. S.
Affiliations
  • Washington University in St. Louis (US)
  • Indiana University Indianapolis (US)
  • The University of Texas Southwestern Medical Center (US)
  • National Hospital for Neurology and Neurosurgery (GB)
  • Harvard University (US)
Corresponding author
Yoo, Andrew S.
ORCID
Venue
Science
Publisher
American Association for the Advancement of Science (AAAS)
Published
2024-08-02
Volume
385
Issue
6708
Pages
adl2992-adl2992
ISSN
  • 0036-8075 (ISSN-L)
  • 1095-9203
DOI
10.1126/science.adl2992
PMC
PMC11787906
OpenAlex
W4401211160
Semantic Scholar
2a2376e4046ae40c5d66bbb1e71072967b998b90
Cited by
77
References
111
Citations by year
2026: 28 · 2025: 32 · 2024: 16 · 2023: 1
FWCI
17.88
Type
journal article
Language
en
Update notices
correction (2026-09-24)
Open access
Locations
  • Science (publishedVersion)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • PubMed (publishedVersion)
  • IUScholarWorks (Indiana University) (submittedVersion)
  • UCL Discovery (University College London) (submittedVersion)
  • PubMed Central (submittedVersion)
Funders
  • Brown University
  • University of Pennsylvania
  • Cure Alzheimer's Fund
  • University of Texas Southwestern Medical Center
  • Children's Discovery Institute (CDI-CORE-2019-813, CDI-CORE-2015-505)
  • Centene Corporation
  • National Institutes of Health (1rf1ag056296-01, R01AG078964, AG066444)
  • Center for Cellular Imaging, Washington University
  • Charles F. and Joanne Knight Alzheimer Disease Research Center, Washington University in St. Louis
  • National Institute on Aging (RF1 AG056296, R01 AG078964, AG066444, P30AG066444)
  • National Institute of Mental Health (P50 MH122379, R01MH123748)
  • National Institute of Neurological Disorders and Stroke (R01NS107488)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords
late-onset Alzheimer's disease, neuronal reprogramming, microRNA, amyloid-beta deposition, tau tangles, neurodegeneration, beta-secretase inhibitors, gamma-secretase inhibitors, autosomal dominant Alzheimer's disease, transposable elements, disease modeling, 3D cell culture

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-17.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-17.

Cited sources are checked by gpt-6-sol.

Statistics and arithmetic are recomputed, not judged.

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