Dnmt3a and Tet2-Driven Clonal Hematopoiesis Have Opposing Effects on the Pathogenesis of Alzheimer's Disease
Open accessAbstract
The clonal expansion of mutant hematopoietic stem cells (HSCs) known as clonal hematopoiesis is associated with an increased likelihood of developing many age-associated diseases. However, the connection to neurodegenerative diseases including Alzheimer's Disease (AD) is less clear. Prior studies have established that inflammation plays a central role in AD pathogenesis. Mounting evidence suggests systemic inflammatory signals can be transmitted to the central nervous system (CNS), where they may play a direct role in microglia activation and beta-amyloid plaque clearance. Here we investigated the role of the two most commonly mutated clonal hematopoiesis-associated genes, DNMT3A and TET2, in the pathogenesis of AD using a mouse model. We utilized 5xFAD (Familial Alzheimer's Disease) mice which express human disease variants of amyloid precursor protein and presenilin and typically develop beta-amyloid plaques and cognitive decline by 6-9 months of age. At 6-8 weeks of age, 5xFAD mice were non-competitively transplanted with Dnmt3a-/-, Tet2-/- or wildtype (WT) bone marrow (BM). Mice were then challenged weekly with LPS to mimic systemic chronic inflammation seen in aging. At 6 months of age, transplanted mice were assessed for signs of AD pathogenesis as well as the presence of infiltrating peripheral immune cells within the brain. 5xFAD mice transplanted with Dnmt3a-/- BM displayed exacerbated AD, including worsened cognitive impairment and decreased microglia activation compared to those transplanted with WT BM. Mice transplanted with Dnmt3a-/- BM also had fewer peripheral immune cells infiltrating the brain compared to WT-transplanted recipients. In contrast, 5xFAD mice transplanted with Tet2-/- BM showed improved cognitive status, decreased amyloid plaques, and increased microglia activation. Unlike mice transplanted with Dnmt3a-/- BM, Tet2-/- transplanted mice had a higher percentage of activated infiltrating myeloid cells within the brain compared to WT controls. Taken together, these data suggest that loss of Dnmt3a and Tet2 exert opposite effects on AD pathogenesis, with divergent impact on peripheral immune cell infiltration to the brain. We hypothesize that Tet2-/- peripheral immune cells can more effectively infiltrate the CNS, leading to enhanced microglia activation, better amyloid plaque clearance and preserved cognitive function. To assess whether peripherally derived immune cells directly replace microglia in the CNS, we performed flow cytometry to identify donor-derived peripheral immune cells that were positive for microglia marker Tmem119 within the brain. Interestingly, mice transplanted with Tet2-/- BM, had a higher proportion of donor-derived mutant microglia-like cells when compared to mice transplanted with WT BM. While the absolute number of peripherally derived microglia-like cells was low, these data indicate that microglial replacement from the periphery can occur. To evaluate the impact of DNMT3A or TET2 mutation on human microglial function, we utilized microglia derived from isogenic human iPSC lines harboring DNMT3A (DNMT3AR882H/WT) or TET2 mutations (TET2DelE3-E11/WT). Cytokine bead array of culture supernatant showed that TET2-mutant induced microglia (iMGs) released significantly more inflammatory cytokines following LPS treatment than either WT or DNMT3A-mutant iMGs. TET2-mutant iMGs also demonstrated a greater capacity to phagocytose both myelin and beta-amyloid upon LPS activation compared to WT or DNMT3A-mutant iMGs. As myelin damage likely precedes and contributes to amyloid plaque buildup in early AD, TET2-mutant microglia may prevent disease through clearance of both damaged myelin and beta-amyloid plaques. In summary, we found that loss of Tet2 provided protection against AD through increased myeloid cell infiltration and microglia activation, leading to more efficient amyloid plaque clearance and improved cognitive performance. In contrast, the opposite was true for loss of Dnmt3a. Our study of clonal hematopoiesis and AD marks the first report in which DNMT3A and TET2, which have opposite roles in DNA methylation, induced opposing effects on disease progression. This work has implications for our understanding of clonal hematopoiesis and AD pathogenesis and confirms that peripheral immune cells can have direct effects on neuroinflammation and immunologic control of neurodegenerative disease.
AI snapshot
Written from the paper’s full text.
TL;DR
In a 5xFAD mouse model of Alzheimer's disease, clonal hematopoiesis driven by loss of Dnmt3a worsened AD pathogenesis, whereas loss of Tet2 was protective. The opposing effects track with divergent peripheral immune cell infiltration and microglial activation, and TET2-mutant human iPSC-derived microglia showed greater inflammatory cytokine release and phagocytic capacity.
Key findings
- 5xFAD mice transplanted with Dnmt3a⁻/⁻ bone marrow displayed exacerbated AD, including worsened cognitive impairment and decreased microglia activation versus WT-transplanted mice, and had fewer peripheral immune cells infiltrating the brain.
- 5xFAD mice transplanted with Tet2⁻/⁻ bone marrow showed improved cognitive status, decreased amyloid plaques, and increased microglia activation, with a higher percentage of activated infiltrating myeloid cells in the brain versus WT controls.
- Tet2⁻/⁻-transplanted mice had a higher proportion of donor-derived Tmem119-positive microglia-like cells than WT-transplanted mice, though absolute numbers of peripherally derived microglia-like cells were low.
- In isogenic human iPSC lines, TET2-mutant induced microglia released significantly more inflammatory cytokines after LPS than WT or DNMT3A-mutant iMGs, and showed greater phagocytosis of myelin and beta-amyloid upon LPS activation.
Methods
- 5xFAD mice (expressing human APP and presenilin variants, developing beta-amyloid plaques and cognitive decline by 6–9 months) were non-competitively transplanted at 6–8 weeks of age with Dnmt3a⁻/⁻, Tet2⁻/⁻, or wildtype bone marrow, then challenged weekly with LPS to mimic chronic systemic inflammation of aging.
- At 6 months of age, transplanted mice were assessed for AD pathogenesis signs and for infiltrating peripheral immune cells in the brain; flow cytometry identified donor-derived Tmem119-positive microglia-like cells.
- Human microglia derived from isogenic iPSC lines harboring DNMT3A (R882H/WT) or TET2 (DelE3-E11/WT) mutations were evaluated by cytokine bead array of culture supernatant and by phagocytosis assays after LPS treatment.
Limitations
- Not stated in the paper (the abstract reports no limitations and declares no relevant conflicts of interest).
- Evident from the text: this is a conference abstract, so quantitative effect sizes, sample sizes, and statistical details are not reported; the microglial-replacement finding rests on a low absolute number of peripherally derived microglia-like cells, and the proposed mechanism (Tet2⁻/⁻ cells infiltrating the CNS to enhance plaque clearance) is stated as a hypothesis rather than demonstrated.
Model-written summary. Check it against the paper before relying on it.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
- Findingown data§ Dnmt3a and Tet2-Driven Clonal Hematopoiesis Have Opposing Effects on the Pathogenesis of Alzheimer's Disease · p. 1
Tet2-/- transplanted mice had a higher percentage of activated infiltrating myeloid cells within the brain compared to WT controls.
“Unlike mice transplanted with Dnmt3a -/- BM, Tet2 -/-transplanted mice had a higher percentage of activated infiltrating myeloid cells within the brain compared to WT controls.”
Quote in the paperSubstantial claim - Findingown data§ Dnmt3a and Tet2-Driven Clonal Hematopoiesis Have Opposing Effects on the Pathogenesis of Alzheimer's Disease · p. 1
Mice transplanted with Dnmt3a-/- BM had fewer peripheral immune cells infiltrating the brain compared to WT-transplanted recipients.
“Mice transplanted with Dnmt3a -/-BM also had fewer peripheral immune cells infiltrating the brain compared to WT-transplanted recipients.”
Quote in the paperSubstantial claim - Findingown data§ Dnmt3a and Tet2-Driven Clonal Hematopoiesis Have Opposing Effects on the Pathogenesis of Alzheimer's Disease · p. 1
Mice transplanted with Tet2-/- BM had a higher proportion of donor-derived mutant microglia-like cells compared to mice transplanted with WT BM.
“Interestingly, mice transplanted with Tet2 -/BM, had a higher proportion of donor-derived mutant microglia-like cells when compared to mice transplanted with WT BM.”
Quote in the paperSubstantial claim - Findingown data§ Dnmt3a and Tet2-Driven Clonal Hematopoiesis Have Opposing Effects on the Pathogenesis of Alzheimer's Disease · p. 1
The absolute number of peripherally derived microglia-like cells was low.
“While the absolute number of peripherally derived microglia-like cells was low, these data indicate that microglial replacement from the periphery can occur.”
Quote in the paperNot a substantial claim - Findingown data§ Dnmt3a and Tet2-Driven Clonal Hematopoiesis Have Opposing Effects on the Pathogenesis of Alzheimer's Disease · p. 1
5xFAD mice transplanted with Tet2-/- BM showed increased microglia activation.
“In contrast, 5xFAD mice transplanted with Tet2 -/-BM showed improved cognitive status, decreased amyloid plaques, and increased microglia activation.”
Quote in the paperSubstantial claim
- Findingown data§ Dnmt3a and Tet2-Driven Clonal Hematopoiesis Have Opposing Effects on the Pathogenesis of Alzheimer's Disease · p. 1
5xFAD mice transplanted with Dnmt3a-/- BM displayed worsened cognitive impairment compared to those transplanted with WT BM.
“5xFAD mice transplanted with Dnmt3a -/BM displayed exacerbated AD, including worsened cognitive impairment and decreased microglia activation compared to those transplanted with WT BM.”
Quote in the paperSubstantial claim - Findingown data§ Dnmt3a and Tet2-Driven Clonal Hematopoiesis Have Opposing Effects on the Pathogenesis of Alzheimer's Disease · p. 1
5xFAD mice transplanted with Tet2-/- BM showed improved cognitive status.
“In contrast, 5xFAD mice transplanted with Tet2 -/-BM showed improved cognitive status, decreased amyloid plaques, and increased microglia activation.”
Quote in the paperSubstantial claim - Findingown data§ Session 503.Clonal Hematopoiesis, Aging, and Inflammation · p. 2
TET2-mutant induced microglia (iMGs) released significantly more inflammatory cytokines following LPS treatment than either WT or DNMT3A-mutant iMGs.
“Cytokine bead array of culture supernatant showed that TET2 -mutant induced microglia (iMGs) released significantly more inflammatory cytokines following LPS treatment than either WT or DNMT3A -mutant iMGs.”
Quote in the paperSubstantial claim - Findingown data§ Dnmt3a and Tet2-Driven Clonal Hematopoiesis Have Opposing Effects on the Pathogenesis of Alzheimer's Disease · p. 1
5xFAD mice transplanted with Tet2-/- BM showed decreased amyloid plaques.
“In contrast, 5xFAD mice transplanted with Tet2 -/-BM showed improved cognitive status, decreased amyloid plaques, and increased microglia activation.”
Quote in the paperSubstantial claim - Findingown data§ Dnmt3a and Tet2-Driven Clonal Hematopoiesis Have Opposing Effects on the Pathogenesis of Alzheimer's Disease · p. 1
5xFAD mice transplanted with Dnmt3a-/- BM displayed decreased microglia activation compared to those transplanted with WT BM.
“5xFAD mice transplanted with Dnmt3a -/BM displayed exacerbated AD, including worsened cognitive impairment and decreased microglia activation compared to those transplanted with WT BM.”
Quote in the paperSubstantial claim - Findingown data§ Session 503.Clonal Hematopoiesis, Aging, and Inflammation · p. 2
TET2-mutant iMGs demonstrated a greater capacity to phagocytose both myelin and beta-amyloid upon LPS activation compared to WT or DNMT3A-mutant iMGs.
“TET2 -mutant iMGs also demonstrated a greater capacity to phagocytose both myelin and beta-amyloid upon LPS activation compared to WT or DNMT3A -mutant iMGs.”
Quote in the paperSubstantial claim - Interpretationown data§ Dnmt3a and Tet2-Driven Clonal Hematopoiesis Have Opposing Effects on the Pathogenesis of Alzheimer's Disease · p. 1
5xFAD mice transplanted with Dnmt3a-/- BM displayed exacerbated AD compared to those transplanted with WT BM.
“5xFAD mice transplanted with Dnmt3a -/BM displayed exacerbated AD, including worsened cognitive impairment and decreased microglia activation compared to those transplanted with WT BM.”
Quote in the paperSubstantial claim - Interpretationown data§ Dnmt3a and Tet2-Driven Clonal Hematopoiesis Have Opposing Effects on the Pathogenesis of Alzheimer's Disease · p. 1
Dnmt3a and Tet2-driven clonal hematopoiesis have opposing effects on the pathogenesis of Alzheimer's disease.
“Dnmt3a and Tet2-Driven Clonal Hematopoiesis Have Opposing Effects on the Pathogenesis of Alzheimer's Disease”
- Also stated in: § Session 503.Clonal Hematopoiesis, Aging, and Inflammation · p. 2 · plain
“In summary, we found that loss of Tet2 provided protection against AD through increased myeloid cell infiltration and microglia activation, leading to more efficient amyloid plaque clearance and improved cognitive performance. In contrast, the opposite was true for loss of Dnmt3a .”
Quote in the paperSubstantial claim - Also stated in: § Session 503.Clonal Hematopoiesis, Aging, and Inflammation · p. 2 · plain
- Interpretationown data§ Dnmt3a and Tet2-Driven Clonal Hematopoiesis Have Opposing Effects on the Pathogenesis of Alzheimer's Disease · p. 1
Microglial replacement from the periphery can occur.
“While the absolute number of peripherally derived microglia-like cells was low, these data indicate that microglial replacement from the periphery can occur.”
Quote in the paperSubstantial claim - Interpretationown data§ Session 503.Clonal Hematopoiesis, Aging, and Inflammation · p. 2
Our study marks the first report in which DNMT3A and TET2 induced opposing effects on disease progression.
“Our study of clonal hematopoiesis and AD marks the first report in which DNMT3A and TET2, which have opposite roles in DNA methylation, induced opposing effects on disease progression.”
Quote in the paperSubstantial claim- Rests on an assumption: DNMT3A and TET2 have opposite roles in DNA methylation.
- Interpretationreasoning§ Session 503.Clonal Hematopoiesis, Aging, and Inflammation · p. 2
TET2-mutant microglia may prevent disease through clearance of both damaged myelin and beta-amyloid plaques.
“As myelin damage likely precedes and contributes to amyloid plaque buildup in early AD, TET2-mutant microglia may prevent disease through clearance of both damaged myelin and beta-amyloid plaques.”
Quote in the paperSubstantial claim- Rests on an assumption: Myelin damage likely precedes and contributes to amyloid plaque buildup in early AD.
- Interpretationown data§ Session 503.Clonal Hematopoiesis, Aging, and Inflammation · p. 2
The opposite was true for loss of Dnmt3a.
“In contrast, the opposite was true for loss of Dnmt3a .”
Quote in the paperSubstantial claim
- May combine two claims. 3
May combine two claims.
Interpretationown data§ Dnmt3a and Tet2-Driven Clonal Hematopoiesis Have Opposing Effects on the Pathogenesis of Alzheimer's Disease · p. 1Loss of Dnmt3a and Tet2 exert opposite effects on AD pathogenesis, with divergent impact on peripheral immune cell infiltration to the brain.
“Taken together, these data suggest that loss of Dnmt3a and Tet2 exert opposite effects on AD pathogenesis, with divergent impact on peripheral immune cell infiltration to the brain.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown data§ Session 503.Clonal Hematopoiesis, Aging, and Inflammation · p. 2Loss of Tet2 provided protection against AD through increased myeloid cell infiltration and microglia activation, leading to more efficient amyloid plaque clearance and improved cognitive performance.
“In summary, we found that loss of Tet2 provided protection against AD through increased myeloid cell infiltration and microglia activation, leading to more efficient amyloid plaque clearance and improved cognitive performance.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown data§ Session 503.Clonal Hematopoiesis, Aging, and Inflammation · p. 2Peripheral immune cells can have direct effects on neuroinflammation and immunologic control of neurodegenerative disease.
“This work has implications for our understanding of clonal hematopoiesis and AD pathogenesis and confirms that peripheral immune cells can have direct effects on neuroinflammation and immunologic control of neurodegenerative disease.”
Quote in the paperSubstantial claim
The paper relies on this without support.
Clonal hematopoiesis is associated with an increased likelihood of developing many age-associated diseases.
“The clonal expansion of mutant hematopoietic stem cells (HSCs) known as clonal hematopoiesis is associated with an increased likelihood of developing many age-associated diseases.”
The paper relies on this without support.
The connection between clonal hematopoiesis and neurodegenerative diseases including Alzheimer's Disease is less clear.
“However, the connection to neurodegenerative diseases including Alzheimer's Disease (AD) is less clear.”
The paper relies on this without support.
Inflammation plays a central role in AD pathogenesis.
“Prior studies have established that inflammation plays a central role in AD pathogenesis.”
The paper relies on this without support.
Systemic inflammatory signals can be transmitted to the central nervous system, where they may play a direct role in microglia activation and beta-amyloid plaque clearance.
“Mounting evidence suggests systemic inflammatory signals can be transmitted to the central nervous system (CNS), where they may play a direct role in microglia activation and beta-amyloid plaque clearance.”
The paper relies on this without support.
5xFAD mice express human disease variants of amyloid precursor protein and presenilin and typically develop beta-amyloid plaques and cognitive decline by 6-9 months of age.
“We utilized 5xFAD (Familial Alzheimer's Disease) mice which express human disease variants of amyloid precursor protein and presenilin and typically develop beta-amyloid plaques and cognitive decline by 6-9 months of age.”
The paper relies on this without support.
LPS challenge mimics systemic chronic inflammation seen in aging.
“Mice were then challenged weekly with LPS to mimic systemic chronic inflammation seen in aging.”
The paper relies on this without support.
Myelin damage likely precedes and contributes to amyloid plaque buildup in early AD.
“As myelin damage likely precedes and contributes to amyloid plaque buildup in early AD, TET2-mutant microglia may prevent disease through clearance of both damaged myelin and beta-amyloid plaques.”
The paper relies on this without support.
DNMT3A and TET2 have opposite roles in DNA methylation.
“Our study of clonal hematopoiesis and AD marks the first report in which DNMT3A and TET2, which have opposite roles in DNA methylation, induced opposing effects on disease progression.”
- Authors
- Matatall, K. A., Wathan, T., Nguyen, M., Fernandez-Sanchez, J., Florez, M. A., Le, D., Cao, R., Kennedy, D., Maknojia, A., Thatavarty, A., Goodell, M., Rodriguez, A., Papapetrou, E., Marro, S., & King, K. Y.
- Affiliations
- Baylor College of Medicine (US)
- Icahn School of Medicine at Mount Sinai (US)
- 41 Baylor plaza, Baylor College of Medicine, Houston, TX
- The University of Texas MD Anderson Cancer Center (US)
- 6Immatics US, Houston, TX
- 9Division of Immunology, Allergy, and Rheumatology, Baylor College of Medicine, Houston, TX
- ORCID
- Venue
- Blood
- Publisher
- American Society of Hematology
- Published
- 2024-11-05
- Volume
- 144
- Issue
- Supplement 1
- Pages
- 4045-4045
- ISSN
- 0006-4971 (ISSN-L)
- 1528-0020
- OpenAlex
- W4405095985
- Cited by
- 0
- References
- 0
- Type
- conference abstract
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Blood (publishedVersion)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- clonal hematopoiesis, Alzheimer's disease, DNMT3A, TET2, hematopoietic stem cells, bone marrow transplantation, 5xFAD mice, systemic inflammation, lipopolysaccharide, microglial activation, amyloid plaques, peripheral immune cell infiltration, cognitive impairment, myeloid cells, neuroinflammation, epigenetic regulation
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 2026-10-28.
Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-28.
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.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
