CoChat
Sign Up
Cited by 49Neuroinflammation and Neurodegeneration MechanismsAlzheimer's disease research and treatmentsDementia and Cognitive Impairment Research

Effect of APOE alleles on the glial transcriptome in normal aging and Alzheimer’s disease

Open access
Serrano-Pozo, Alberto, Li, Zhaozhi, Noori, Ayush, Nguyen, Huong N., Mezlini, Aziz, Li, Liang, Hudry, Eloise, Jackson, Rosemary J. +2 more·2021·Nature Aging
DOI 10.1038/s43587-021-00123-6PMC PMC9531903
Open this paper in CoChat — free account

Abstract

The roles of APOE ε4 and APOE ε2-the strongest genetic risk and protective factors for Alzheimer's disease-in glial responses remain elusive. We tested the hypothesis that APOE alleles differentially impact glial responses by investigating their effects on the glial transcriptome from elderly control brains with no neuritic amyloid plaques. We identified a cluster of microglial genes that are upregulated in APOE ε4 and downregulated in APOE ε2 carriers relative to APOE ε3 homozygotes. This microglia-APOE cluster is enriched in phagocytosis-including TREM2 and TYROBP-and proinflammatory genes, and is also detectable in brains with frequent neuritic plaques. Next, we tested these findings in APOE knock-in mice exposed to acute (lipopolysaccharide challenge) and chronic (cerebral β-amyloidosis) insults and found that these mice partially recapitulate human APOE-linked expression patterns. Thus, the APOE ε4 allele might prime microglia towards a phagocytic and proinflammatory state through an APOE-TREM2-TYROBP axis in normal aging as well as in Alzheimer's disease.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1038/s43587-021-00123-6

Cites

32 of 32 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

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 disease-associated microglial (DAM) response is differentially regulated by the various APOE isoforms, probably through their differential binding to specific surface microglial receptors such as TREM2.

    “This so-called disease-associated microglial (DAM) response is differentially regulated by the various APOE isoforms, probably through their differential binding to specific surface microglial receptors such as TREM2 (refs. 152,153)”

    From Multifaceted roles of APOE in Alzheimer disease (2024) · cites this paper as [152]

    The Results (Testing of microglia-APOE cluster in APOE knock-in mice; page not provided) report APOE-dependent differences in microglial gene expression and suggest regulation through the TREM2–TYROBP axis. The Discussion also links APOE and TREM2 to the switch toward AD-associated microglia. Neither passage establishes that differential binding of APOE isoforms to TREM2 or other surface receptors explains the effect. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • Microglia and astrocytes have APOE genotype-dependent immune and inflammatory metabolic changes.

    “Additionally, microglia and astrocytes, which have been extensively studied in vivo, have APOE genotype dependent immune and inflammatory metabolic changes 22,25,26 .”

    From APOE4-drives brain bioenergetic shifts independent of Alzheimer’s disease pathology (2026) · cites this paper as [26]

    The Results section reports APOE genotype-dependent proinflammatory gene expression in microglia and changes in astrocyte genes involved in lipid metabolism, with some astrocyte immune-response genes also identified. The Discussion characterizes the astrocyte association as more modest and chiefly involving lipid metabolism and extracellular-matrix genes, so the claim overstates a shared inflammatory pattern across both cell types. (LLM, conf=0.83)

    Experimental — accuracy not yet measured

  • The APOE-TREM2 axis has been found in transcriptomic post-mortem analyses of human brains, with APOEε4 carriers exhibiting a more prominent pro-inflammatory and phagocytic microglial transcriptomic signature.

    “this APOE–TREM2 axis has also been found in transcriptomic post-mortem analyses of human brains, with APOEε4 carriers exhibiting a more prominent pro-inflammatory and phagocytic microglial transcriptomic signature152,153.”

    From Multifaceted roles of APOE in Alzheimer disease (2024) · cites this paper as [152]

  • At transcriptional level, microglia from the APOE4 group upregulated several DAM markers (Cd74, Cst7, Cd63, Cd9, Ccl6), complement cascade genes (C1qa, C1qb, C1qc) and the pro-inflammatory gene Nfkbia, similar to transcriptomic changes in microglia from APOE4 AD individuals.

    “At transcriptional level, microglia from the APOE4 group upregulated several DAM markers (Cd74, Cst7, Cd63, Cd9, Ccl6), complement cascade genes (C1qa, C1qb, C1qc) and the pro-inflammatory gene Nfkbia (Sousa et al, 2018), similar to transcriptomic changes in microglia from APOE4 AD individuals (Serrano-Pozo et al, 2021).”

    From APOE from astrocytes restores Alzheimer’s Aβ-pathology and DAM-like responses in APOE deficient microglia (2024) · cites this paper as Serrano-Pozo et al, 2021

Self-check

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

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 49

  1. [1]Kunkle BW Genetic meta-analysis of diagnosed Alzheimer’s disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing. Nat. Genet 51, 414– 430 (2019). 30820047 PMC6463297
  2. [2]Yamazaki Y, Zhao N, Caulfield TR, Liu C-C & Bu G Apolipoprotein E and Alzheimer disease: pathobiology and targeting strategies. Nat. Rev. Neurol 15, 501– 518 (2019). 31367008 PMC7055192
  3. [4]Serrano-Pozo A, Qian J, Monsell SE, Betensky RA & Hyman BT APOEε2 is associated with milder clinical and pathological Alzheimer disease. Ann. Neurol 77, 917– 929 (2015). 25623662 PMC4447539
  4. [5]Ossenkoppele R Prevalence of amyloid PET positivity in dementia syndromes: a meta-analysis. JAMA 313, 1939– 1949 (2015). 25988463 PMC4517678
  5. [6]Goldberg TE, Huey ED & Devanand DP Association of APOE e2 genotype with Alzheimer’s and non-Alzheimer’s neurodegenerative pathologies. Nat. Commun 11, 4727 (2020). 32948752 PMC7501268
  6. [7]West HL, Rebeck GW & Hyman BT Frequency of the apolipoprotein E epsilon 2 allele is diminished in sporadic Alzheimer disease. Neurosci. Lett 175, 46– 48 (1994). 7970208
  7. [8]Serrano-Pozo A, Das S & Hyman BT APOE and Alzheimer’s disease: advances in genetics, pathophysiology, and therapeutic approaches. Lancet Neurol. 20, 68– 80 (2021). 33340485 PMC8096522
  8. [11]Serrano-Pozo A, Betensky RA, Frosch MP & Hyman BT Plaque-associated local toxicity increases over the clinical course of Alzheimer disease. Am. J. Pathol 186, 375– 384 (2016). 26687817 PMC4729270
  9. [14]Zhao N Alzheimer’s risk factors age, APOE genotype, and sex drive distinct molecular pathways. Neuron 106, 727– 742 (2020). 32199103 PMC7388065
  10. [16]Shi Y Microglia drive APOE-dependent neurodegeneration in a tauopathy mouse model. J. Exp. Med 216, 2546– 2561 (2019). 31601677 PMC6829593
  11. [17]Fitz NF Trem2 deficiency differentially affects phenotype and transcriptome of human APOE3 and APOE4 mice. Mol. Neurodegener 15, 41 (2020). 32703241 PMC7379780
  12. [18]Konttinen H PSEN1ΔE9, APPswe, and APOE4 confer disparate phenotypes in human iPSC-derived microglia. Stem Cell Rep. 13, 669– 683 (2019). PMC6829767 31522977
  13. [19]Julia TCW Cholesterol and matrisome pathways dysregulated in human APOE ε4 glia. Preprint at bioRxiv 10.1101/713362 (2019). · DOI
  14. [21]Lefterov I APOE2 orchestrated differences in transcriptomic and lipidomic profiles of postmortem AD brain. Alzheimers Res. er 11, 113 (2019). PMC6937981 31888770
  15. [26]Zhang B Integrated systems approach identifies genetic nodes and networks in late-onset Alzheimer’s disease. Cell 153, 707– 720 (2013). 23622250 PMC3677161
  16. [27]Han SH Apolipoprotein E is present in hippocampal neurons without neurofibrillary tangles in Alzheimer’s disease and in age-matched controls. Exp. Neurol 128, 13– 26 (1994). 8070517
  17. [28]Keren-Shaul H A unique microglia type associated with restricting development of Alzheimer’s disease. Cell 169, 1276– 1290 (2017). 28602351
  18. [30]Zhou Y Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and TREM2-independent cellular responses in Alzheimer’s disease. Nat. Med 26, 131– 142 (2020). 31932797 PMC6980793
  19. [31]Srinivasan K Untangling the brain’s neuroinflammatory and neurodegenerative transcriptional responses. Nat. Commun 7, 11295 (2016). 27097852 PMC4844685
  20. [33]Heneka MT Neuroinflammation in Alzheimer’s disease. Lancet Neurol. 14, 388– 405 (2015). 25792098 PMC5909703
  21. [34]Perry VH & Holmes C Microglial priming in neurodegenerative disease. Nat. Rev. Neurol 10, 217– 224 (2014). 24638131
  22. [35]Ismail R The relationships between neuroinflammation, beta-amyloid and tau deposition in Alzheimer’s disease: a longitudinal PET study. J. Neuroinflammation 17, 151 (2020). 32375809 PMC7203856
  23. [37]Hori Y, Hashimoto T, Nomoto H, Hyman BT & Iwatsubo T Role of apolipoprotein E in B-amyloidogenesis: isoform-specific effects on protofibril to fibril conversion of Aβ in vitro and brain Aβ deposition in vivo. J. Biol. Chem 290, 15163– 15174 (2015). 25918154 PMC4463458
  24. [38]Liu C-C ApoE4 accelerates early seeding of amyloid pathology. Neuron 96, 1024– 1032 (2017). 29216449 PMC5948105
  25. [41]Wu T Complement C3 is activated in human AD brain and is required for neurodegeneration in mouse models of amyloidosis and tauopathy. Cell Rep. 28, 2111– 2123 (2019). 31433986
  26. [44]Stone DJ, Molony C, Suver C, Schadt EE & Potter WZ ApoE genotyping as a progression-rate biomarker in phase II disease-modification trials for Alzheimer’s disease. Pharmacogenomics J. 10, 161– 164 (2010). 19997085
  27. [45]Yu L APOE ε4, Alzheimer’s disease pathology, cerebrovascular disease, and cognitive change over the years prior to death. Psychol. Aging 28, 1015– 1023 (2013). 23647000 PMC3766432
  28. [46]Qian J, Betensky RA, Hyman BT & Serrano-Pozo A Association of APOE genotype with heterogeneity of cognitive decline rate in Alzheimer disease. Neurology 96, e2414– e2428 (2021). 33771840 PMC8166439
  29. [47]Guerreiro R TREM2 variants in Alzheimer’s disease. N. Engl. J. Med 368, 117– 127 (2013). 23150934 PMC3631573
  30. [48]Jonsson T Variant of TREM2 associated with the risk of Alzheimer’s disease. N. Engl. J. Med 368, 107– 116 (2013). 23150908 PMC3677583
  31. [50]Parhizkar S Loss of TREM2 function increases amyloid seeding but reduces plaque-associated ApoE. Nat. Neurosci 22, 191– 204 (2019). 30617257 PMC6417433
  32. [51]Leyns CEG TREM2 function impedes tau seeding in neuritic plaques. Nat. Neurosci 22, 1217– 1222 (2019). 31235932 PMC6660358
  33. [52]Bemiller SM TREM2 deficiency exacerbates tau pathology through dysregulated kinase signaling in a mouse model of tauopathy. Mol. Neurodegener 12, 74 (2017). 29037207 PMC5644120
  34. [55]Ulrich JD ApoE facilitates the microglial response to amyloid plaque pathology. J. Exp. Med 215, 1047– 1058 (2018). 29483128 PMC5881464
  35. [56]Serrano-Pozo A Stable size distribution of amyloid plaques over the course of Alzheimer disease. J. Neuropathol. Exp. Neurol 71, 694– 701 (2012). 22805771 PMC3407299
  36. [58]Audrain M Integrative approach to sporadic Alzheimer’s disease: deficiency of TYROBP in a tauopathy mouse model reduces C1q and normalizes clinical phenotype while increasing spread and state of phosphorylation of tau. Mol. Psychiatry 24, 1383– 1397 (2019). 30283031 PMC6447470
  37. [59]Audrain M Reactive or transgenic increase in microglial TYROBP reveals a TREM2-independent TYROBP–APOE link in wild-type and Alzheimer’s-related mice. Alzheimers Dement. 17, 149– 163 (2021). 33314529 PMC7938663
  38. [63]Masuda T IRF8 is a critical transcription factor for transforming microglia into a reactive phenotype. Cell Rep. 1, 334– 340 (2012). 22832225 PMC4158926
  39. [65]Mathys H Single-cell transcriptomic analysis of Alzheimer’s disease. Nature 570, 332– 337 (2019). 31042697 PMC6865822
  40. [69]Gearing M, Rebeck GW, Hyman BT, Tigges J & Mirra SS Neuropathology and apolipoprotein E profile of aged chimpanzees: implications for Alzheimer disease. Proc. Natl Acad. Sci. USA 91, 9382– 9386 (1994). 7937774 PMC44816
  41. [70]Patrick E Deconvolving the contributions of cell-type heterogeneity on cortical gene expression. PLoS Comput. Biol 16, e1008120 (2020). 32804935 PMC7451979
  42. [71]Wang X Deciphering cellular transcriptional alterations in Alzheimer’s disease brains. Mol. Neurodegener 15, 38 (2020). 32660529 PMC7359236
  43. [72]Zhang Y Purification and characterization of progenitor and mature human astrocytes reveals transcriptional and functional differences with mouse. Neuron 89, 37– 53 (2016). 26687838 PMC4707064
  44. [73]De Jager PL A multi-omic atlas of the human frontal cortex for aging and Alzheimer’s disease research. Sci. Data 5, 180142 (2018). 30084846 PMC6080491
  45. [74]Wang M The Mount Sinai cohort of large-scale genomic, transcriptomic and proteomic data in Alzheimer’s disease. Sci. Data 5, 180185 (2018). 30204156 PMC6132187
  46. [75]Mirra SS The Consortium to Establish a Registry for Alzheimer’s Disease (CERAD). Part II. Standardization of the neuropathologic assessment of Alzheimer’s disease. Neurology 41, 479– 486 (1991). 2011243
  47. [77]Wang B Similarity network fusion for aggregating data types on a genomic scale. Nat. Methods 11, 333– 337 (2014). 24464287
  48. [78]Ritchie ME limma Powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res. 43, e47 (2015). 25605792 PMC4402510
  49. [81]Jankowsky JL Mutant presenilins specifically elevate the levels of the 42 residue beta-amyloid peptide in vivo: evidence for augmentation of a 42-specific gamma secretase. Hum. Mol. Genet 13, 159– 170 (2004). 14645205

Cited by

Sorted by citations

Authors
Serrano-Pozo, A., Li, Z., Noori, A., Nguyen, H. N., Mezlini, A., Li, L., Hudry, E., Jackson, R. J., Hyman, B. T., & Das, S.
Affiliations
  • Massachusetts General Hospital (US)
  • Harvard University (US)
Corresponding author
Das, Sudeshna
ORCID
Venue
Nature Aging
Publisher
Springer Science and Business Media LLC
Published
2021-10-11
Volume
1
Issue
10
Pages
919-931
ISSN
2662-8465 (ISSN-L)
DOI
10.1038/s43587-021-00123-6
PMC
PMC9531903
OpenAlex
W3206683634
Cited by
49
References
32
Citations by year
2026: 13 · 2025: 13 · 2024: 15 · 2023: 3 · 2022: 5
FWCI
2.30
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Aging (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • Discovery Research Portal (University of Dundee) (submittedVersion)
Funders
  • U.S. Department of Health & Human Services | NIH | National Institute on Aging (K08AG064039, P30AG062421)
  • Alzheimer’s Association (AACF-17-524184, AACF-17-524184-RAPID)
  • JPB Foundation
Topics
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords
apolipoprotein E, Alzheimer's disease, normal aging, microglia, TREM2, TYROBP, phagocytosis, pro-inflammatory genes, lipopolysaccharide challenge, genetic risk
MeSH terms
Aged, Alleles, Alzheimer Disease, Animals, Apolipoproteins E, Brain, Humans, Mice, Plaque, Amyloid, Transcriptome

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.

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