Conserved epigenomic signals in mice and humans reveal immune basis of Alzheimer's disease
Open accessAbstract
Analysis of transcriptional and epigenomic changes in the hippocampus of a mouse model of Alzheimer’s disease shows that immune function genes and regulatory regions are upregulated, whereas genes and regulatory regions involved in synaptic plasticity, learning and memory are downregulated; genetic variants associated with Alzheimer’s disease are only enriched in orthologues of upregulated immune regions, suggesting that dysregulation of immune processes may underlie Alzheimer’s disease predisposition. Recent genome-wide association studies have shown substantial genetic variation in non-coding regions associated with Alzheimer's disease, suggesting the involvement of aberrant gene regulation. However, the functional significance of these variants remained unclear. By profiling transcriptional and chromatin state dynamics in a mouse model, Elizabeta Gjoneska and colleagues now show that the immune response genes and their regulatory regions are upregulated, whereas those involved in synaptic plasticity and learning and memory are downregulated. These changes are highly conserved between the mouse model and the human disease. Surprisingly, Alzheimer's disease-associated genetic variants are mainly enriched in higher-activity, immune-related enhancers, and are depleted in lower-activity, neural enhancers. This suggests that genetic predisposition to Alzheimer's may be primarily associated with immune functions, while neuronal plasticity may be affected primarily by non-genetic effects. Alzheimer’s disease (AD) is a severe1 age-related neurodegenerative disorder characterized by accumulation of amyloid-β plaques and neurofibrillary tangles, synaptic and neuronal loss, and cognitive decline. Several genes have been implicated in AD, but chromatin state alterations during neurodegeneration remain uncharacterized. Here we profile transcriptional and chromatin state dynamics across early and late pathology in the hippocampus of an inducible mouse model of AD-like neurodegeneration. We find a coordinated downregulation of synaptic plasticity genes and regulatory regions, and upregulation of immune response genes and regulatory regions, which are targeted by factors that belong to the ETS family of transcriptional regulators, including PU.1. Human regions orthologous to increasing-level enhancers show immune-cell-specific enhancer signatures as well as immune cell expression quantitative trait loci, while decreasing-level enhancer orthologues show fetal-brain-specific enhancer activity. Notably, AD-associated genetic variants are specifically enriched in increasing-level enhancer orthologues, implicating immune processes in AD predisposition. Indeed, increasing enhancers overlap known AD loci lacking protein-altering variants, and implicate additional loci that do not reach genome-wide significance. Our results reveal new insights into the mechanisms of neurodegeneration and establish the mouse as a useful model for functional studies of AD regulatory regions.
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Processing of ChIP-seq and ATAC-seq reads adhered to ENCODE/Roadmap guidelines, with small changes.
“The techniques described for processing the ChIP-seq and ATAC-seq reads are based on ENCODE/Roadmap guidelines with a few modifications (Gjoneska et al., 2015; Landt et al., 2012; Roadmap Epigenomics et al., 2015).”
From Loss of epigenetic information as a cause of mammalian aging (2023) · cites this paper as Gjoneska et al., 2015
The Materials and Methods sections on ChIP-seq read mapping and differential analysis say the procedures were consistent with ENCODE standards and describe an adjustment for limited sequencing depth. The paper does not describe ATAC-seq read processing or say that its read-processing procedures followed Roadmap guidelines. Page numbers are not available in our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measuredGenes expressed in myeloid cells display abnormal patterns of chromatin modification in AD mouse models and human samples.
“At the epigenetic level, genes expressed in myeloid cells display abnormal patterns of chromatin modification in AD mouse models and human samples18–20.”
From A common haplotype lowers PU.1 expression in myeloid cells and delays onset of Alzheimer's disease (2017) · cites this paper as [19]
The paper’s epigenome analysis and Extended Data Figures 4–5 report altered histone marks at regulatory regions in the AD mouse model, alongside increased immune-gene expression. Its human analyses compare gene expression in AD patients and identify immune-cell enhancer activity at regions corresponding to the altered mouse enhancers; they do not show abnormal chromatin modifications measured in human AD samples. No page numbers are provided in our copy. (LLM, conf=0.87)
Experimental — accuracy not yet measuredIncreased PU.1 expression levels are associated with Alzheimer's disease and Huntington's disease.
“Increased PU.1 expression levels are associated with AD (Gjoneska et al., 2015; Huang et al., 2017; Rustenhoven et al., 2018) and Huntington’s disease (Crotti et al., 2014)”
From A novel molecular class that recruits HDAC/MECP2 complexes to PU.1 motifs reduces neuroinflammation (2023) · cites this paper as Gjoneska et al., 2015
The paper reports increased PU.1 (SPI1) expression in a CK-p25 mouse model of AD-like neurodegeneration (passage [1], section labeled Abstract). That supports the AD association, but does not establish increased PU.1 expression in people with AD. The Huntington’s disease portion of the citing sentence is attributed to Crotti et al., not to this paper. (LLM, conf=0.83)
Experimental — accuracy not yet measuredIn brain tissue from human Alzheimer's disease patients, microglia display the morphology and gene expression profile characteristic of an activated cell state and cluster around β-amyloid plaques.
“In brain tissue from human AD patients, microglia display the morphology (Heppner et al., 2015) and gene expression profile (Gjoneska et al., 2015; Mathys et al., 2019) characteristic of an activated cell state and cluster around β-amyloid plaques.”
From A novel molecular class that recruits HDAC/MECP2 complexes to PU.1 motifs reduces neuroinflammation (2023) · cites this paper as Gjoneska et al., 2015
The paper reports higher immune-gene expression in hippocampal tissue from human AD patients and an activated microglial gene-expression signature in its mouse model (main text, page unavailable). It does not establish an activated gene-expression profile specifically in microglia isolated from human patients. The sentence cites Heppner et al. for morphology, not this paper; this paper also does not establish microglial clustering around plaques. (LLM, conf=0.87)
Experimental — accuracy not yet measuredAD is characterized by neuroinflammation driven by activated microglia, a phenotype shared by many other forms of neurodegeneration.
“In addition to β-amyloid and hyperphosphorylated tau accumulation in the brain, a major hallmark of AD is that of neuroinflammation driven by activated microglia, a phenotype shared by many other forms of neurodegeneration (Gjoneska et al., 2015).”
From A novel molecular class that recruits HDAC/MECP2 complexes to PU.1 motifs reduces neuroinflammation (2023) · cites this paper as Gjoneska et al., 2015
The paper’s main text (indexed under Abstract; page unavailable) reports increased immune-gene expression in human AD samples and a significant contribution from microglial activation in an AD-like mouse model. It does not establish that activated microglia drive neuroinflammation in human AD or that this phenotype is shared by many other forms of neurodegeneration. (LLM, conf=0.86)
Experimental — accuracy not yet measured
The beneficial effects of A11 might stem from a reduction in PU.1 activity below a threshold that otherwise causes microglia to acquire a detrimental and hyperinflammatory phenotype or that helps undo unresolved microglial activation.
“The beneficial effects of A11 might stem from a reduction in PU.1 activity below a threshold that otherwise causes the microglia to acquire a detrimental and hyperinflammatory phenotype (Crotti et al., 2014; Gjoneska et al., 2015) or that helps the undoing of unresolved microglial activation (Leng and Edison, 2021).”
From A novel molecular class that recruits HDAC/MECP2 complexes to PU.1 motifs reduces neuroinflammation (2023) · cites this paper as Gjoneska et al., 2015
The paper’s Abstract reports increased PU.1 expression in the neurodegeneration model, links PU.1 to microglial activation, and proposes it as a therapeutic target. It does not establish a PU.1 activity threshold or show that crossing one causes microglia to acquire a detrimental, hyperinflammatory phenotype. The A11 effect and reversal of unresolved activation are not attributed to Gjoneska et al. in the citing sentence. (LLM, conf=0.84)
Experimental — accuracy not yet measuredMultiple variants at the SPI1 locus modify risk and age of onset for Alzheimer's disease.
“Genetic association studies have identified multiple variants at the SPI1 locus that modify risk and age of onset for Alzheimer’s Disease (AD).”
From Modest changes in Spi1 dosage reveal the potential for altered microglial function as seen in Alzheimer’s disease (2021) · cites this paper as [6]
The passage discussing the CELF1/SPI1 locus (page not provided) identifies multiple AD-associated variants near SPI1, supporting the genetic-association and risk portion of the claim. It does not report that these variants modify age of onset, and its enhancer assay does not establish that they causally modify AD risk. (LLM, conf=0.88)
Experimental — accuracy not yet measuredSPI1 was recently identified as a genetic risk factor for Alzheimer's disease in large-scale genome-wide association studies.
“Human genetic studies recently identified SPI1 (encoding PU.1) as a risk factor for Alzheimer’s disease (AD)1–3.”
From Effects of SPI1-mediated transcriptome remodeling on Alzheimer's disease-related phenotypes in mouse models of Aβ amyloidosis (2024) · cites this paper as [3]
The passage labelled Abstract (page not supplied) reports that a large AD genome-wide association signal at the CELF1 locus spans several genes, with its strongest signal upstream of SPI1. It supports an association implicating SPI1, but does not say that the studies identified SPI1 itself unequivocally as the risk gene. (LLM, conf=0.83)
Experimental — accuracy not yet measuredBiological network analyses of AD loci have consistently implicated both innate and adaptive immune responses as central contributors to AD pathogenesis.
“Biological network analyses of these loci have consistently implicated both innate and adaptive immune re sponses as central contributors to AD pathogenesis.”
From Is there a role for B cells in Alzheimer's disease? (2026) · cites this paper as [21]
In the supplied passage labeled Abstract (page not given), AD-associated variants are enriched in immune-related enhancers, especially those active in CD14+ monocytes; it also reports enhancer eQTL enrichment in CD4+ T cells. This supports an immune contribution, but the paper does not establish that both innate and adaptive responses are central to AD pathogenesis or that biological network analyses have consistently reached that conclusion. (LLM, conf=0.85)
Experimental — accuracy not yet measuredA substantial proportion of AD-associated risk alleles regulate enhancers specifically in microglia, and approximately 25% of candidate AD risk genes are highly or exclusively expressed by microglia or functionally tied to immune responses.
“Notably, a sub stantial proportion of AD-associated risk alleles have been shown to regulate enhancers specifically in microglia, and approximately 25% of candidate AD risk genes are highly or exclusively expressed by microglia or functionally tied to immune responses [21,22].”
From Is there a role for B cells in Alzheimer's disease? (2026) · cites this paper as [21]
The passages labeled Abstract (Figs. 2c and 3d; no page given) report enrichment of AD-associated variants in immune-related enhancers and show that one AD-associated variant increases enhancer activity in a microglial cell line. They do not establish that a substantial proportion of risk alleles regulate enhancers specifically in microglia, nor do they report that approximately 25% of candidate AD risk genes have the stated expression or immune-function characteristics. (LLM, conf=0.85)
Experimental — accuracy not yet measuredrs1377416 is located in a predicted enhancer in the vicinity of SPI1 and altered enhancer activity when assayed in vitro using a reporter construct transfected in BV2 cells.
“rs1377416, is located in a predicted enhancer in the vicinity of SPI1 and altered enhancer activity when assayed in vitro using a reporter construct transfected in BV2 cells19.”
From A common haplotype lowers PU.1 expression in myeloid cells and delays onset of Alzheimer's disease (2017) · cites this paper as [19]
The findings strengthen the growing evidence linking AD to a network of genes expressed in microglia.
“These results reinforce the emerging genetic and epigenetic association between AD and a network of microglial expressed genes2,5,17–21”
From A common haplotype lowers PU.1 expression in myeloid cells and delays onset of Alzheimer's disease (2017) · cites this paper as [19]
PU.1 activity is increased in mouse models of neurodegeneration.
“PU.1 activity is increased in mouse models of neurodegeneration (Crotti et al., 2014; Gjoneska et al., 2015)”
From A novel molecular class that recruits HDAC/MECP2 complexes to PU.1 motifs reduces neuroinflammation (2023) · cites this paper as Gjoneska et al., 2015
SPI1 gene has been identified as a genetic risk factor in recent human AD genetic studies.
“SPI1 gene has been identified as a genetic risk factor in recent human AD genetic studies1–3.”
From Effects of SPI1-mediated transcriptome remodeling on Alzheimer's disease-related phenotypes in mouse models of Aβ amyloidosis (2024) · cites this paper as [3]
DMR_394 displays epigenetic signatures of transcription start and enhancer activity in hippocampus tissue of adult wild-type mice.
“By overlaying public chromatin state characterizations27, we found that DMR_394 displayed epigenetic signatures of transcription start and enhancer activity in hippocampus tissue of adult wild-type mice.”
From Integrated analysis of behavioral, epigenetic, and gut microbiome analyses in AppNL-G-F, AppNL-F, and wild type mice (2021) · cites this paper as [27]
When not considering fetal astrocytes, mature astrocytes (21%) and microglial cells (20.3%) became the highest expressed cell types in the genome-wide set of genes, with 5.3% of the 400 genes showing high microglial expression.
“When not considering fetal astrocytes, mature astrocytes (21%), and microglial cells (20.3%), the resident macrophage cells of the brain thought to play a key role in the pathologic immune response in LOAD8,14,60, became the highest expressed cell types in the genome-wide set of genes, with 5.3% of the 400 genes showing high microglial expression”
From Genetic meta-analysis of diagnosed Alzheimer’s disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing (2019) · cites this paper as [60]
Previous omics studies concluded that microglia show the most prominent changes in Alzheimer's disease brains, due to increased numbers and strong per-cell transcriptional activation.
“These studies have largely concluded that microglia undergo the most prominent changes in diseased brains, due to a combination of increased microglia numbers along with a robust transcriptional activation signature on a per-microglia basis.”
From Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and TREM2-independent cellular responses in Alzheimer’s disease (2020) · cites this paper as [5]
Comparison of omics data between human and animal models can help validate biological relevance of the model itself.
“Comparison of omics data between human and animal models can help validate biological relevance of the model itself, as was used in a recent study of Alzheimer’s disease (AD) [20].”
From Multi-omics approaches to disease (2017) · cites this paper as [20]
Gjoneska et al. used transcriptomic and epigenomic data to show that genomic and environmental contributions to Alzheimer's disease act through different cell types.
“For example, Gjoneska et al. [20] used transcriptomic and epigenomic data to show that genomic and environmental contributions to AD act through different cell types.”
From Multi-omics approaches to disease (2017) · cites this paper as [20]
Gjoneska et al. showed that epigenetic changes correspond to observed changes in gene expression, and identified five transcription factor motifs enriched in activated promoters and enhancers and two in repressed elements.
“Next, the authors showed that these epigenetic changes correspond to the observed changes in gene expression, and used enrichment analysis to identify five transcription factor motifs enriched in the activated promoters and enhancers and two in the repressed elements.”
From Multi-omics approaches to disease (2017) · cites this paper as [20]
Alzheimer's disease-associated genetic variants are significantly enriched in immune function-related enhancers but not promoters or neuronal function-related enhancers.
“Notably, they found that AD-associated genetic variants are significantly enriched in the immune function-related enhancers but not promoters or neuronal function-related enhancers.”
From Multi-omics approaches to disease (2017) · cites this paper as [20]
Gjoneska et al. identified thousands of promoters and enhancers that showed significantly different chromatin states in Alzheimer's disease versus control.
“They were able to identify thousands of promoters and enhancers that showed significantly different chromatin states in AD versus control.”
From Multi-omics approaches to disease (2017) · cites this paper as [20]
In Alzheimer's disease, transcriptomic data showed a sustained increase in immune-related genes, while synaptic and learning functions showed a sustained decrease.
“Consistent with the pathophysiology of AD, the transcriptomic data showed a sustained increase in immune-related genes, while synaptic and learning functions showed a sustained decrease.”
From Multi-omics approaches to disease (2017) · cites this paper as [20]
Alzheimer's disease GWAS loci are preferentially enriched in enhancer sequences implicated in innate immune processes.
“epigenomic analysis has shown that Alzheimer’s disease GWAS loci are preferentially enriched in enhancer sequences implicated in innate immune processes7”
From Interplay between innate immunity and Alzheimer disease: APOE and TREM2 in the spotlight (2018) · cites this paper as [7]
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Sex specific molecular networks and key drivers of Alzheimer’s disease
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“2), which are consistent with prior studies [56, 57].”
ResultJones, R. E., Andrews, R., Holmans, P., Hill, M., & Taylor, P. R. (2021) · Scientific Reports · doi:10.1038/s41598-021-94324-z · Cited by 39 · see citing works
“Several single-nucleotide polymorphisms (SNPs) associated with an increased risk of AD are thought to lie within the Spi1 gene locus [3,6,7].”
BackgroundA novel molecular class that recruits HDAC/MECP2 complexes to PU.1 motifs reduces neuroinflammation
Ralvenius, W. T., Mungenast, A. E., Woolf, H., Huston, M. M., Gillingham, T. Z., Godin, S. K., Penney, J., Cam, H. P., Gao, F., Fernandez, C. G., et al. (2023) · Journal of Experimental Medicine · doi:10.1084/jem.20222105 · Cited by 31 · see citing works
“Hippocampi from male mice were collected as previously described (Gjoneska et al., 2015) immediately after euthanasia.”
InfluentialSelf-citationArtificial intelligence for dementia genetics and omics
Bettencourt, C., Skene, N., Bandres‐Ciga, S., Anderson, E., Winchester, L. M., Foote, I. F., Schwartzentruber, J., Botia, J. A., Nalls, M., Singleton, A., et al. (2023) · Alzheimer's & Dementia · doi:10.1002/alz.13427 · Cited by 30 · see citing works
Erosion of the Epigenetic Landscape and Loss of Cellular Identity as a Cause of Aging in Mammals
Yang, J.-H., Griffin, P. T., Vera, D. L., Apostolides, J. K., Hayano, M., Meer, M. V., Salfati, E. L., Su, Q., Munding, E. M., Blanchette, M., et al. (2019) · doi:10.1101/808642 · Cited by 38 · see citing works
Self-citationKim, B., Dabin, L. C., Tate, M. D., Karahan, H., Sharify, A. D., Acri, D. J., Al-Amin, M. M., Philtjens, S., Smith, D. C., Wijeratne, H. R. S., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-48484-x · Cited by 28 · see citing works
“3, 4, and 8).”
InfluentialGrubman, A., Choo, X. Y., Chew, G., Ouyang, J. F., Sun, G., Croft, N. P., Rossello, F. J., Simmons, R., Buckberry, S., Landin, D. V., et al. (2019) · doi:10.1101/639054 · Cited by 7 · see citing works
Is there a role for B cells in Alzheimer's disease?
Charavner, E.-L., Fillatreau, S., & El Behi, M. (2026) · Cellular Immunology · doi:10.1016/j.cellimm.2026.105154
- Authors
- Gjoneska, E., Pfenning, A. R., Mathys, H., Quon, G., Kundaje, A., Tsai, L.-H., & Kellis, M.
- Affiliations
- Broad Institute (US)
- Massachusetts Institute of Technology (US)
- Corresponding author
- Tsai, Li-Huei
- Kellis, Manolis
- ORCID
- Venue
- Nature
- Published
- 2015-02-18
- Volume
- 518
- Issue
- 7539
- Pages
- 365-369
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC4530583
- OpenAlex
- W2125805216
- Cited by
- 576
- References
- 62
- Citations by year
- 2026: 18 · 2025: 31 · 2024: 54 · 2023: 40 · 2022: 22 · 2021: 62 · 2020: 71 · 2019: 55 · 2018: 65 · 2017: 55 · 2016: 65 · 2015: 33 · 2014: 4
- FWCI
- 53.53
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Nature (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- RePEc: Research Papers in Economics (submittedVersion)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc-sa)
- eScholarship (California Digital Library) (submittedVersion, cc-by-nc-sa)
- PMC
- Funders
- National Science Foundation
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (151885)
- National Institutes of Health
- National Institute on Aging
- National Human Genome Research Institute (RC1HG005334, R01HG004037)
- National Institute of Neurological Disorders and Stroke (R01NS078839)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- Alzheimer's disease, epigenetics, chromatin state, enhancers, immune response genes, synaptic plasticity, hippocampus, ETS transcription factors, PU.1, neuroinflammation, expression quantitative trait loci, learning and memory, neurodegeneration, non-coding variants
- MeSH terms
- Proto-Oncogene Protein Spi-1, Alzheimer Disease, Animals, Chromatin, Disease Models, Animal, Enhancer Elements, Genetic, Female, Hippocampus, Humans, Immunity, Memory, Models, Biological, Neuronal Plasticity, Proto-Oncogene Proteins, Transcription, Genetic, Trans-Activators, Down-Regulation, Up-Regulation, Conserved Sequence, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Epigenesis, Genetic, Mice, Genome-Wide Association Study, Epigenomics
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