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Cited by 23Neuroinflammation and Neurodegeneration MechanismsAlzheimer's disease research and treatmentsDementia and Cognitive Impairment Research

TET2-mutant myeloid cells mitigate Alzheimer’s disease progression via CNS infiltration and enhanced phagocytosis in mice

Open access
Matatall, Katie A., Wathan, Trisha K., Nguyen, Minh, Chen, Hu, McDonald, Alexandra, Qi, Guantong, Belk, Julia A., Florez, Marcus A. +21 more·2025·Cell Stem Cell
DOI 10.1016/j.stem.2025.06.006PMC PMC12233156
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Abstract

Clonal hematopoiesis (CH) is associated with many age-related diseases, but its interaction with Alzheimer's disease (AD) remains unclear. Here, we show that TET2-mutant CH is associated with a 47% reduced risk of late-onset AD (LOAD) in the UK Biobank, whereas other drivers of CH do not confer protection. In a mouse model of AD, transplantation of Tet2-mutant bone marrow reduced cognitive decline and β-amyloid plaque formation, effects not observed with Dnmt3a-mutant marrow. Bone-marrow-derived microglia-like cells were detected at an increased rate in Tet2-mutant marrow recipients, and TET2-mutant human induced pluripotent stem cell (iPSC)-derived microglia were more phagocytic and hyperinflammatory than DNMT3A-mutant or wild-type microglia. Strikingly, single-cell RNA sequencing (scRNA-seq) revealed that macrophages and patrolling monocytes were increased in brains of mice transplanted with Tet2-mutant marrow in response to chemokine signaling. These studies reveal a TET2-specific protective effect of CH on AD pathogenesis mediated by peripheral myeloid cell infiltration.

AI snapshot

Written from the paper’s full text.

TL;DR

TET2-mutant clonal hematopoiesis was associated with reduced late-onset Alzheimer’s disease risk in UK Biobank, while other CH drivers were not. In 5xFAD mice, Tet2-mutant bone marrow improved memory and reduced β-amyloid plaques after low-dose LPS, with increased CNS infiltration of phagocytic myeloid cells.

Key findings

  • In UK Biobank WES data (451,053 individuals; 3,637 incident LOAD), overall CH was not significantly associated with LOAD (OR 0.98, 95% CI 0.84–1.13, p = 0.76), but TET2-CH was inversely associated with LOAD (adjusted OR 0.53, 95% CI 0.32–0.86, p = 0.01), corresponding to ~47% lower odds. DNMT3A-, ASXL1-, and SF3B1-mutant CH trended toward increased risk but were not statistically significant.
  • In LPS-treated 5xFAD mice, Tet2-mutant bone marrow recipients showed enhanced novel object recognition and significantly fewer β-amyloid plaques than WT recipients; Dnmt3a-mutant recipients showed no memory change, increased anxiety, increased learned fear, and no plaque reduction.
  • TET2-mutant human iPSC-derived microglia-like cells were more phagocytic for myelin and amyloid-β after LPS and produced higher inflammatory cytokines than DNMT3A-mutant or WT iMGLs, including CCL2, CCL5, CCL7, and CX3CL1.
  • scRNA-seq of brains from transplanted 5xFAD mice showed increased macrophages and monocytes, especially non-classical Ly6C− patrolling monocytes and M1 inflammatory macrophages, in Tet2-mutant recipients compared with WT or Dnmt3a-mutant recipients, alongside decreased microglia and shifts in disease-associated microglia states.

Methods

  • UK Biobank association study: WES-based CHIP calls in 451,053 participants, incident LOAD defined as Alzheimer’s diagnosis after age 65; logistic regression adjusted for age, sex, smoking, alcohol, APOE or PRS, and Townsend Deprivation Index.
  • Mouse AD model: young 5xFAD mice lethally irradiated and transplanted with whole bone marrow from Tet2−/−, Vav-iCre+ Dnmt3a−/−, or WT controls; after transplantation, weekly low-dose LPS (1 mg/kg) for eight weeks; behavioral assays, β-amyloid staining, flow cytometry, and scRNA-seq on brain immune cells.
  • Human iPSC model: isogenic DNMT3AR882H/WT, TET2DelE3-E11/WT, and WT iPSC lines differentiated into iMGLs; phagocytosis assays with myelin or amyloid-β, bulk RNA-seq, and Luminex cytokine measurements.

Limitations

  • Stated: mouse CH was modeled by transplanting bone marrow with both Dnmt3a or Tet2 alleles ablated and replacing essentially 100% of recipient marrow, whereas human CH typically involves heterozygous mutations at <50% mosaicism; murine results are interpreted as an extreme proof-of-concept model.
  • Stated: irradiation preconditioning may affect blood-brain barrier integrity, though applied consistently across groups; Vav-Cre causes heterozygous Commd10 loss-of-function, but validation scRNA-seq from Vav-Cre+ Dnmt3awt/wt mice suggested differences were not attributable to Commd10.
  • Stated: UKB is ~94% western European, limiting generalizability; sample size became limited when stratified by driver mutation, reducing power for less frequently mutated CH genes. Evident from the text: scRNA-seq differential abundance had only two samples per genotype, so statistical power was insufficient and the authors focused on fold changes without p-value-based filtering.

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

Integrity signals

Registry

Crossref · 10.1016/j.stem.2025.06.006

Cites

94 of 94 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

37 of 56 cited sources checked · 15 supported · 2 flagged · accuracy not yet measured

  • Findingcitation

    A low but significant number of donor-derived immune cells in the brain were Tmem119+, indicating that they had adopted a microglia-like phenotype.

    “We thereby identified a low but significant number of donor-derived immune cells that were Tmem119+, indicating that they had adopted a microglia-like phenotype35 (Figure 2E).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [35] Bennett ML, Bennett FC, Liddelow SA, Ajami B, Zamanian JL, Fernhoff NB, Mulinyawe SB, Bohlen CJ, Adil A, Tucker A, (2016). New tools for studying microglia in the mouse and human CNS. Proc Natl Acad Sci U S A 113, E1738– E1746. 10.1073/PNAS.1525528113/SUPPL_FILE/PNAS.1525528113.SD01.XLSX. 26884166 PMC4812770 source
  • Premisecitation

    Several known AD susceptibility genes associated with late-onset AD have been linked to alterations in peripheral immune cell function rather than microglial activation.

    “Notably, several of the known AD susceptibility genes that are associated with late-onset AD have been linked to alterations in peripheral immune cell function rather than microglial activation.20,21”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [20] Jones L, Lambert JC, Wang LS, Choi SH, Harold D, Vedernikov A, Escott-Price V, Stone T, Richards A, Bellenguez C, (2015). Convergent genetic and expression data implicate immunity in Alzheimer’s disease. Alzheimer’s & Dementia 11, 658– 671. 10.1016/J.JALZ.2014.05.1757. PMC4672734 25533204 source

      The Discussion (page unavailable) links the AD susceptibility gene CR1 to B-cell subsets and notes macrophage-related activity for another implicated gene, supporting a peripheral-immune connection. It does not establish that several known late-onset AD susceptibility genes act through peripheral immune cells rather than microglia; instead, it discusses TREM2-mediated microglial activation as a possible contributor to susceptibility. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [21] Kamboh MI A Brief Synopsis on the Genetics of Alzheimer’s Disease. 10.1007/s40142-018-0155-8. PMC6223698 30460168 source

      The main text and Table 1 (page unavailable) identify several susceptibility genes for late-onset AD. They do not link those genes to altered peripheral immune cell function rather than microglial activation; a reference title instead mentions microglial-mediated innate immunity. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
  • Premisecitation

    Systemic inflammatory signals can be transmitted to the CNS, where they may directly impact AD pathogenesis.

    “Furthermore, mounting evidence suggests that systemic inflammatory signals can be transmitted to the CNS, where they may directly impact AD pathogenesis.12–14”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites [12] Zhou J, Yu W, Zhang M, Tian X, Li Y, and Lü Y (2019). Imbalance of Microglial TLR4/TREM2 in LPS-Treated APP/PS1 Transgenic Mice: A Potential Link Between Alzheimer’s Disease and Systemic Inflammation. Neurochem Res 44. 10.1007/s11064-019-02748-x. 30756214 source
    • cites [13] Montacute R, Foley K, Forman R, Else KJ, Cruickshank SM, and Allan SMR (2017). Enhanced susceptibility of triple transgenic Alzheimer’s disease (3xTg-AD) mice to acute infection. J Neuroinflammation 14. 10.1186/s12974-017-0826-5. PMC5346250 28284226 source
    • cites [14] Jiang C, Li G, Huang P, Liu Z, and Zhao B (2017). The Gut Microbiota and Alzheimer’s Disease. J Alzheimers Dis 58, 1– 15. 10.3233/JAD-161141. 28372330 source
  • Findingown data

    Dnmt3a-mutant bone marrow transplantation did not reduce β-amyloid plaque number in LPS-treated 5xFAD mice.

    “whereas LPS-treated Dnmt3aAD mice showed no change in the number of β-amyloid plaques (Figure 1M).”
    Quote in the paperSubstantial claim
    • The authors state this as an assumption: Low-dose LPS injections model low-level systemic inflammation relevant to AD pathogenesis.
  • Findingown data

    LPS-treated Dnmt3aAD mice had a significant increase in anxiety levels compared to WTAD mice.

    “In contrast, Dnmt3aAD mice showed no change in memory function (Figure 1I), but had a significant increase in anxiety levels (Figure 1J) compared to WTAD mice following LPS.”
    Quote in the paperNot a substantial claim
    • The authors state this as an assumption: Low-dose LPS injections model low-level systemic inflammation relevant to AD pathogenesis.
  • Classified as probably not a substantial claim. 47
  • May combine two claims. 26
  • The quote only partly states this claim. 4

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

    Premisecitation

    Mutations in DNMT3A and TET2 account for over 90% of CH cases.

    “Mutations in DNMT3A and TET2 account for over 90% of CH cases2,6”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [2] Jaiswal S, Fontanillas P, Flannick J, Manning A, Grauman PV, Mar BG, Lindsley RC, Mermel CH, Burtt N, Chavez A, (2014). Age-Related Clonal Hematopoiesis Associated with Adverse Outcomes. New England Journal of Medicine 371. 10.1056/nejmoa1408617. PMC4306669 25426837 source

      The Results (Identification of Candidate Somatic Mutations; Increase in the Frequency of Clonal Somatic Mutations with Age, page unavailable) report 746 people with detectable mutations, including 403 DNMT3A variants and 72 TET2 variants. Even if each of those 475 variants occurred in a different person, they would account for at most about 64% of the detected cases, not over 90%. The paper notes that TET2 mutations were probably underrepresented because capture covered only part of the gene. (LLM, conf=0.88)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured
    • cites [6] Xie M, Lu C, Wang J, McLellan MD, Johnson KJ, Wendl MC, McMichael JF, Schmidt HK, Yellapantula V, Miller CA, (2014). Age-related mutations associated with clonal hematopoietic expansion and malignancies. Nat Med 20. 10.1038/nm.3733. PMC4313872 25326804 source

      The Results section (page unavailable) reports DNMT3A mutations in 18 cases and TET2 mutations in 9 among 58 cases with blood-specific mutations. Even if those cases did not overlap, the two genes would account for at most 27 of 58 cases—not over 90%. (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).

    Premisecitation

    Peripheral immune cells may replace microglial populations, though this is controversial.

    “Peripheral immune cells may also replace microglial populations,5,23,30–32 though this is controversial.”
    Quote in the paperNot a substantial claim3 of 5 sources checked
    • cites [5] Bouzid H, Belk JA, Jan M, Qi Y, Sarnowski C, Wirth S, Ma L, Chrostek MR, Ahmad H, Nachun D, (2023). Clonal hematopoiesis is associated with protection from Alzheimer’s disease. Nat Med 29. 10.1038/s41591-023-02397-2. PMC10353941 37322115 source
    • cites [23] Ginhoux F, Greter M, Leboeuf M, Nandi S, See P, Gokhan S, Mehler MF, Conway SJ, Ng LG, Stanley ER, (2010). Fate Mapping Analysis Reveals That Adult Microglia Derive from Primitive Macrophages. Science 330, 841. 10.1126/SCIENCE.1194637. 20966214 PMC3719181 source
    • cites [30] Grassivaro F, Menon R, Acquaviva M, Ottoboni L, Ruffini F, Andrea Bergamaschi X, Muzio L, Farina C, and Gianvito Martino X (2020). Convergence between microglia and peripheral macrophages phenotype during development and neuroinflammation. Journal of Neuroscience 40. 10.1523/JNEUROSCI.1523-19.2019. PMC6975289 31818979 source
    • cites [31] Cronk JC, Filiano AJ, Louveau A, Marin I, Marsh R, Ji E, Goldman DH, Smirnov I, Geraci N, Acton S, (2018). Peripherally derived macrophages can engraft the brain independent of irradiation and maintain an identity distinct from microglia. Journal of Experimental Medicine 215. 10.1084/jem.20180247. PMC5987928 29643186 source
    • cites [32] Guilliams M, and Scott CL (2017). Does niche competition determine the origin of tissue-resident macrophages? Nat Rev Immunol 17, 451– 460. 10.1038/NRI.2017.42. 28461703 source

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

    Premisecitation

    There is conflicting evidence regarding the impact of CH on Alzheimer's disease.

    “However, there is conflicting evidence regarding the impact of CH on Alzheimer’s disease (AD).5,10”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [5] Bouzid H, Belk JA, Jan M, Qi Y, Sarnowski C, Wirth S, Ma L, Chrostek MR, Ahmad H, Nachun D, (2023). Clonal hematopoiesis is associated with protection from Alzheimer’s disease. Nat Med 29. 10.1038/s41591-023-02397-2. PMC10353941 37322115 source

      The Results (Association between CHIP and AD dementia; page unavailable) report that CHIP was associated with lower AD dementia risk, contrary to the authors’ expectations. The Methods (Statistical analysis plan; page unavailable) explain that those expectations came from prior findings on inflammation and mouse AD phenotypes, not from a conflicting finding about CH and AD. This source supplies one side of the cited sentence but does not itself establish conflicting evidence on the CH–AD association. (LLM, conf=0.80)

      Experimental — accuracy not yet measured
    • cites [10] Dumanski JP, Lambert JC, Rasi C, Giedraitis V, Davies H, Grenier-Boley B, Lindgren CM, Campion D, Dufouil C, Pasquier F, (2016). Mosaic Loss of Chromosome y in Blood Is Associated with Alzheimer Disease. Am J Hum Genet 98. 10.1016/j.ajhg.2016.05.014. PMC4908225 27231129 source

      The Results (page unavailable) report that men with Alzheimer’s disease had more mosaic loss of chromosome Y in blood than controls, supporting one finding about a blood-cell clone and AD. The paper does not establish that evidence about clonal hematopoiesis and AD is conflicting; that broader characterization requires other evidence. (LLM, conf=0.83)

      Experimental — accuracy not yet measured

  • Classified as probably not a substantial claim.

    Premisecitation

    Some studies suggest that infiltrating macrophages possess a greater ability than resident microglia to remove CNS plaques.

    “Some studies suggest that infiltrating macrophages possess a greater ability than resident microglia to remove CNS plaques,15–17”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites [15] Ní Chasaide C, and Lynch MA (2020). The role of the immune system in driving neuroinflammation. Brain Neurosci Adv 4. 10.1177/2398212819901082. PMC7085916 32219178 source
    • cites [16] Shechter R, London A, Varol C, Raposo C, Cusimano M, Yovel G, Rolls A, Mack M, Pluchino S, Martino G, (2009). Infiltrating blood-derived macrophages are vital cells playing an anti-inflammatory role in recovery from spinal cord injury in mice. PLoS Med 6. 10.1371/journal.pmed.1000113. PMC2707628 19636355 source

      The Discussion (page unavailable) says infiltrating macrophages and resident microglia have different roles in recovery from spinal cord injury, and notes that macrophages can clear cell debris. It does not compare their ability to remove CNS plaques or report plaque removal. (LLM, conf=0.78)

      Experimental — accuracy not yet measured
    • cites [17] Simard AR, Soulet D, Gowing G, Julien JP, and Rivest S (2006). Bone marrow-derived microglia play a critical role in restricting senile plaque formation in Alzheimer’s disease. Neuron 49. 10.1016/j.neuron.2006.01.022. 16476660 source

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

    Premisecitation

    Other studies suggest that macrophages contribute to microglial activation, exacerbating pathogenic neuroinflammation.

    “while others suggest that macrophages contribute to microglial activation, exacerbating pathogenic neuroinflammation.18,19”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [18] Barrett JP, Costello DA, O’Sullivan J, Cowley TR, and Lynch MA (2015). Bone marrow-derived macrophages from aged rats are more responsive to inflammatory stimuli. J Neuroinflammation 12. 10.1186/s12974-015-0287-7. PMC4397943 25890218 source
    • cites [19] Blau CW, Cowley TR, O’Sullivan J, Grehan B, Browne TC, Kelly L, Birch A, Murphy N, Kelly AM, Kerskens CM, (2012). The age-related deficit in LTP is associated with changes in perfusion and blood-brain barrier permeability. Neurobiol Aging 33. 10.1016/j.neurobiolaging.2011.09.035. 22071124 source

      The Introduction (page unavailable) reports that infiltrating peripheral cells can activate glia, and the Discussion (page unavailable) describes macrophage infiltration into the brain. The paper does not specifically show that macrophages activate microglia or thereby exacerbate neuroinflammation; its own findings concern age-related changes in rats. (LLM, conf=0.82)

      Experimental — accuracy not yet measured

  • Classified as probably not a substantial claim.

    Premisecitation

    Inflammation plays a central role in AD pathogenesis.

    “Inflammation plays a central role in AD pathogenesis; neurofibrillary tangles and extracellular amyloid protein deposits that characterize AD are thought to be both a cause and consequence of persistent central nervous system (CNS) inflammation.11”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [11] Serpente M, Bonsi R, Scarpini E, and Galimberti D (2014). Innate immune system and inflammation in Alzheimer’s disease: From pathogenesis to treatment. Neuroimmunomodulation 21. 10.1159/000356529. 24557039 source

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

    Premisecitation

    Myelin damage likely precedes and contributes to amyloid plaque buildup in early AD.

    “This is notable because myelin damage likely precedes and contributes to amyloid plaque buildup in early AD.55–57”
    Quote in the paperNot a substantial claim3 of 3 sources checked
    • cites [55] Bartzokis G (2011). Alzheimer’s disease as homeostatic responses to age-related myelin breakdown. Neurobiol Aging 32, 1341– 1371. 10.1016/j.neurobiolaging.2009.08.007. 19775776 PMC3128664 source
    • cites [56] Papuć E, and Rejdak K (2020). State of the art paper The role of myelin damage in Alzheimer’s disease pathology. Arch Med Sci 16, 345– 351. 10.5114/aoms.2018.76863. 32190145 PMC7069444 source

      The 'Myelin damage in AD' section says some studies suggest myelin damage precedes Aβ pathology. It also proposes that myelin loss could accelerate plaque deposition, but presents that contribution as possible; the animal-model section says it remains unclear whether myelin damage triggers AD pathology. Thus the claim is stronger than the source on contribution to plaque buildup. (LLM, conf=0.82)

      Experimental — accuracy not yet measured
    • cites [57] Depp C, Sun T, Octavian Sasmita A, Spieth L, Berghoff SA, Nazarenko T, Overhoff K, Steixner-Kumar AA, Subramanian S, Arinrad S, (2023). Myelin dysfunction drives amyloid-β deposition in models of Alzheimer’s disease. Nature | 618, 349. 10.1038/s41586-023-06120-6. 37258678 PMC10247380 source

  • May combine two claims.

    Premisecitation

    LPS is elevated in both the blood and brain of AD patients.

    “LPS is elevated in both the blood and brain of AD patients.25–29”
    Quote in the paperSubstantial claim4 of 5 sources checked
    • cites [25] Zhang R, Miller RG, Gascon R, Champion S, Katz J, Lancero M, Narvaez A, Honrada R, Ruvalcaba D, and McGrath MS (2008). Circulating endotoxin and systemic immune activation in sporadic Amyotrophic Lateral Sclerosis (sALS). J Neuroimmunol 206, 121. 10.1016/J.JNEUROIM.2008.09.017. 19013651 PMC2995297 source

      Results §3.1 reports significantly elevated LPS in plasma from AD patients compared with healthy controls. The supplied passages do not report elevated LPS in the brains of AD patients, so they support only the blood portion of the claim. (LLM, conf=0.90)

      Experimental — accuracy not yet measured
    • cites [26] Loffredo L, Ettorre E, Zicari AM, Inghilleri M, Nocella C, Perri L, Spalice A, Fossati C, De Lucia MC, Pigozzi F, (2020). Oxidative Stress and Gut-Derived Lipopolysaccharides in Neurodegenerative Disease: Role of NOX2. Oxid Med Cell Longev 2020. 10.1155/2020/8630275. PMC7016401 32089785 source

      The Results report significantly higher blood LPS in the AD subgroup than in controls. The Discussion says LPS has been found in AD brains, including in amyloid plaques and around vessels, but does not say brain LPS is elevated relative to controls. (LLM, conf=0.87)

      Experimental — accuracy not yet measured
    • cites [27] Andreadou EG, Katsipis G, Tsolaki M, and Pantazaki AA (2021). Involvement and relationship of bacterial lipopolysaccharides and cyclooxygenases levels in Alzheimer’s Disease and Mild Cognitive Impairment patients. J Neuroimmunol 357. 10.1016/J.JNEUROIM.2021.577561. 34091099 source
    • cites [28] Marizzoni M, Mirabelli P, Mombelli E, Coppola L, Festari C, Lopizzo N, Luongo D, Mazzelli M, Naviglio D, Blouin JL, (2023). A peripheral signature of Alzheimer’s disease featuring microbiota-gut-brain axis markers. Alzheimers Res Ther 15. 10.1186/S13195-023-01218-5. PMC10230724 37254223 source

      The Results (Immune and endothelial microbiota-gut-brain axis mediators; page unavailable) report high LPS levels in patients with cognitive impairment due to AD, and the Methods specify that LPS was measured in plasma. The paper does not report elevated LPS levels in those patients’ brains; the Discussion mentions possible co-localization with amyloid plaques, not a brain-level comparison. (LLM, conf=0.89)

      Experimental — accuracy not yet measured
    • cites [29] Sánchez-Tapia M, Mimenza-Alvarado A, Granados-Domínguez L, Flores-López A, López-Barradas A, Ortiz V, Pérez-Cruz C, Sánchez-Vidal H, Hernández-Acosta J, Ávila-Funes JA, (2023). The Gut Microbiota-Brain Axis during Aging, Mild Cognitive Impairment and Dementia: Role of Tau Protein, β-Amyloid and LPS in Serum and Curli Protein in Stool. Nutrients 15. 10.3390/NU15040932. PMC9961602 36839291 source

      Results §3.2 and the Discussion report substantially higher serum LPS in the dementia group than in healthy controls, supporting the blood portion of the claim. Methods §2.7 says LPS was measured in serum; the paper does not report elevated LPS in patients’ brains. Its studied group is described as having dementia, not specifically diagnosed AD. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

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

    Premisecitation

    Stage 2 DAMs are activated microglia that are closely associated with amyloid plaques.

    “Stage 2 DAMs (sometimes referred to as TREM2-dependent) are activated microglia that are closely associated with amyloid plaques.42,43”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [42] Zhou Y, Song WM, Andhey PS, Swain A, Levy T, Miller KR, Poliani PL, Cominelli M, Grover S, Gilfillan S, (2020). Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and TREM2-independent cellular responses in Alzheimer’s disease. Nature Medicine 2020 26:1 26, 131– 142. 10.1038/s41591-019-0695-9. PMC6980793 31932797 source

      The Results section, “DAM signature is Trem2-dependent at early and late stages of Aβ accumulation” (page not provided), identifies an Aβ- and Trem2-dependent microglial cluster expressing DAM genes. It does not identify that cluster as stage 2 DAM or establish that those cells are closely associated with amyloid plaques. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [43] Keren-Shaul H, Spinrad A, Weiner A, Matcovitch-Natan O, Dvir-Szternfeld R, Ulland TK, David E, Baruch K, Lara-Astaiso D, Toth B, (2017). A Unique Microglia Type Associated with Restricting Development of Alzheimer’s Disease. Cell 169, 1276– 1290.e17. 10.1016/J.CELL.2017.05.018. 28602351 source

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

    Premisecitation

    Stage 2 DAMs are essential early in AD but may become dysregulated and ultimately detrimental later in disease progression.

    “Although Stage 2 DAMs are essential early in AD, they may become dysregulated and ultimately detrimental later in disease progression.44–46”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites [44] Deczkowska A, Keren-Shaul H, Weiner A, Colonna M, Schwartz M, and Amit I (2018). Disease-Associated Microglia: A Universal Immune Sensor of Neurodegeneration. Cell 173, 1073– 1081. 10.1016/J.CELL.2018.05.003. 29775591 source
    • cites [45] Jay TR, Hirsch AM, Broihier ML, Miller CM, Neilson LE, Ransohoff RM, Lamb BT, and Landreth GE (2017). Disease Progression-Dependent Effects of TREM2 Deficiency in a Mouse Model of Alzheimer’s Disease. Journal of Neuroscience 37, 637– 647. 10.1523/JNEUROSCI.2110-16.2016. 28100745 PMC5242410 source
    • cites [46] Dagher NN, Najafi AR, Kayala KMN, Elmore MRP, White TE, Medeiros R, West BL, and Green KN (2015). Colony-stimulating factor 1 receptor inhibition prevents microglial plaque association and improves cognition in 3xTg-AD mice. J Neuroinflammation 12, 1– 14. 10.1186/S12974-015-0366-9/FIGURES/8. PMC4522109 26232154 source

      The Discussion (page unavailable) suggests that microglial association with Aβ deposits may be protective early in AD, while preventing that association may be beneficial later. The Introduction (page unavailable) also describes an initially beneficial microglial response that can become chronically inflammatory and damaging. Neither passage identifies Stage 2 DAMs specifically, and the Discussion presents early protection as a possibility rather than establishing that those cells are essential. (LLM, conf=0.87)

      Experimental — accuracy not yet measured

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

    Premisecitation

    Covariates were selected based on their known associations with Alzheimer Disease in the UK Biobank cohort.

    “Covariates were selected based on their known associations with Alzheimer Disease in the UKB cohort.”
    Quote in the paperNot a substantial claim2 of 4 sources checked
    • cites [75] Shang X, Roccati E, Zhu Z, Kiburg K, Wang W, Huang Y, Zhang X, Zhang X, Liu J, Tang S, (2023). Leading mediators of sex differences in the incidence of dementia in community-dwelling adults in the UK Biobank: a retrospective cohort study. Alzheimers Res Ther 15, 1– 12. 10.1186/S13195-022-01140-2/FIGURES/4. 36617573 PMC9827665 source

      The Methods > Study population section identifies age as an important determinant of dementia and explains why participants were matched by age. Methods > Statistical analysis lists factors examined as potential mediators, but does not say they were selected because of known associations with Alzheimer disease. The paper studies incident dementia rather than specifically Alzheimer disease; page numbers are unavailable in our copy. (LLM, conf=0.78)

      Experimental — accuracy not yet measured
    • cites [76] UK Biobank data shows dose-dependent link between smoking and brain shrinkage https://www.news-medical.net/news/20231212/UK-Biobank-data-shows-dose-dependent-link-between-smoking-and-brain-shrinkage.aspx.

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

    • cites [77] Allwright M, Mundell HD, McCorkindale AN, Lindley RI, Austin PJ, Guennewig B, and Sutherland GT (2023). Ranking the risk factors for Alzheimer’s disease; findings from the UK Biobank study. Aging Brain 3, 100081. 10.1016/J.NBAS.2023.100081. 37384134 PMC10293768 source
    • cites [78] Klee M, Leist AK, Veldsman M, Ranson JM, and Llewellyn DJ (2023). Socioeconomic Deprivation, Genetic Risk, and Incident Dementia. Am J Prev Med 64, 621– 630. 10.1016/J.AMEPRE.2023.01.012. 37085245 PMC10126314 source

      The Methods > Measures section lists covariates used in models of the UK Biobank cohort. It does not say they were selected because of known associations with Alzheimer disease; the study’s modeled outcome was incident all-cause dementia. Page numbers are not available in our copy. (LLM, conf=0.84)

      Experimental — accuracy not yet measured

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

    Premisecitation

    CCL2 has the known capacity to break down the blood brain barrier and recruit peripheral immune cells to sites of damage.

    “consistent with the known capacity of CCL2 to break down the blood brain barrier and recruit peripheral immune cells to sites of damage.58–62”
    Quote in the paperSubstantial claim2 of 5 sources checked
    • cites [58] Naert G, and Rivest S (2013). A deficiency in CCR2+ monocytes: the hidden side of Alzheimer’s disease. J Mol Cell Biol 5, 284– 293. 10.1093/JMCB/MJT028. 23892208 source
    • cites [59] El Khoury J, Toft M, Hickman SE, Means TK, Terada K, Geula C, and Luster AD (2007). Ccr2 deficiency impairs microglial accumulation and accelerates progression of Alzheimer-like disease. Nature Medicine 2007 13:4 13, 432– 438. 10.1038/nm1555. 17351623 source
    • cites [60] Wojcieszak J, Kuczyńska K, and Zawilska JB (2022). Role of Chemokines in the Development and Progression of Alzheimer’s Disease. Journal of Molecular Neuroscience 2022 72:9 72, 1929– 1951. 10.1007/S12031-022-02047-1. PMC9392685 35821178 source
    • cites [61] Zeng zihang D, qingyi M, tianhuan Q, and Si-Yan L (2023). CCL2 and Neuronal Inflammation: Implications for Neurodegenerative Diseases. bioRxiv, 2023.08.16.553459. 10.1101/2023.08.16.553459. source

      The Introduction (page unavailable) describes CCL2 as a potent chemoattractant for monocytes and immune cells, supporting the recruitment aspect in general. It does not specify recruitment of peripheral cells to damage sites, and the passages found do not say that CCL2 breaks down the blood–brain barrier. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [62] Arfaei R, Mikaeili N, Daj F, Boroumand A, Kheyri A, Zahra Shirzad PY, Keshavarz M, Hassanshahi G, Jafarzadeh A, Shahrokhi VM, (2024). Decoding the role of the CCL2/CCR2 axis in Alzheimer’s disease and innovating therapeutic approaches: Keeping All options open. Int Immunopharmacol 135. 10.1016/J.INTIMP.2024.112328. 38796962 source

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

    Premisecitation

    Non-classical monocytes are known as patrolling monocytes, named for their role in surveilling the vasculature and crossing the blood brain barrier to remove damaged tissue, including amyloid plaques.

    “Non-classical monocytes are known as patrolling monocytes, named for their role in surveilling the vasculature and crossing the blood brain barrier to remove damaged tissue, including amyloid plaques.39–41”
    Quote in the paperNot a substantial claim2 of 3 sources checked
    • cites [39] Michaud JP, Bellavance MA, Préfontaine P, and Rivest S (2013). Real-time in vivo imaging reveals the ability of monocytes to clear vascular amyloid beta. Cell Rep 5, 646– 653. 10.1016/j.celrep.2013.10.010. 24210819 source
    • cites [40] Audoy-Rémus J, Richard JF, Soulet D, Zhou H, Kubes P, and Vallières L (2008). Rod-Shaped monocytes patrol the brain vasculature and give rise to perivascular macrophages under the influence of proinflammatory cytokines and angiopoietin-2. J Neurosci 28, 10187– 10199. 10.1523/JNEUROSCI.3510-08.2008. 18842879 PMC6671016 source

      The Discussion (page unavailable) reports that type 2 monocytes crawl on cerebral blood vessels and can give rise to perivascular macrophages; the Introduction discusses monocyte traffic across the blood–brain barrier. The paper does not say that these monocytes cross it to remove damaged tissue or amyloid plaques. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [41] Thomas G, Tacke R, Hedrick CC, and Hanna RN (2015). Nonclassical Patrolling Monocyte Function in the Vasculature. Arterioscler Thromb Vasc Biol 35, 1306– 1316. 10.1161/ATVBAHA.114.304650/ASSET/EB723143-1EFD-4633-AD05-375F1B4C550B/ASSETS/GRAPHIC/1306FIG01.JPEG. 25838429 PMC4441550 source

      The Introduction identifies nonclassical monocytes as patrolling cells, and “Neurological diseases and damage” says they patrol brain vasculature and remove amyloid beta from it. That section does not say they cross the blood-brain barrier to remove damaged tissue or amyloid plaques; it instead describes the barrier as maintained by perivascular macrophages. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

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

    Premisecitation

    The PRS was derived using external GWAS training data and has been validated for its association with late-onset Alzheimer's disease within the UK Biobank.

    “The PRS was derived using external Genome-wide association study (GWAS) training data and has been validated for its association with Late-Onset Alzheimer’s Disease (LOAD) within the UKB.80”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [80] Thompson DJ, Wells D, Selzam S, Peneva I, Moore R, Sharp K, Tarran WA, Beard EJ, Riveros-Mckay F, Palmer D, (2022). UK Biobank release and systematic evaluation of optimised polygenic risk scores for 53 diseases and quantitative traits. medRxiv, 2022.06.16.22276246. 10.1101/2022.06.16.22276246. source

      The Performance of the PRS Release in UK Biobank section says the Standard PRS was derived from external GWAS sources and evaluated in UKB; the Methods figure caption identifies Alzheimer’s disease among the diseases considered. The copy does not identify a specifically late-onset Alzheimer’s disease phenotype or report a LOAD-specific association. It also distinguishes the Enhanced PRS, which was trained using both external and UKB data. (LLM, conf=0.82)

      Experimental — accuracy not yet measured

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

    Premisecitation

    Tet2-mediated CH is associated with resolution of inflammation in the subacute period after ischemic stroke.

    “These findings are consistent with a recent study showing that Tet2-mediated CH is associated with resolution of inflammation in the subacute period after ischemic stroke.63”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [63] Evans MA, Chavkin NW, Sano S, Sun H, Sardana T, Ravi R, Doviak H, Wang Y, Yura Y, Polizio AH, (2024). Tet2-mediated clonal hematopoiesis modestly improves neurological deficits and is associated with inflammation resolution in the subacute phase of experimental stroke. Front Cell Neurosci 18. 10.3389/FNCEL.2024.1487867. PMC11685025 39742155 source

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

    Study design and conductcitation

    APOE genotype was determined using SNP data at rs429358 and rs7412, defining the three major APOE isoforms, consistent with prior UK Biobank studies.

    “APOE genotype was determined using SNP data at rs429358 and rs7412, which define the three major APOE isoforms (ε2, ε3, and ε4) based on established haplotypes. Genotypes were assigned according to allele combinations, consistent with prior UK Biobank studies,79”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [79] Lumsden AL, Mulugeta A, Zhou A, and Hyppönen E (2020). Apolipoprotein E (APOE) genotype-associated disease risks: a phenome-wide, registry-based, case-control study utilising the UK Biobank. EBioMedicine 59. 10.1016/J.EBIOM.2020.102954. PMC7452404 32818802 source

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

    Findingcitation

    We identified three microglia subtypes: Stage 1 disease associated microglia, Stage 2 disease associated microglia, and homeostatic microglia, using signature genes from a published Alzheimer's disease mouse model scRNA-seq study.

    “We identified three subtypes of microglia, namely Stage 1 disease associated microglia (Stage 1 DAM), Stage 2 DAM and homeostatic microglia, using signature genes reported in a single cell RNA-seq study of Alzheimer’s disease mouse model.89”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [89] Keren-Shaul H, Spinrad A, Weiner A, Matcovitch-Natan O, Dvir-Szternfeld R, Ulland TK, David E, Baruch K, Lara-Astaiso D, Toth B, (2017). A Unique Microglia Type Associated with Restricting Development of Alzheimer’s Disease. Cell 169, 1276– 1290.e17. 10.1016/J.CELL.2017.05.018/ATTACHMENT/63D76284-8C53-4D00-93AA-E1E70B1AE6DE/MMC7.XLSX. 28602351 source

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

    Premisecitation

    The UK Biobank is a comprehensive population-based cohort study involving approximately 500,000 adults from the United Kingdom, aged 40-70 years.

    “The UKB is a comprehensive population-based cohort study involving approximately 500,000 adults from the United Kingdom, age ranged from 40–70 years.22”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [22] Sudlow C, Gallacher J, Allen N, Beral V, Burton P, Danesh J, Downey P, Elliott P, Green J, Landray M, (2015). UK Biobank: An Open Access Resource for Identifying the Causes of a Wide Range of Complex Diseases of Middle and Old Age. PLoS Med 12, e1001779. 10.1371/JOURNAL.PMED.1001779. 25826379 PMC4380465 source

      The Summary Points describe UK Biobank as a large, population-based prospective study with over 500,000 participants. However, both the Summary Points and Cohort Size section specify an age range of 40–69 years at recruitment, not 40–70. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

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

    Findingown data

    TET2 was the second most common driver among individuals with CH in the UKB cohort, representing 14.56%.

    “Consistent with other studies, TET2 was the second most common driver among individuals with CH in the UKB cohort, representing 14.56% (Figure 1B).”
    Quote in the paperNot a substantial claim

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

    Findingown data

    Age, APOE subgroup, and a broader AD polygenic risk score were significant predictors of incident LOAD.

    “As expected, age, APOE subgroup and a broader AD polygenic risk score (PRS) were significant predictors of incident LOAD (Figure S1A).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    In the LOAD cohort, ASXL1 was the second most common driver at 16.41%, while TET2 dropped to third at 8.71%.

    “In contrast, in the LOAD cohort, ASXL1 emerged as the second most common driver at 16.41%, while TET2 dropped to third at 8.71% (Figure 1C).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Six months after transplantation without LPS, there were no significant differences in behavior or β-amyloid plaque deposition between WTAD and Tet2AD or between WTAD and Dnmt3aAD.

    “Six months after transplantation, we observed no significant differences in behavior or β-amyloid plaque deposition between WTAD and Tet2AD (Figure S1B–D) or WTAD and Dnmt3aAD (Figure S1E–I).”
    Quote in the paperSubstantial claim

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

    Findingown data

    All mice had normal motor function.

    “All mice had normal motor function (Figure S1J–K).”
    Quote in the paperNot a substantial claim

  • The quote only partly states this claim.

    Findingown data

    LPS-treated Tet2AD mice had significantly more myeloid cells compared to controls.

    “Further assessment revealed fewer CD4+ and CD8+ T cells (Figure 3D) and significantly more myeloid cells in Tet2AD mice (Figure 3F) compared to controls.”
    Quote in the paperSubstantial claim
    • The authors state this as an assumption: Low-dose LPS injections model low-level systemic inflammation relevant to AD pathogenesis.

  • May combine two claims.

    Findingown data

    TET2-mutant CH is associated with reduced risk of incident LOAD in the UKB, while DNMT3A- and ASXL1-mutant CH trended to increased LOAD risk.

    “We report that TET2-mutant CH is associated with reduced risk of incident LOAD in the UKB, while DNMT3A- and ASXL1-mutant CH trended to increased LOAD risk.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    TET2-deficient human iPSC-derived microglia-like cells were hyperinflammatory and demonstrated a greater capacity to phagocytose both myelin and β-amyloid upon LPS activation compared to WT or DNMT3A-mutant iMGLs.

    “Furthermore, TET2-deficient human iPSC-derived microglia-like cells (iMGLs) were hyperinflammatory and demonstrated a greater capacity to phagocytose both myelin and β-amyloid upon LPS activation compared to WT or DNMT3A-mutant iMGLs.”
    Quote in the paperSubstantial claim
    • The authors state this as an assumption: Low-dose LPS injections model low-level systemic inflammation relevant to AD pathogenesis.

  • May combine two claims.

    Findingown data

    Peripheral blood-derived replacement of brain-resident microglia does occur, though at low levels, and this effect was enhanced in mice that received Tet2-mutant bone marrow.

    “Indeed, our data indicate that peripheral blood-derived replacement of brain-resident microglia does occur, though at low levels, and this effect was enhanced in mice that received Tet2-mutant bone marrow.”
    Quote in the paperSubstantial claim

  • The quote only partly states this claim.

    Findingown data

    LPS-treated Dnmt3aAD mice had no change in infiltrating myeloid cells compared to controls.

    “In contrast, Dnmt3aAD mice had fewer CD4+ T cells (Figure 3E), but no change in infiltrating myeloid cells (Figure 3G).”
    Quote in the paperNot a substantial claim
    • The authors state this as an assumption: Low-dose LPS injections model low-level systemic inflammation relevant to AD pathogenesis.

  • Probably not a substantial claim: may not pass S3 (load-bearing). The quote only partly states this claim.

    Findingown data

    LPS-treated Dnmt3aAD mice had fewer CD4+ T cells compared to controls.

    “In contrast, Dnmt3aAD mice had fewer CD4+ T cells (Figure 3E), but no change in infiltrating myeloid cells (Figure 3G).”
    Quote in the paperNot a substantial claim
    • The authors state this as an assumption: Low-dose LPS injections model low-level systemic inflammation relevant to AD pathogenesis.

  • The quote only partly states this claim.

    Findingnone given

    Tet2-mutant myeloid cells demonstrated increased capacity to phagocytose myelin and β-amyloid.

    “Additionally, Tet2-mutant myeloid cells demonstrated increased capacity to phagocytose myeloid and β-amyloid.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Subpopulation analysis of scRNAseq data identified distinct populations of M1 and M2 macrophages, classical and non-classical monocytes, as well as homeostatic and disease associated microglia (DAMs).

    “Subpopulation analysis of scRNAseq data identified distinct populations of M1 and M2 macrophages, classical and non-classical monocytes as well as homeostatic and disease associated microglia (DAMs) (Figure 4C and S4C–E).”
    Quote in the paperNot a substantial claim

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

    Findingown data

    We identified an Oligodendrocyte cluster highly expressing Mog and a general vascular cell cluster highly expressing Vtn.

    “In addition, we identifed a cluster of Oligodendrocyte that highly express Mog, and a cluster of general vascular cell types that highly express Vtn.”
    Quote in the paperNot a substantial claim

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

    Findingcitation

    Stage 1 disease associated microglia have increased expression of Tyrobp, Ctsb, Ctsd, B2m, Fth1, and Lyz2.

    “Specifically, homeostatic microglia highly express Tmem119, P2ry12, and Cx3cr1, Stage 1 DAM have increased expressions of Tyrobp, Ctsb, Ctsd, B2m, Fth1, Lyz2, while Stage 2 DAM are more abundant in another set of genes including Axl1, Cst7, Ctsl, Lpl, Cd8, Csf1, Ccl6, Itgax, Clec7a and Timp2.”
    Quote in the paperNot a substantial claim

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

    Findingown data

    We identified a cDC cluster composed of mixed cDC1 (marked by Clec9a) and cDC2 (marked by Cd209a).

    “We identified a cDC cluster which composes of both cDC1 (marked by Clec9a) and cDC2 (marked by Cd209a) that were mixed.”
    Quote in the paperNot a substantial claim

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

    Findingown data

    The classical microglial markers Tmem119, P2ry12, and Cx3cr1 are reduced in both Stage 1 and Stage 2 disease associated microglia.

    “The classical microglial markers, Tmem119, P2ry12, and Cx3cr1, are reduced in both Stage 1 and Stage 2 DAMs.”
    Quote in the paperNot a substantial claim

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

    Findingown data

    We identified a M1-like macrophage population (MHCII positive) and a M2-like macrophage population (Mrc1 positive).

    “We identified a M1-like macrophage population (MHCII positive), and a M2-like macrophage population (Mrc1 position).”
    Quote in the paperNot a substantial claim

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

    Findingcitation

    Homeostatic microglia highly express Tmem119, P2ry12, and Cx3cr1.

    “Specifically, homeostatic microglia highly express Tmem119, P2ry12, and Cx3cr1, Stage 1 DAM have increased expressions of Tyrobp, Ctsb, Ctsd, B2m, Fth1, Lyz2, while Stage 2 DAM are more abundant in another set of genes including Axl1, Cst7, Ctsl, Lpl, Cd8, Csf1, Ccl6, Itgax, Clec7a and Timp2.”
    Quote in the paperNot a substantial claim

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

    Findingcitation

    Stage 2 disease associated microglia are more abundant in Axl1, Cst7, Ctsl, Lpl, Cd8, Csf1, Ccl6, Itgax, Clec7a, and Timp2.

    “Specifically, homeostatic microglia highly express Tmem119, P2ry12, and Cx3cr1, Stage 1 DAM have increased expressions of Tyrobp, Ctsb, Ctsd, B2m, Fth1, Lyz2, while Stage 2 DAM are more abundant in another set of genes including Axl1, Cst7, Ctsl, Lpl, Cd8, Csf1, Ccl6, Itgax, Clec7a and Timp2.”
    Quote in the paperNot a substantial claim

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

    Findingown data

    We identified a Ribo-high Macrophage cluster that resembles M1-like and M2-like macrophages but has relatively lower UMI counts and higher expression of ribosomal genes.

    “We identified another cluster generally resembles the M1-like and M2-like macrophages, but with relatively lower UMI counts, and higher expression of ribosomal genes. This cluster was retained and annotated as Ribo-high Macrophage.”
    Quote in the paperNot a substantial claim

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

    Findingown data

    We identified 17 major cell types based on expression patterns of marker genes.

    “We identified 17 major cell types based on the expression patterns of marker genes.”
    Quote in the paperNot a substantial claim

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

    Findingown data

    We identified a classical monocyte cluster highly expressing Ly6c2 and a non-classical monocyte cluster highly expressing Itgal.

    “We identified a classical monocyte cluster that highly express Ly6c2, and a non-classical monocyte cluster highly express Itgal, similarly as a published single cell RNA-seq study.88”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [88] Van Hove H, Martens L, Scheyltjens I, De Vlaminck K, Pombo Antunes AR, De Prijck S, Vandamme N, De Schepper S, Van Isterdael G, Scott CL, (2019). A single-cell atlas of mouse brain macrophages reveals unique transcriptional identities shaped by ontogeny and tissue environment. Nature Neuroscience 2019 22:6 22, 1021– 1035. 10.1038/s41593-019-0393-4. 31061494 source

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

    Findingown data

    The cell types identified and annotated in the validation cohort are largely the same as the main cohort.

    “The cell types identified and annotated in the validation cohort are largely the same as the main cohort.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    Loss of Tet2, but not Dnmt3a, in peripheral immune cells led to an improvement in AD pathogenesis.

    “Taken together, these data suggest that loss of Tet2, but not Dnmt3a, in peripheral immune cells led to an improvement in AD pathogenesis.”
    Quote in the paperSubstantial claim
    • The authors state this as an assumption: Low-dose LPS injections model low-level systemic inflammation relevant to AD pathogenesis.

  • May combine two claims.

    Interpretationown data

    Tet2-mutant bone marrow leads to an increase in infiltrating myeloid cells and a decrease in total microglia.

    “Altogether, these data support the key finding that Tet2-mutant bone marrow leads to an increase in infiltrating myeloid cells and a decrease in total microglia.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Loss of Tet2 leads to increased recruitment of patrolling monocytes and M1 macrophages to sites of damage within the brain, ultimately leading to improved AD pathogenesis.

    “Taken together, our data suggest that loss of Tet2 leads to increased recruitment of patrolling monocytes and M1 macrophages to sites of damage within the brain, ultimately leading to improved AD pathogenesis.”
    Quote in the paperSubstantial claim

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

    Interpretationreasoning

    Enhanced recruitment of Tet2−/− immune cells with higher phagocytic capacity into the CNS may have wide-reaching implications for other neurodegenerative diseases.

    “Enhanced recruitment of Tet2−/− immune cells with higher phagocytic capacity into the CNS may have wide-reaching implications for other neurodegenerative diseases in which the CCL2/CCR2 axis has been shown to be important for disease progression.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Improved disease outcomes may be attributable to a reduction in Stage 2 DAMs and a concomitant increase in homeostatic microglia in Tet2AD mice.

    “Thus, improved disease outcomes may be attributable to a reduction in Stage 2 DAMs and a concomitant increase in homeostatic microglia in Tet2AD mice.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    TET2 but not DNMT3A mutation confers enhanced phagocytic and inflammatory properties to iMGLs that may promote immune cell recruitment and clearance of pathogenic material.

    “These findings underscore distinct roles for TET2 and DNMT3A in regulating microglial behavior, with TET2 but not DNMT3A mutation conferring enhanced phagocytic and inflammatory properties to iMGLs that may promote immune cell recruitment and clearance of pathogenic material.”
    Quote in the paperSubstantial claim
    • The authors state this as an assumption: Low-dose LPS injections model low-level systemic inflammation relevant to AD pathogenesis.

  • May combine two claims.

    Interpretationreasoning

    TET2-mutant CH may lead to improved disease outcome through combined effects of enhanced signaling by TET2-mutant microglia and recruitment of peripheral immune cells which together clear damaged myelin and β-amyloid plaques.

    “Overall, our findings indicate that TET2-mutant CH may lead to improved disease outcome through combined effects of enhanced signaling by TET2-mutant microglia and recruitment of peripheral immune cells which together clear damaged myelin and β-amyloid plaques.”
    Quote in the paperSubstantial claim

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

    Study design and conductnone given

    Multiple independent iPSC lines from each genotype were used.

    “Multiple independent lines from each genotype were used.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    All statistical tests were two-sided, and a p-value of less than 0.05 was considered statistically significant.

    “All statistical tests were two-sided, and a p-value of less than 0.05 was considered statistically significant.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    Donor and recipient mice were sex and age matched in transplantation experiments.

    “Both donor and recipient mice were sex and age matched.”
    • Also stated in: § METHOD DETAILS · plain
      “Donor and recipient mice were sex and age matched for all experiments.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    UK Biobank data linkage to national health records allows identification of both prevalent diseases and incident events.

    “This linkage allows for the identification of both prevalent diseases (onset before enrollment) and incident events (onset after enrolment).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [71] Health-related outcomes data – UK Biobank https://community.ukbiobank.ac.uk/hc/en-gb/articles/15467565352093-Health-related-outcomes-data.

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

  • Classified as probably not a substantial claim.

    Study design and conductreasoning

    The differential abundance analysis focused on fold changes in cell abundance between genotypes without applying p-value-based filtering.

    “Therefore, we focused on fold changes in cell abundance between genotypes without applying p-value-based filtering.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    The UK Biobank Outcome Adjudication Group, with clinical experts, created algorithmically defined health outcomes covering Alzheimer's disease as defined by ICD-9 or ICD-10 codes.

    “The UKB Outcome Adjudication Group, in collaboration with clinical experts, created ADOs to cover a range of health conditions, including Alzheimer’s disease as defined by ICD-9 or ICD-10 codes.71”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [71] Health-related outcomes data – UK Biobank https://community.ukbiobank.ac.uk/hc/en-gb/articles/15467565352093-Health-related-outcomes-data.

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

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

    Study design and conductown data

    Variance inflation factor was calculated well below the conservative threshold of <2.515.

    “Variance inflation factor (VIF) was calculated, well below the conservative threshold of <2.515.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    All iPSC lines were confirmed to have a normal karyotype.

    “All lines were confirmed to have a normal karyotype.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductown data

    With only two samples per genotype, the statistical power was insufficient to robustly assess the significance of differential abundance.

    “Since we only had two samples per genotype, the statistical power was insufficient to robustly assess the significance of differential abundance.”
    Quote in the paperSubstantial claim

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

    Study design and conductnone given

    Each scRNA-seq sample was manually reviewed by overlaying QC metrics and markers to confirm the quality of filtered cells for downstream analysis.

    “Each sample was manually reviewed by overlaying the total UMI count, mtDNA proportions, empty droplet scores, doublet scores, and gene markers to confirm the quality of the filtered cells for downstream analysis.”
    Quote in the paperNot a substantial claim

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

    Study design and conductown data

    All generalized variance inflation factors were close to 1, indicating that multicollinearity was not a concern.

    “All generalized variance inflation factors (GVIFs) were close to 1, indicating that multicollinearity was not a concern.”
    Quote in the paperNot a substantial claim

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

    Study design and conductcitation

    The logistic regression model's goodness-of-fit was assessed using the Hosmer-Lemeshow test and Akaike Information Criterion.

    “Additionally, the logistic regression model’s goodness-of-fit was assessed using the Hosmer-Lemeshow test and Akaike Information Criterion (AIC).82”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [82] Liu H, Li X, Chen F, Härdle W, and Liang H (2024). A comprehensive comparison of goodness-of-fit tests for logistic regression models. Stat Comput 34, 1– 16. 10.1007/S11222-024-10487-5/FIGURES/10. source

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

    Study design and conductcitation

    Model diagnostics were performed to assess goodness-of-fit and multicollinearity.

    “Model diagnostics were performed to assess the goodness-of-fit and the presence of multicollinearity.82”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [82] Liu H, Li X, Chen F, Härdle W, and Liang H (2024). A comprehensive comparison of goodness-of-fit tests for logistic regression models. Stat Comput 34, 1– 16. 10.1007/S11222-024-10487-5/FIGURES/10. source

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

    Study design and conductown data

    CHIP variants were filtered using depth and bidirectional sequencing criteria to minimize false-positive CHIP calls.

    “To minimize false-positive CHIP calls, variants were retained for further analysis if they met the following criteria: (i) total depth of coverage was ≥20; (ii) minimum read depth for the alternate allele was ≥5; and (iii) the genetic variant was detected in both directions of sequencing.”
    Quote in the paperNot a substantial claim
63 of 63

  • The authors state this as an assumption.

    Low-dose LPS injections model low-level systemic inflammation relevant to AD pathogenesis.

    “To model low-level systemic inflammation, we applied weekly low dose LPS injections (1 mg/kg) in our mouse model.”

  • The paper relies on this without support.

    Human CH typically presents with heterozygous mutations at less than 50% blood mosaicism.

    “In contrast, human CH typically presents with heterozygous mutations at less than 50% blood mosaicism.”
2 of 2

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • In mouse models, CHIP-derived myeloid cells can infiltrate the central nervous system and modulate microglial function and amyloid clearance.

    “Experimental work in mouse models (such as 5xFAD and APP/PS1), utilizing bone marrow chimeric and parabiosis systems, has further added complexity, demonstrating that CHIP-derived myeloid cells can infiltrate the central nervous system and modulate microglial function and amyloid clearance in these mice [14].”

    From Clonal Hematopoiesis of Indeterminate Potential as an Emerging Interdisciplinary Risk Factor in Alzheimer’s Disease: Current Evidence and Future Directions (2026) · cites this paper as [14]

    The Results report that Tet2-mutant bone marrow-derived cells infiltrated the brains of 5xFAD mice, alongside changes in microglial populations; the Abstract reports reduced β-amyloid plaque formation. The cited paper used bone marrow transplantation, but the provided evidence does not support the sentence’s reference to parabiosis or to APP/PS1 as a separate mouse model. Its direct test of increased amyloid phagocytosis used human microglia-like cells in vitro, not infiltrating cells in mice. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • TET2-mutant microglia-like cells lead to a significant reduction in Aβ plaque burden and disease progression.

    “These factors lead to a significant reduction in Aß plaque burden and disease progression [14].”

    From Clonal Hematopoiesis of Indeterminate Potential as an Emerging Interdisciplinary Risk Factor in Alzheimer’s Disease: Current Evidence and Future Directions (2026) · cites this paper as [14]

    The Results section ('Loss of Tet2 but not Dnmt3a in peripheral immune cells improves AD pathogenesis'; page unavailable) reports significantly fewer β-amyloid plaques and improved memory in LPS-treated mice transplanted with Tet2-mutant bone marrow. However, the paper does not establish that microglia-like cells themselves caused those outcomes: its microglia-like-cell experiments show increased amyloid phagocytosis in vitro. The plaque and memory differences were not significant in mice without LPS treatment. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • TET2-deficient immune cells exhibit altered inflammatory and chemotactic signaling, specifically the CXCL12/CXCR4 axis, which facilitates migration of peripheral TET2-mutant myeloid cells toward sites of amyloid deposition.

    “TET2-deficient immune cells exhibit altered inflammatory and chemotactic signaling, specifically the CXCL12/CXCR4 axis, which facilitates the migration of peripheral TET2-mutant myeloid cells toward sites of amyloid deposition [14].”

    From Clonal Hematopoiesis of Indeterminate Potential as an Emerging Interdisciplinary Risk Factor in Alzheimer’s Disease: Current Evidence and Future Directions (2026) · cites this paper as [14]

    The Results section, “Tet2-mutant macrophages and monocytes are primed for chemotaxis” (page unavailable), reports altered inflammatory and chemotactic signaling and supports recruitment of Tet2-mutant myeloid cells to sites of neuroinflammation. It identifies CCL2–CCR2, not CXCL12–CXCR4, as the signaling axis; the specific axis attributed to this paper is unsupported. (LLM, conf=0.90)

    Experimental — accuracy not yet measured

  • TET2 mutations have been most consistently associated with enhanced amyloid clearance and attenuated neuropathology in experimental systems.

    “While TET2 mutations have been most consistently associated with enhanced amyloid clearance and attenuated neuropathology in experimental systems [10,14]”

    From Clonal Hematopoiesis of Indeterminate Potential as an Emerging Interdisciplinary Risk Factor in Alzheimer’s Disease: Current Evidence and Future Directions (2026) · cites this paper as [14]

    The Results section reports increased β-amyloid phagocytosis by LPS-treated Tet2-deficient myeloid cells and fewer brain plaques in LPS-treated Tet2AD mice. But it also reports no significant difference in plaque deposition or behavior without LPS, so the unqualified characterization of these effects as the most consistent finding across experimental systems goes beyond this paper. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • In 5xFAD and APP/PS1 mouse models, TET2-deficient monocytes exhibit a fitness advantage, infiltrating the brain to differentiate into microglia-like cells.

    “In 5xFAD and APP/PS1 mouse models, TET2-deficient monocytes exhibit a fitness advantage, infiltrating the brain to differentiate into microglia-like cells (MLCs).”

    From Clonal Hematopoiesis of Indeterminate Potential as an Emerging Interdisciplinary Risk Factor in Alzheimer’s Disease: Current Evidence and Future Directions (2026) · cites this paper as [14]

    The Results sections on infiltration and peripherally derived microglia-like cells report more monocytes and macrophages in Tet2-mutant 5xFAD mouse brains and more donor-derived cells with a microglia-like phenotype. The study used noncompetitive bone-marrow transplants, so these findings do not establish a monocyte fitness advantage. Our copy does not report the same finding in a separate APP/PS1 model or establish that the microglia-like cells specifically arose from monocytes. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Donor age ranges differ between methods sections

    Major

    The mice section says all donors were used at 6-12 weeks of age, but the main-cohort transplantation section gives a donor age range of 12-16 weeks. The stated ranges disagree except at 12 weeks.

1 of 1

Cites

Flagged first, then by citations

Research works printed but not linked: 1

  1. Keren-Shaul, 2017, A Unique Microglia Type Associated with Restricting Development of Alzheimer’s Disease, Cell, 169, 1276, 10.1016/j.cell.2017.05.018 · DOI · Paper page

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Related

Authors
Matatall, K. A., Wathan, T. K., Nguyen, M., Chen, H., McDonald, A., Qi, G., Belk, J. A., Florez, M. A., Le, D. T., Olarinde, T., Vlasschaert, C., Buttigieg, M. M., Fan, C.-W., Carcamo, S., Cao, R., Kennedy, D. E., Maknojia, A. A., Thatavarty, A., Fernandez Sanchez, J. V., Bouzid, H., Veeraragavan, S., Crocker, S., Goodell, M. A., Rodriguez, A., Jaiswal, S., Rauh, M. J., Papapetrou, E. P., Marro, S. G., & King, K. Y.
Affiliations
  • Baylor College of Medicine (US)
  • The University of Texas MD Anderson Cancer Center (US)
  • Tisch Cancer Institute
  • Queen's University (CA)
  • Stanford Medicine (US)
  • Rice University (US)
  • Icahn School of Medicine at Mount Sinai (US)
Corresponding author
King, Katherine Y.
ORCID
Venue
Cell Stem Cell
Publisher
Elsevier BV
Published
2025-08
Volume
32
Issue
8
Pages
1285-1298.e8
ISSN
  • 1875-9777 (ISSN-L)
  • 1934-5909
DOI
10.1016/j.stem.2025.06.006
PMC
PMC12233156
OpenAlex
W4411932090
Cited by
23
References
92
Citations by year
2026: 18 · 2025: 5
FWCI
6.77
Type
journal article
Language
en
Update notices
erratum (2025-09-04)
Open access
Licence
Locations
  • Cell stem cell (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (submittedVersion)
  • Digital Commons-TMC (Texas Medical Center) (submittedVersion)
  • PubMed Central (submittedVersion)
Funders
  • American Society of Hematology
  • Intramural Research Program, National Institute on Drug Abuse
  • National Eye Institute
  • Cancer Prevention and Research Institute of Texas
  • National Institutes of Health National Cancer Institute
  • Howard Hughes Medical Institute
  • National Institute of Child Health and Human Development
  • Huffington Foundation
  • Ting Tsung and Wei Fong Chao Family Foundation
  • Edward P Evans Foundation
  • National Institutes of Health
  • National Institute of Diabetes and Digestive and Kidney Diseases
  • National Institute of Mental Health and Neurosciences
  • National Heart Lung and Blood Institute
Topics
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords
TET2 mutation, clonal hematopoiesis, Alzheimer's disease, late-onset Alzheimer's disease, bone marrow transplantation, microglia, phagocytosis, macrophages, non-classical monocytes, chemokine signaling, amyloid plaques, cognitive decline, DNMT3A mutation, myeloid cell infiltration, neuroinflammation
MeSH terms
Clonal Hematopoiesis, DNA Methyltransferase 3A, Alzheimer Disease, Animals, Brain, Central Nervous System, Disease Models, Animal, DNA-Binding Proteins, Female, Humans, Male, Mice, Inbred C57BL, Mutation, Phagocytosis, Proto-Oncogene Proteins, Microglia, Disease Progression, Myeloid Cells, Dioxygenases, Mice

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 2026-10-19.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-19.

Cited sources are checked by gpt-6-sol.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

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