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Cited by 169Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

Clonal hematopoiesis is associated with protection from Alzheimer’s disease

Open access
Bouzid, Hind, Belk, Julia A., Jan, Max, Qi, Yanyan, Sarnowski, Chloé, Wirth, Sara, Ma, Lisa, Chrostek, Matthew R. +23 more·2023·Nature Medicine
DOI 10.1038/s41591-023-02397-2PMC PMC10353941

Published version of a preprint

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Abstract

Clonal hematopoiesis of indeterminate potential (CHIP) is a premalignant expansion of mutated hematopoietic stem cells. As CHIP-associated mutations are known to alter the development and function of myeloid cells, we hypothesized that CHIP may also be associated with the risk of Alzheimer’s disease (AD), a disease in which brain-resident myeloid cells are thought to have a major role. To perform association tests between CHIP and AD dementia, we analyzed blood DNA sequencing data from 1,362 individuals with AD and 4,368 individuals without AD. Individuals with CHIP had a lower risk of AD dementia (meta-analysis odds ratio (OR) = 0.64, P = 3.8 × 10 −5 ), and Mendelian randomization analyses supported a potential causal association. We observed that the same mutations found in blood were also detected in microglia-enriched fraction of the brain in seven of eight CHIP carriers. Single-nucleus chromatin accessibility profiling of brain-derived nuclei in six CHIP carriers revealed that the mutated cells comprised a large proportion of the microglial pool in the samples examined. While additional studies are required to validate the mechanistic findings, these results suggest that CHIP may have a role in attenuating the risk of AD.

AI snapshot

Written from the paper’s full text.

TL;DR

Clonal hematopoiesis of indeterminate potential (CHIP) was associated with lower risk of Alzheimer’s disease (AD) dementia across cohorts, with Mendelian randomization supporting a potential causal protective effect. CHIP-mutant cells were also detected in brain microglia-enriched fractions, suggesting marrow-derived myeloid cells may infiltrate the brain and influence AD risk.

Key findings

  • In a meta-analysis of ADSP, CHS, and FHS, CHIP carriers had lower risk of AD dementia (OR = 0.64, P = 3.8 × 10−5); in ADSP APOE ε3ε3 participants, CHIP with VAF > 0.08 was associated with lower AD risk (OR = 0.66, P = 5.5 × 10−4).
  • Mendelian randomization using 24 CHIP-associated polymorphisms found higher genetic risk of CHIP associated with reduced odds of AD (OR = 0.90 per 1 log-odds increase in CHIP risk, P = 3.3 × 10−4), while reverse-direction MR showed no evidence (OR = 0.97, P = 0.26).
  • CHIP was associated with lower AD neuropathologic change in participants without dementia: lower CERAD neuritic plaque score (OR = 0.50, P = 3.2 × 10−3) and lower Braak stage (OR = 0.56, P = 0.015).
  • CHIP variants were detected in the microglia-enriched NeuN− c-MAF+ brain fraction in seven of eight CHIP carriers; snATAC-seq estimated 30% to 95% of microglia were mutant in six CHIP samples, and microglia proportion among glia was higher in CHIP carriers (8.2%) than controls (5.1%; P = 0.042).

Methods

  • Association analyses used blood DNA sequencing from TOPMed cohorts FHS (n = 2,437; 92 incident AD) and CHS (n = 743; 166 incident AD), plus ADSP case-control WES limited to APOE ε3ε3 individuals (1,104 AD cases, 1,446 controls), with CHIP defined from curated gene variants and VAF cutoffs.
  • Time-to-event competing risks regression, logistic regression, fixed-effects meta-analysis, and Mendelian randomization were used; ADSP autopsy subsets were analyzed for CERAD score (n = 427) and Braak stage (n = 454) by ordinal logistic regression.
  • Brain validation used postmortem ACT samples from eight CHIP carriers and four noncarriers, with nuclei isolation, NeuN/c-MAF sorting, amplicon sequencing, and snATAC-seq of 94,367 high-quality nuclei plus reference datasets.

Limitations

  • The paper states that no differences in chromatin accessibility were found between microglia from CHIP carriers and noncarriers that could explain AD protection, possibly due to limited sample size, mutational heterogeneity, or assessment only in people without AD or significant ADNC.
  • The paper states it cannot conclude that protection from AD is due to infiltrating mutant cells; identifying biologically meaningful differences between mutant and wild-type microglia would strengthen the causal hypothesis.
  • Evident from the text: brain mechanistic analyses relied on small numbers of donors (eight CHIP carriers, four noncarriers; six with snATAC-seq), and the ADSP association replication was restricted to APOE ε3ε3 individuals because of age/sex imbalance in other genotype groups.

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

Integrity signals

Registry

Crossref · 10.1038/s41591-023-02397-2

Cites

59 of 59 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

23 of 28 cited sources checked · 13 supported · 0 flagged · accuracy not yet measured

  • Premisecitation

    CHIP-associated mutations alter the development and function of myeloid cells.

    “As CHIP-associated mutations are known to alter the development and function of myeloid cells”
    • Also stated in: § Main · plain
      “Because CHIP-associated mutations influence the function of myeloid cells8,11,14, we tested whether CHIP was associated with the risk of AD.”
    Quote in the paperSubstantial claim3 of 3 sources checked
    • cites [8] Jaiswal, S. et al. Clonal hematopoiesis and risk of atherosclerotic cardiovascular disease. N. Engl. J. Med. 377, 111–121 (2017). source

      The Results section on Tet2 loss in myeloid cells reports altered macrophage inflammatory gene expression and secretion, supporting an effect on myeloid-cell function. The Introduction says CHIP-associated mutations give hematopoietic stem cells a selective advantage, but does not establish that they alter myeloid-cell development; the demonstrated functional effect is chiefly for Tet2, not CHIP-associated mutations generally. The copy provides no page numbers for these passages. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites [11] Fuster, J. J. et al. Clonal hematopoiesis associated with TET2 deficiency accelerates atherosclerosis development in mice. Science 355, 842–847 (2017). source

      The indexed paper reports that TET2-deficient cells in mice show a myeloid differentiation bias and that TET2-deficient macrophages have altered inflammatory responses. This supports the claim for TET2, but the paper does not establish the same effects for CHIP-associated mutations generally. The indexed passages are labeled “Abstract”; no page numbers are supplied. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [14] Zhang, Q. et al. Tet2 is required to resolve inflammation by recruiting Hdac2 to specifically repress IL-6. Nature 525, 389–393 (2015). source

      The paper reports that Tet2 deficiency changes inflammatory gene expression and IL-6 production in dendritic cells and macrophages, supporting an effect on myeloid-cell function. But it explicitly says developmental defects in those cells were not observed (main text, Extended Data Fig. 1f), and its findings concern Tet2 loss rather than CHIP-associated mutations generally. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
  • Premisecitation

    GWAS have implicated functional alterations of microglia as a major driver of Alzheimer's disease risk.

    “Genome-wide association studies (GWAS) have implicated functional alterations of microglia (MG), the macrophage-like hematopoietic cells in the brain, as a major driver of AD risk13.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [13] Nott, A. et al. Brain cell type-specific enhancer-promoter interactome maps and disease-risk association. Science 366, 1134–1139 (2019). source
  • Findingown data

    Two-sample MR using 36 AD risk polymorphisms as instruments and CHIP as the outcome found no evidence of a causal effect of AD on CHIP (OR = 0.97, P = 0.26).

    “we also performed two-sample MR using 36 polymorphisms for risk of AD as the instruments18 and CHIP as the outcome, which found no evidence of a causal effect in this direction (OR = 0.97 per 1 log-odds increase in risk of AD, P = 0.26 using the weighted median estimator).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [18] Schwartzentruber, J. et al. Genome-wide meta-analysis, fine-mapping and integrative prioritization implicate new Alzheimer’s disease risk genes. Nat. Genet. 53, 392–402 (2021). source
  • Findingown data

    Mutations consistent with CHIP were found in 17 brain samples from 1,776 persons in ADSP.

    “Similar to a prior study22, we found mutations consistent with CHIP in 17 brain samples (Fig. 4a and Supplementary Table 13), although paired blood samples were not available for this set.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [22] Keogh, M. J. et al. High prevalence of focal and multi-focal somatic genetic variants in the human brain. Nat. Commun. 9, 4257 (2018). source
  • Findingown data

    MR using 24 CHIP-associated polymorphisms found that higher genetic risk of CHIP was associated with reduced odds of AD using the weighted median estimator (OR = 0.90 per 1 log-odds increase, P = 3.3 × 10−4).

    “One- and two-sample MR using 24 CHIP-associated polymorphisms18 as the instruments (Supplementary Table 7) found that higher genetic risk of CHIP was associated with reduced odds of AD using the weighted median estimator (OR = 0.90 per 1 log-odds increase in risk of CHIP, P = 3.3 × 10−4, Fig. 2c).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [18] Schwartzentruber, J. et al. Genome-wide meta-analysis, fine-mapping and integrative prioritization implicate new Alzheimer’s disease risk genes. Nat. Genet. 53, 392–402 (2021). source

      The Results section reports an Alzheimer’s disease GWAS meta-analysis, and Online Methods describes fine-mapping and AD meta-analysis, but neither reports the claimed CHIP Mendelian-randomization result. Searches for CHIP, Mendelian randomization, the weighted-median estimate, and the stated P value found no passage addressing it. (LLM, conf=0.76)

      Experimental — accuracy not yet measured
  • Classified as probably not a substantial claim. 33
  • May combine two claims. 22

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

    Premisecitation

    APOE genotype is the strongest genetic risk factor for AD, with APOE ε2 conferring protection and APOE ε4 conferring higher risk compared to APOE ε3.

    “APOE genotype is the strongest genetic risk factor for AD21, with APOE ε2 conferring protection from disease and APOE ε4 conferring higher risk, compared to the APOE ε3 allele”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [21] Yamazaki, Y., Zhao, N., Caulfield, T. R., Liu, C. C. & Bu, G. Apolipoprotein E and Alzheimer disease: pathobiology and targeting strategies. Nat. Rev. Neurol. 15, 501–518 (2019). source

      The Introduction identifies APOE as a major risk determinant of late-onset AD and says ε2 is associated with decreased risk and ε4 with increased risk relative to ε3. It does not establish that APOE is the strongest genetic risk factor for AD generally; its risk-factor framing is specifically about late-onset AD. (LLM, conf=0.85)

      Experimental — accuracy not yet measured

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

    Premisecitation

    Clone size, approximated by variant allele fraction, has previously been shown to be an important predictor of risk for blood cancer and cardiovascular outcomes.

    “Clone size, which is approximated by the variant allele fraction (VAF), has previously been shown to be an important predictor of risk for blood cancer1,17 and cardiovascular outcomes8,9.”
    Quote in the paperNot a substantial claim4 of 4 sources checked
    • cites [1] Jaiswal, S. et al. Age-related clonal hematopoiesis associated with adverse outcomes. N. Engl. J. Med. 371, 2488–98 (2014). source
    • cites [17] Abelson, S. et al. Prediction of acute myeloid leukaemia risk in healthy individuals. Nature 559, 400–404 (2018). source
    • cites [8] Jaiswal, S. et al. Clonal hematopoiesis and risk of atherosclerotic cardiovascular disease. N. Engl. J. Med. 377, 111–121 (2017). source
    • cites [9] Bick, A. G. et al. Inherited causes of clonal haematopoiesis in 97,691 whole genomes. Nature 586, 763–768 (2020). source

      Extended Data Fig. 1 (page unavailable) explicitly uses variant allele fraction to measure CHIP clone size. The Abstract and ‘Germline genetic determinants of CHIP’ section (pages unavailable) describe associations between CHIP and hematologic cancer or cardiovascular disease, but do not establish that clone size predicts risk for either outcome. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

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

    Premisecitation

    APOE ε2 is the most protective common inherited variant for AD.

    “which is the most protective common inherited variant for AD26.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [26] Serrano-Pozo, A., Das, S. & Hyman, B. T. APOE and Alzheimer’s disease: advances in genetics, pathophysiology, and therapeutic approaches. Lancet Neurol. 20, 68–80 (2021). source

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

    Premisecitation

    A recent paper found that the genetic liability of CHIP was associated with an increased risk of lung, prostate, ovarian, oral and endometrial cancers.

    “a recent paper found that the genetic liability of CHIP was associated with an increased risk of lung, prostate, ovarian, oral and endometrial cancers7”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [7] Kar, S. P. et al. Genome-wide analyses of 200,453 individuals yield new insights into the causes and consequences of clonal hematopoiesis. Nat. Genet. https://doi.org/10.1038/s41588-022-01121-z (2022). source

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

    Premisecitation

    Marrow-derived cells may have an ameliorative effect on neurodegenerative phenotypes in mice, possibly due to their superior phagocytic capacity.

    “Marrow-derived cells may have an ameliorative effect on neurodegenerative phenotypes in mice33,34, possibly due to their superior phagocytic capacity35.”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites [33] Simard, A. R., Soulet, D., Gowing, G., Julien, J. P. & Rivest, S. Bone marrow-derived microglia play a critical role in restricting senile plaque formation in Alzheimer’s disease. Neuron 49, 489–502 (2006). source
    • cites [34] El Khoury, J. et al. Ccr2 deficiency impairs microglial accumulation and accelerates progression of Alzheimer-like disease. Nat. Med. 13, 432–438 (2007). source
    • cites [35] Lund, H. et al. Competitive repopulation of an empty microglial niche yields functionally distinct subsets of microglia-like cells. Nat. Commun. 9, 4845 (2018). source

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

    Premisecitation

    Previous observational studies have found inverse associations between cancer and Alzheimer's disease, but the mechanism for this is unknown.

    “previous observational studies have found inverse associations between cancer and AD, but the mechanism for this is unknown50”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [50] Ospina-Romero, M. et al. Association between Alzheimer disease and cancer with evaluation of study biases: a systematic review and meta-analysis. JAMA Netw. Open 3, e2025515 (2020). source

  • Classified as probably not a substantial claim.

    Premisecitation

    There is a growing body of evidence from mice that bone marrow-derived myeloid cells can enter the brain during homeostasis.

    “There is a growing body of evidence from mice that bone marrow-derived myeloid cells can enter the brain during homeostasis31,32.”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [31] Cugurra, A. et al. Skull and vertebral bone marrow are myeloid cell reservoirs for the meninges and CNS parenchyma. Science 373, eabf7844 (2021). source

      The Introduction and Results report that, in mice, bone marrow-derived myeloid cells reach the dural meninges and other brain borders under homeostatic conditions. They distinguish this from entry into CNS parenchyma, which the paper reports following injury or neuroinflammation. Thus the source supports homeostatic entry to brain borders, but not clearly entry into brain tissue during homeostasis. (LLM, conf=0.87)

      Experimental — accuracy not yet measured
    • cites [32] Herisson, F. et al. Direct vascular channels connect skull bone marrow and the brain surface enabling myeloid cell migration. Nat. Neurosci. 21, 1209–1217 (2018). source

      The Results section (“Tracking cell origins in different inflammatory sites”; page unavailable) reports skull marrow-derived cells in mouse brain parenchyma after induced meningoencephalitis. That supports entry into the brain, but the paper studies stroke and induced inflammation; it does not establish entry during homeostasis. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • Classified as probably not a substantial claim.

    Premisecitation

    CHIP mutations increase the fitness of HSCs and myeloid progenitors.

    “as CHIP mutations are known to increase the fitness of HSCs and myeloid progenitors5”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [5] Jaiswal, S. & Elbert, B. L. Clonal hematopoiesis in human aging and disease. Science 366, eaan4673 (2019). source

      The Introduction (page unavailable) describes mutations that confer a fitness advantage on HSCs, and “Mechanisms of clonal expansion” reports an HSC competitive advantage for some CHIP-associated mutations. The paper does not establish increased fitness in myeloid progenitors, and it notes that mice with certain CHIP-associated spliceosome mutations show an HSC competitive disadvantage. Thus the unqualified claim is broader than the evidence in our copy. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • Classified as probably not a substantial claim.

    Premisecitation

    GWAS have strongly implicated microglial genes involved in ligand recognition and phagocytosis, such as APOE, TREM2, CD33 and the MS4A cluster, in the biology of AD.

    “GWAS have strongly implicated microglial genes involved in ligand recognition and phagocytosis, such as APOE, TREM2, CD33 and the MS4A cluster, in the biology of AD36.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [36] Efthymiou, A. G. & Goate, A. M. Late onset Alzheimer’s disease genetics implicates microglial pathways in disease risk. Mol. Neurodegener. 12, 43 (2017). source

      The AD GWAS studies section links the MS4A cluster to AD risk, and the sequencing and rare-variants section describes TREM2’s role in ligand binding and microglial phagocytosis. The Conclusion also implicates CD33 and TREM2 in phagocytosis. But the common-variants section says the MS4A proteins’ exact function and ligand-binding partners remain unknown, so the claim overstates the evidence that all the listed genes have the stated functions. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Findingown data

    snATAC-seq identified 14 clusters encompassing major brain and hematopoietic cell types, including one cluster containing microglia and myeloid cells from each sample (C6).

    “We identified 14 clusters encompassing the major brain and hematopoietic cell types (Fig. 5a,b), including one cluster that contained previously described MG, as well as myeloid cells from each of our samples (C6; Fig. 5b, Extended Data Fig. 6 and Supplementary Table 15).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    In CHS and FHS, the decrement in AD dementia risk associated with CHIP was similar among people with APOE ε3ε3 or an APOE ε4 allele, but not seen in those with APOE ε2ε2 or APOE ε2ε3 genotypes.

    “In CHS and FHS, the decrement in risk for AD dementia associated with CHIP was of a similar magnitude among people with the APOE ε3ε3 genotype or with an APOE ε4 allele, but not seen in those with APOE ε2ε2 or APOE ε2ε3 genotypes”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    CHIP somatic variants were found in the NeuN− c-MAF+ population in seven of eight brains, with VAF from 0.02 to 0.28, representing 4% to 56% of NeuN− c-MAF+ nuclei.

    “We observed that the same mutations found in blood were also detected in microglia-enriched fraction of the brain in seven of eight CHIP carriers.”
    • Also stated in: § Detection of CHIP variants in the human brain · plain
      “The CHIP somatic variants were found in the NeuN− c-MAF+ population in seven out of eight brains, with a VAF that ranged from 0.02 to 0.28 (representing 4% to 56% of NeuN− c-MAF+ nuclei).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Regression models examining the interaction of CHIP with APOE genotype showed a consistent direction of effect as the stratified models for both AD and ADNC, although individual interaction terms did not reach statistical significance.

    “Regression models that examined the interaction of CHIP with APOE genotype showed a consistent direction of effect as the stratified models for both AD and ADNC, although the individual interaction terms did not reach statistical significance”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Reclustering cells within C6 identified three subclusters with accessibility profiles consistent with MG, but no consistent differences in subcluster proportions between CHIP and non-CHIP samples.

    “We identified three subclusters, all of which exhibited accessibility profiles consistent with MG, but we did not observe consistent differences in subcluster proportions between CHIP and non-CHIP samples”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Small numbers of cells in brain samples clustered with circulating immune cells, predominantly T cells, and were found in all unsorted brains (mean = 7.2%, range 3.7-12.5%).

    “Small numbers of cells in our brain samples clustered with circulating immune cells, predominantly T cells, and were found in all unsorted brains (mean = 7.2% of total hematopoietic cells, range 3.7–12.5%).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    APOE genotype was strongly associated with AD dementia risk in those without CHIP age 60 years or older (P = 8.1 × 10−8), but not in CHIP carriers of the same age (P = 0.42).

    “APOE genotype was strongly associated with AD dementia risk in those without CHIP age 60 years or older (P = 8.1 × 10−8 by log-rank test), but not in CHIP carriers of the same age (P = 0.42 by log-rank test)”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In ADSP participants without dementia, ADNC was lower in CHIP carriers compared to noncarriers with APOE ε3ε3 or an APOE ε4 allele, but not in those with APOE ε2ε2 or APOE ε2ε3 genotypes.

    “In ADSP participants without dementia, ADNC was lower in CHIP carriers compared to noncarriers with the APOE ε3ε3 genotype or with an APOE ε4 allele, but this effect was seen not in those with APOE ε2ε2 or APOE ε2ε3 genotypes”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The percentage of MG ranged from 7.6% to 25% in the sorted samples, representing an 11.5-fold to 34.5-fold enrichment for MG in the occipital cortex and cerebellum.

    “We determined that the percentage of MG ranged from 7.6% to 25% in the sorted samples, representing an 11.5-fold to 34.5-fold enrichment for MG in the occipital cortex and cerebellum”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    In MR using CHIP as exposure and systolic blood pressure as outcome, there was a significant effect in some methods but not others (IVW effect = 0.144, P = 0.62; weighted median effect = 0.666, P = 6.3 × 10−5; MR-PRESSO effect = 0.144, P = 0.63; MR-RAPS effect = 0.173, P = 0.014).

    “We found that there was a significant effect in some methods, but not others (IVW, effect = 0.144, P = 0.62; weighted median, effect = 0.666, P = 6.3 × 10−5; MR-PRESSO, effect = 0.144, P = 0.63; MR-RAPS, effect = 0.173, P = 0.014).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Amongst APOE ε4 carriers, AD cases were strongly enriched for younger females and controls were preferentially older males.

    “This is illustrated by the distribution of AD cases and controls amongst APOE ε4 carriers, where AD cases were strongly enriched for younger females and controls were preferentially older males.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    Microglia are believed to have little contribution from marrow-derived cells in adulthood.

    “MG are believed to have little contribution from marrow-derived cells in adulthood23, so it would be surprising to find the mutations in this compartment.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [23] Ginhoux, F. & Jung, S. Monocytes and macrophages: developmental pathways and tissue homeostasis. Nat. Rev. Immunol. 14, 392–404 (2014). source

  • May combine two claims.

    Interpretationown data

    CHIP somatic variants were not detected in the NeuN+ c-MAF− neuronal population and were absent or at low levels in the other two populations, effectively excluding granulocytes and lymphocytes as the source of the mutations.

    “In contrast, CHIP somatic variants were not detected in the NeuN+ c-MAF− neuronal population and were absent or at low levels in the other two populations (Fig. 4c and Extended Data Fig. 3), effectively excluding granulocytes and lymphocytes as the source of the mutations.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    The cells in C6 exhibit aggregate similarity to microglia and are distinct from monocytes (C7) and dendritic cells (C8).

    “In total, these results indicate that the cells in C6 exhibit aggregate similarity to MG and are distinct from monocytes (C7) and dendritic cells (C8).”
    Quote in the paperNot a substantial claim

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

    Study design and conductown data

    VAF measurement in the NeuN− c-MAF+ gate for four mutations was reproducible across replicates.

    “To determine whether the observed VAF was reproducible across replicates, we repeated the VAF measurement in the NeuN− c-MAF+ gate for four mutations and obtained concordant results”
    Quote in the paperNot a substantial claim

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

    Study design and conductown data

    The linearity assumption was met.

    “visual examination of a plot of the Martingale residuals for age revealed that the linearity assumption was met.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    We cannot currently conclude that the mechanism of protection from AD seen in CHIP carriers is due to these infiltrating cells.

    “Therefore, while the data presented here are suggestive, we cannot currently conclude that the mechanism of protection from AD seen in CHIP carriers is due to these infiltrating cells.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductreasoning

    To exclude confounding due to survivorship bias, the analysis used competing risk regression with death as the competing risk.

    “To exclude confounding due to survivorship bias, we performed the analysis using CRR, with death as the competing risk.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    Mid-life hypertension has been reported to be associated with an increased risk of Alzheimer's disease in observational studies.

    “As mid-life hypertension has been reported to be associated with an increased risk of AD in observational studies52”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [52] Reitz, C., Brayne, C. & Mayeux, R. Epidemiology of Alzheimer disease. Nat. Rev. Neurol. 7 137–152 (2011). source

  • Classified as probably not a substantial claim.

    Premisenone given

    Some proximal genes to CHIP instrumental variables (TERT, PARP1, ATM, TP53, BCL2L1, SETBP1) are thought to be relevant to cancers generally, including solid tumors.

    “some are thought to be relevant to cancers generally, including solid tumors (TERT, PARP1, ATM, TP53, BCL2L1 and SETBP1)”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Study design and conductnone given

    The selected germline IVs are independent of sex and other unlinked genetic variants.

    “Clearly, our selected germline IVs are independent of sex and other unlinked genetic variants.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductreasoning

    Including family as a cluster variable in the CRR model for FHS controls for biased estimates due to correlated genetic or environmental factors.

    “To control for this possibility, we also included family as a cluster variable in the CRR model for FHS using the R package crrSC”
    Quote in the paperSubstantial claim

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

    Study design and conductcitation

    Adjudication for Alzheimer's phenotypes was done by a committee comprising at least two neurologists and a neuropsychologist.

    “Adjudication for Alzheimer’s phenotypes was done by a committee41, comprising at least two neurologists and a neuropsychologist.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [41] Seshadri, S. et al. Plasma homocysteine as a risk factor for dementia and Alzheimer’s disease. N. Engl. J. Med. 346, 476–483 (2002). source

  • May combine two claims.

    Interpretationreasoning

    Given that higher blood pressure is a risk factor for Alzheimer's disease, the positive association between genetic risk of CHIP and blood pressure does not explain the inverse association between CHIP and Alzheimer's disease seen in the MR analysis and observational study.

    “Given that higher blood pressure is a risk factor for AD, this does not explain the inverse association between CHIP and AD seen in our MR analysis and observational study.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Higher blood pressure is a risk factor for Alzheimer's disease.

  • Classified as probably not a substantial claim.

    Study design and conductown data

    To confirm the reproducibility of the VAF measurements, DNA from unsorted brain nuclei or sorted Maf+ NeuN− was used for library prep and sequencing in a second replicate.

    “To confirm the reproducibility of the VAF measurements, DNA from unsorted brain nuclei or sorted Maf+ NeuN− was used for library prep and sequencing in a second replicate.”
    Quote in the paperSubstantial claim

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

    Study design and conductown data

    The proportional hazards assumption was met for each covariate.

    “visual examination of a plot of the Schoenfeld residuals revealed that the proportional hazards assumption was met for each covariate”
    Quote in the paperNot a substantial claim

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

    Interpretationown data

    The observation that the effect sizes were similar with several different driver genes suggests that there could be shared mechanisms leading to protection from AD across several different mutations.

    “The observation that the effect sizes were similar with several different driver genes suggests that there could be shared mechanisms leading to protection from AD across several different mutations.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    It is unlikely that tumors of solid organs could directly influence the biology of Alzheimer's disease.

    “It is unlikely that tumors of solid organs could directly influence the biology of AD.”
    Quote in the paperNot a substantial claim

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

    Interpretationcitation

    CHIP has moderate heritability relative to other traits.

    “CHIP has moderate heritability relative to other traits”
    Quote in the paperNot a substantial claim

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

    Study design and conductown data

    The 1,104 AD cases and 1,446 controls were well matched by age.

    “we had 1,104 AD cases and 1,446 controls who were well matched by age.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Study design and conductnone given

    The estimated fraction of mutant cells is likely more reliable from the unsorted brain.

    “although the estimated fraction of mutant cells is likely more reliable from the unsorted brain.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductown data

    To rule out sequencing errors or other technical artifacts that could artificially inflate the mutant allele fraction, amplicon sequencing using the same primers was performed on a negative control brain sample from a donor known not to be a CHIP carrier.

    “To rule out sequencing errors or other technical artifacts that could be artificially inflating the mutant allele fraction, we also performed amplicon sequencing using the same primers on a negative control brain sample from a donor known to not be a CHIP carrier.”
    Quote in the paperSubstantial claim

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

    Study design and conductnone given

    Consent for brain donation was obtained from each donor and the study was approved by the University of Washington Institutional Review Board and by the Kaiser Permanente Washington Institutional Review Board.

    “Consent for brain donation was obtained from each donor and the study was approved by the University of Washington Institutional Review Board and by the Kaiser Permanente Washington Institutional Review Board.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    After clustering, reproducible peaks were determined for each cluster individually to ensure that cell type-specific peaks were retained.

    “After clustering, reproducible peaks were determined for each cluster individually to ensure that cell type-specific peaks were retained.”
    Quote in the paperNot a substantial claim

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

    Study design and conductown data
    § or 103%.

    Simulations indicated that the confidence intervals for the estimate of mutant MG are not overly broad based on expected input parameters.

    “These simulations indicated that the confidence intervals for the estimate of mutant MG are not overly broad based on expected input parameters.”
    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

    Doublets were removed in two steps: first, based on similarity to computationally simulated doublets; second, after initial clustering, a cluster of putative doublets weakly enriched for markers of multiple cell types was removed and the remaining nuclei were reprocessed and reclustered.

    “Doublets were removed in two steps. First, for each sample, doublets were predicted and removed based on similarity to computationally simulated doublets. Second, after initial clustering, we identified a cluster of putative doublets that was weakly enriched for markers of multiple cell types. This cluster was removed and the remaining nuclei were reprocessed and reclustered.”
    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 conductreasoning

    Although Harmony batch correction is implemented and part of the standard workflow in ArchR, no batch correction was used to ensure that any biological differences between the samples would be preserved.

    “Although Harmony batch correction is implemented and part of the standard workflow in ArchR, we did not use any batch correction to ensure that any biological differences between the samples would be preserved.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    The eight CHIP carriers represented all donors known to have CHIP and with autopsy specimens available, and the four without CHIP represented a random selection of the study cohort.

    “The eight CHIP carriers represented all donors known to have CHIP and with autopsy specimens available. The four without CHIP represented a random selection of the study cohort.”
    Quote in the paperSubstantial claim
47 of 47

  • The authors state this as an assumption.

    All nonmicroglial hematopoietic cells in the brain samples were mutant.

    “We conservatively assumed that all nonmicroglial hematopoietic cells were mutant and subtracted the number of these cells from the total mutant cell count”

  • The authors state this as an assumption.

    The instrumental variables for CHIP are relevant, i.e., associated with CHIP.

    “The assumptions for the validity of MR analyses are relevance, independence and exclusion restriction of the independent variables (IVs)48.”

  • The authors state this as an assumption.

    The instrumental variables for CHIP are independent of unmeasured confounders.

    “Independence: This assumption presupposes that the CHIP IVs are not associated with unmeasured confounders.”

  • The authors state this as an assumption.

    The instrumental variables affect AD only through CHIP (exclusion restriction).

    “The assumptions for the validity of MR analyses are relevance, independence and exclusion restriction of the independent variables (IVs)48.”

  • The authors state this as an assumption.

    All nonmicroglial hematopoietic cells were mutant.

    “We assumed that all nonmicroglial hematopoietic cells were mutant”

  • The authors state this as an assumption.

    Only hematopoietic cells can carry the CHIP variant.

    “We assume that only hematopoietic cells can carry the CHIP variant.”

  • The paper relies on this without support.

    Higher blood pressure is a risk factor for Alzheimer's disease.

    “Given that higher blood pressure is a risk factor for AD”
7 of 7

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?

  • The protective association between CHIP and AD was strongest among APOE ε3/ε3 individuals, whereas no significant effect was detected in ε2 or ε4 carriers.

    “Stratification by APOE genotype indicated that the protective association was strongest among APOE ε3/ε3 individuals, whereas no significant effect was detected in ε2 or ε4 carriers [10].”

    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 [10]

    The Results section, “Stratified associations between CHIP and AD” (page unavailable), says the reduction in AD dementia risk was of similar magnitude in APOE ε3/ε3 individuals and ε4 carriers, rather than strongest in ε3/ε3 individuals alone. It also reports lower AD neuropathologic change in both groups; the effect was not seen in the ε2/ε2 or ε2/ε3 groups. The nonsignificant interaction terms do not establish an absence of an effect in ε4 carriers. (LLM, conf=0.88)

    Checked by a reasoning model — may be wrong.

    Experimental — accuracy not yet measured

  • Two recent studies investigating CHIP variants primarily using whole-exome sequencing data from blood cells found no effect or a protective effect on Alzheimer's disease risk.

    “Two recent studies investigating CHIP variants primarily using whole-exome sequencing (WES) data from blood cells found no effect24 or a protective effect25 on AD risk.”

    From Somatic cancer variants enriched in Alzheimer’s disease microglia-like cells drive inflammatory and proliferative states (2026) · cites this paper as [25]

    The Results (Association between CHIP and AD dementia; page not available) report a protective association between CHIP and Alzheimer’s dementia, including in the blood-derived WES replication cohort. But the discovery cohorts identified CHIP from blood-derived whole-genome sequencing, so describing this study as primarily using WES is not supported by the cited passages. The separate “no effect” finding is attributed to citation 24, not this paper. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • 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”

    From TET2-mutant myeloid cells mitigate Alzheimer’s disease progression via CNS infiltration and enhanced phagocytosis in mice (2025) · cites this paper as [5]

    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

  • During neurodegeneration, blood-brain barrier integrity declines, which may facilitate peripheral monocytes to infiltrate the CNS and differentiate into microglia-like cells.

    “during neurodegeneration, the integrity of the blood–brain barrier declines. This may facilitate debated levels of peripheral monocytes to infiltrate the central nervous system and differentiate into microglia-like cells.”

    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 [10]

    The Discussion (page unavailable) proposes that peripherally derived myeloid cells may enter the brain, and the Results describe MG-like cells in brain samples. But the paper does not say that blood–brain barrier integrity declines during neurodegeneration or that such a decline enables entry; it also does not establish that the cells are infiltrating monocytes that differentiate into MG-like cells. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Somatic mutations present in the peripheral hematopoietic system could theoretically be imported into the brain's immune environment, posing a mechanistic link between systemic aging and local neuroinflammation.

    “any somatic mutations present in the peripheral hematopoietic system could theoretically be imported into the brain’s immune environment, posing a mechanistic link between systemic aging and local neuroinflammation [10,24,25,26].”

    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 [10]

    The Results (Detection of CHIP variants in the human brain) found blood-associated CHIP mutations in a brain cell population, and the Discussion proposes that peripheral myeloid cells may enter the brain. This supports the proposed route from blood to brain, but the paper examines CHIP mutations—not any somatic mutation—and does not establish a mechanistic link to local neuroinflammation. (LLM, conf=0.85)

    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.

  • CHS analysis sample is reported as both 743 and 620

    Major

    The Methods state that 743 CHS participants remained after excluding those missing AD diagnosis information, but later say that 620 remained after excluding those without AD diagnosis information.

  • Brain WES sample count differs between text and figure

    Minor

    The Results report brain-derived WES data from 1,776 people, whereas the caption for the corresponding figure reports 1,775.

  • Mutant-microglia calculation points to the wrong figure panel

    Minor

    The Methods point to Fig. 5d for the fraction of mutated microglia, but the caption identifies Fig. 5d as chromatin-accessibility tracks and Fig. 5e as the mutant-microglia calculation.

  • Two different CHS counts are assigned to the same APOE genotype

    Minor

    The CHS genotype breakdown lists both 424 and 162 people with the ε3ε4 genotype, without distinguishing the two groups.

4 of 4

Cites

Flagged first, then by citations

1 of the 60 references couldn’t be matched to a known paper.

Cited by

Sorted by citations

Related

Authors
Bouzid, H., Belk, J. A., Jan, M., Qi, Y., Sarnowski, C., Wirth, S., Ma, L., Chrostek, M. R., Ahmad, H., Nachun, D., Yao, W., NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, Bis, J., Psaty, B., Beiser, A., Bick, A. G., Bis, J. C., Fornage, M., Longstreth, W. T., Lopez, O. L., Natarajan, P., Psaty, B. M., Satizabal, C. L., Weinstock, J., Larson, E. B., Crane, P. K., Keene, C. D., Seshadri, S., Satpathy, A. T., Montine, T. J., & Jaiswal, S.
Affiliations
  • Stanford Medicine (US)
  • Stanford University (US)
  • Massachusetts General Hospital (US)
  • The University of Texas Health Science Center at Houston (US)
  • Boston University (US)
  • Vanderbilt University Medical Center (US)
  • Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases (US)
  • Broad Institute (US)
  • University of Michigan (US)
  • Kaiser Permanente Washington Health Research Institute (US)
  • University of Washington (US)
  • The University of Texas at San Antonio Health Science Center (US)
Corresponding author
Jaiswal, Siddhartha
ORCID
Venue
Nature Medicine
Publisher
Springer Science and Business Media LLC
Published
2023-06-15
Volume
29
Issue
7
Pages
1662-1670
ISSN
  • 1078-8956 (ISSN-L)
  • 1546-170X
DOI
10.1038/s41591-023-02397-2
PMC
PMC10353941
OpenAlex
W4380785142
Semantic Scholar
3970db4d8b0a3f1881e30cd191d2f97be962e3ea
Cited by
169
References
60
Citations by year
2026: 42 · 2025: 58 · 2024: 44 · 2023: 19 · 2022: 6
FWCI
23.48
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Medicine (publishedVersion, cc-by)
  • medRxiv (acceptedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion, cc-by)
  • Digital Commons-TMC (Texas Medical Center) (submittedVersion)
  • Informationszentrum Lebenswissenschaften (ZB MED) (submittedVersion, cc-by)
Funders
  • U.S. Department of Health & Human Services | National Institutes of Health (DP2-HL157540, R01-HL148565, K08CA230188)
  • Burroughs Wellcome Fund (DP5 OD029586)
  • Fondation Leducq (TNE-18CVD04)
  • Ludwig Center for Cancer Stem Cell Research at Stanford University Knight Initiative for Brain Resilience
  • U.S. Department of Health & Human Services | NIH | National Institute on Aging (R00 AG066849)
  • Fireman Endowed Chair in Vascular Medicine
  • Nancy and Buster Alvord Endowment
  • U.S. Department of Health & Human Services | NIH | Office of Extramural Research, National Institutes of Health (AG053959)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
clonal hematopoiesis of indeterminate potential, Alzheimer's disease, dementia risk, microglia, myeloid cells, brain microglia, Mendelian randomization, causal relationship
MeSH terms
Clonal Hematopoiesis, Alzheimer Disease, Hematopoiesis, Hematopoietic Stem Cells, Humans, Mutation, Precancerous Conditions

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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