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Cited by 225Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

Alzheimer’s Risk Factors Age, APOE Genotype, and Sex Drive Distinct Molecular Pathways

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Zhao, Na, Ren, Yingxue, Yamazaki, Yu, Qiao, Wenhui, Li, Fuyao, Felton, Lindsey M., Mahmoudiandehkordi, Siamak, Kueider-Paisley, Alexandra +24 more·2020·Neuron
DOI 10.1016/j.neuron.2020.02.034PMC PMC7388065
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Abstract

Evidence suggests interplay among the three major risk factors for Alzheimer's disease (AD): age, APOE genotype, and sex. Here, we present comprehensive datasets and analyses of brain transcriptomes and blood metabolomes from human apoE2-, apoE3-, and apoE4-targeted replacement mice across young, middle, and old ages with both sexes. We found that age had the greatest impact on brain transcriptomes highlighted by an immune module led by Trem2 and Tyrobp, whereas APOE4 was associated with upregulation of multiple Serpina3 genes. Importantly, these networks and gene expression changes were mostly conserved in human brains. Finally, we observed a significant interaction between age, APOE genotype, and sex on unfolded protein response pathway. In the periphery, APOE2 drove distinct blood metabolome profile highlighted by the upregulation of lipid metabolites. Our work identifies unique and interactive molecular pathways underlying AD risk factors providing valuable resources for discovery and validation research in model systems and humans.

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  • These lipid species are known to accumulate with aging and AD.

    “lipid species known to accumulate with aging and AD 32,55,56”

    From APOE2 attenuates APOE4-associated amyloid pathology and related toxicity in a mouse model of Alzheimer’s disease (2026) · cites this paper as [55]

    The Results section on mouse serum metabolite modules reports that acylcarnitines, particularly long-chain fatty acids, increase with aging. It does not establish that those lipid species also accumulate in AD; the Discussion instead reports lower blood phospholipids associated with progression to AD. No page numbers were provided for these passages. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • DEGs associated with the E4 to E2 switch strongly reflected several APOE-associated and AD-associated gene lists, particularly LOAD genes from publicly available human transcriptomic datasets.

    “Finally, the DEGs associated with the E4 to E2 switch also strongly reflected several APOE-associated and AD-associated gene lists, particularly the late-onset AD (LOAD) genes identified in and merged from publicly available human transcriptomic datasets (Fig. 3i)25–28.”

    From APOE4 to APOE2 allelic switching in mice improves Alzheimer’s disease-related metabolic signatures, neuropathology and cognition (2025) · cites this paper as [26]

    The Results section on mouse-brain DEGs reports differences between APOE2 and APOE4 genotypes, and the section on human AD brains examines preservation of gene modules. Neither passage reports that DEGs from an E4-to-E2 switch strongly overlap APOE- or AD-associated gene lists, particularly a merged LOAD list. Searches for “LOAD genes” and overlap with human transcriptomic gene lists did not find that analysis in our copy. (LLM, conf=0.74)

    Experimental — accuracy not yet measured

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References 101 · Cited by 225

Research works printed but not linked: 66

  1. Abraham CR, McGraw WT, Slot F, and Yamin R (2000). Alpha 1-antichymotrypsin inhibits A beta degradation in vitro and in vivo. Ann N Y Acad Sci 920, 245– 248. 11193158
  2. Abraham CR, Selkoe DJ, and Potter H (1988). Immunochemical identification of the serine protease inhibitor alpha 1-antichymotrypsin in the brain amyloid deposits of Alzheimer’s disease. Cell 52, 487– 501. 3257719
  3. Abraham CR, Shirahama T, and Potter H (1990). Alpha 1-antichymotrypsin is associated solely with amyloid deposits containing the beta-protein. Amyloid and cell localization of alpha 1-antichymotrypsin. Neurobiol Aging 11, 123– 129. 2190106
  4. Allen M, Carrasquillo MM, Funk C, Heavner BD, Zou F, Younkin CS, Burgess JD, Chai HS, Crook J, Eddy JA, (2016). Human whole genome genotype and transcriptome data for Alzheimer’s and other neurodegenerative diseases. Sci Data 3, 160089. 27727239 PMC5058336
  5. Allen M, Wang X, Serie DJ, Strickland SL, Burgess JD, Koga S, Younkin CS, Nguyen TT, Malphrus KG, Lincoln SJ, (2018b). Divergent brain gene expression patterns associate with distinct cell-specific tau neuropathology traits in progressive supranuclear palsy. Acta Neuropathol 136, 709– 727. 30136084 PMC6208732
  6. Altmann A, Tian L, Henderson VW, and Greicius MD (2014). Sex modifies the APOE-related risk of developing Alzheimer disease. Ann Neurol 75, 563– 573. 24623176 PMC4117990
  7. Baker C, Belbin O, Kalsheker N, and Morgan K (2007). SERPINA3 (aka alpha-1-antichymotrypsin). Front Biosci 12, 2821– 2835. 17485262
  8. Basso M, and Bonetto V (2016). Extracellular Vesicles and a Novel Form of Communication in the Brain. Front Neurosci 10, 127. 27065789 PMC4814526
  9. Bennett DA, Buchman AS, Boyle PA, Barnes LL, Wilson RS, and Schneider JA (2018). Religious Orders Study and Rush Memory and Aging Project. J Alzheimers Dis 64, S161– S189. 29865057 PMC6380522
  10. Blennow K, de Leon MJ, and Zetterberg H (2006). Alzheimer’s disease. Lancet 368, 387– 403. 16876668
  11. Boisvert MM, Erikson GA, Shokhirev MN, and Allen NJ (2018). The Aging Astrocyte Transcriptome from Multiple Regions of the Mouse Brain. Cell Rep 22, 269– 285. 29298427 PMC5783200
  12. Brookmeyer R, Gray S, and Kawas C (1998). Projections of Alzheimer’s disease in the United States and the public health impact of delaying disease onset. Am J Public Health 88, 1337– 1342. 9736873 PMC1509089
  13. Bu G (2009). Apolipoprotein E and its receptors in Alzheimer’s disease: pathways, pathogenesis and therapy. Nat Rev Neurosci 10, 333– 344. 19339974 PMC2908393
  14. Colombo M, Raposo G, and Thery C (2014). Biogenesis, secretion, and intercellular interactions of exosomes and other extracellular vesicles. Annu Rev Cell Dev Biol 30, 255– 289. 25288114
  15. Damoiseaux JS, Seeley WW, Zhou J, Shirer WR, Coppola G, Karydas A, Rosen HJ, Miller BL, Kramer JH, Greicius MD, (2012). Gender modulates the APOE epsilon4 effect in healthy older adults: convergent evidence from functional brain connectivity and spinal fluid tau levels. J Neurosci 32, 8254– 8262. 22699906 PMC3394933
  16. Davis AA, Inman CE, Wargel ZM, Dube U, Freeberg BM, Galluppi A, Haines JN, Dhavale DD, Miller R, Choudhury FA, (2020). APOE genotype regulates pathology and disease progression in synucleinopathy. Sci Transl Med 12. PMC7289511 32024799
  17. Delpech JC, Herron S, Botros MB, and Ikezu T (2019). Neuroimmune Crosstalk through Extracellular Vesicles in Health and Disease. Trends Neurosci 42, 361– 372. 30926143 PMC6486849
  18. Guerreiro R, Wojtas A, Bras J, Carrasquillo M, Rogaeva E, Majounie E, Cruchaga C, Sassi C, Kauwe JS, Younkin S, (2013). TREM2 variants in Alzheimer’s disease. N Engl J Med 368, 117– 127. 23150934 PMC3631573
  19. Heit C, Jackson BC, McAndrews M, Wright MW, Thompson DC, Silverman GA, Nebert DW, and Vasiliou V (2013). Update of the human and mouse SERPIN gene superfamily. Hum Genomics 7, 22. 24172014 PMC3880077
  20. Holtzman DM, Herz J, and Bu G (2012). Apolipoprotein E and apolipoprotein E receptors: normal biology and roles in Alzheimer disease. Cold Spring Harb Perspect Med 2, a006312. 22393530 PMC3282491
  21. Horvath AJ, Irving JA, Rossjohn J, Law RH, Bottomley SP, Quinsey NS, Pike RN, Coughlin PB, and Whisstock JC (2005). The murine orthologue of human antichymotrypsin: a structural paradigm for clade A3 serpins. J Biol Chem 280, 43168– 43178. 16141197
  22. Hu Z, Chang YC, Wang Y, Huang CL, Liu Y, Tian F, Granger B, and Delisi C (2013). VisANT 4.0: Integrative network platform to connect genes, drugs, diseases and therapies. Nucleic Acids Res 41, W225– 231. 23716640 PMC3692070
  23. Irving JA, Pike RN, Lesk AM, and Whisstock JC (2000). Phylogeny of the serpin superfamily: implications of patterns of amino acid conservation for structure and function. Genome Res 10, 1845– 1864. 11116082
  24. Jonsson T, Stefansson H, Steinberg S, Jonsdottir I, Jonsson PV, Snaedal J, Bjornsson S, Huttenlocher J, Levey AI, Lah JJ, (2013). Variant of TREM2 associated with the risk of Alzheimer’s disease. N Engl J Med 368, 107– 116. 23150908 PMC3677583
  25. Kalari KR, Nair AA, Bhavsar JD, O’Brien DR, Davila JI, Bockol MA, Nie J, Tang X, Baheti S, Doughty JB, (2014). MAP-RSeq: Mayo Analysis Pipeline for RNA sequencing. BMC Bioinformatics 15, 224. 24972667 PMC4228501
  26. Karjalainen JP, Mononen N, Hutri-Kahonen N, Lehtimaki M, Juonala M, Ala-Korpela M, Kahonen M, Raitakari O, and Lehtimaki T (2019). The effect of apolipoprotein E polymorphism on serum metabolome - a population-based 10-year follow-up study. Sci Rep 9, 458. 30679475 PMC6346097
  27. Kim D, Pertea G, Trapnell C, Pimentel H, Kelley R, and Salzberg SL (2013). TopHat2: accurate alignment of transcriptomes in the presence of insertions, deletions and gene fusions. Genome Biol 14, R36. 23618408 PMC4053844
  28. Kowal RC, Herz J, Weisgraber KH, Mahley RW, Brown MS, and Goldstein JL (1990). Opposing effects of apolipoproteins E and C on lipoprotein binding to low density lipoprotein receptor-related protein. J Biol Chem 265, 10771– 10779. 2355022
  29. Kramer A, Green J, Pollard J Jr., and Tugendreich S (2014). Causal analysis approaches in Ingenuity Pathway Analysis. Bioinformatics 30, 523– 530. 24336805 PMC3928520
  30. Lahoz C, Schaefer EJ, Cupples LA, Wilson PW, Levy D, Osgood D, Parpos S, Pedro-Botet J, Daly JA, and Ordovas JM (2001). Apolipoprotein E genotype and cardiovascular disease in the Framingham Heart Study. Atherosclerosis 154, 529– 537. 11257253
  31. Langfelder P, and Horvath S (2008). WGCNA: an R package for weighted correlation network analysis. BMC Bioinformatics 9, 559. 19114008 PMC2631488
  32. Langmead B, Trapnell C, Pop M, and Salzberg SL (2009). Ultrafast and memory-efficient alignment of short DNA sequences to the human genome. Genome Biol 10, R25. 19261174 PMC2690996
  33. Law RH, Zhang Q, McGowan S, Buckle AM, Silverman GA, Wong W, Rosado CJ, Langendorf CG, Pike RN, Bird PI, (2006). An overview of the serpin superfamily. Genome Biol 7, 216. 16737556 PMC1779521
  34. Liao Y, Smyth GK, and Shi W (2014). featureCounts: an efficient general purpose program for assigning sequence reads to genomic features. Bioinformatics 30, 923– 930. 24227677
  35. Liu CC, Zhao N, Fu Y, Wang N, Linares C, Tsai CW, and Bu G (2017). ApoE4 Accelerates Early Seeding of Amyloid Pathology. Neuron 96, 1024– 1032 e1023. 29216449 PMC5948105
  36. Loy CT, Schofield PR, Turner AM, and Kwok JB (2014). Genetics of dementia. Lancet 383, 828– 840. 23927914
  37. Mahley RW (2016). Central Nervous System Lipoproteins: ApoE and Regulation of Cholesterol Metabolism. Arterioscler Thromb Vasc Biol 36, 1305– 1315. 27174096 PMC4942259
  38. Maly DJ, and Papa FR (2014). Druggable sensors of the unfolded protein response. Nat Chem Biol 10, 892– 901. 25325700 PMC4664160
  39. Mapstone M, Cheema AK, Fiandaca MS, Zhong X, Mhyre TR, MacArthur LH, Hall WJ, Fisher SG, Peterson DR, Haley JM, (2014). Plasma phospholipids identify antecedent memory impairment in older adults. Nat Med 20, 415– 418. 24608097 PMC5360460
  40. Mayeux R, Saunders AM, Shea S, Mirra S, Evans D, Roses AD, Hyman BT, Crain B, Tang MX, and Phelps CH (1998). Utility of the apolipoprotein E genotype in the diagnosis of Alzheimer’s disease. Alzheimer’s Disease Centers Consortium on Apolipoprotein E and Alzheimer’s Disease. N Engl J Med 338, 506– 511. 9468467
  41. McGeer PL, McGeer E, Rogers J, and Sibley J (1990). Anti-inflammatory drugs and Alzheimer disease. Lancet 335, 1037. 1970087
  42. Padmanabhan J, Levy M, Dickson DW, and Potter H (2006). Alpha1-antichymotrypsin, an inflammatory protein overexpressed in Alzheimer’s disease brain, induces tau phosphorylation in neurons. Brain 129, 3020– 3034. 16987932
  43. Pasternack JM, Abraham CR, Van Dyke BJ, Potter H, and Younkin SG (1989). Astrocytes in Alzheimer’s disease gray matter express alpha 1-antichymotrypsin mRNA. Am J Pathol 135, 827– 834. 2817081 PMC1880107
  44. Pathan M, Fonseka P, Chitti SV, Kang T, Sanwlani R, Van Deun J, Hendrix A, and Mathivanan S (2019). Vesiclepedia 2019: a compendium of RNA, proteins, lipids and metabolites in extracellular vesicles. Nucleic Acids Res 47, D516– D519. 30395310 PMC6323905
  45. Payami H, Montee KR, Kaye JA, Bird TD, Yu CE, Wijsman EM, and Schellenberg GD (1994). Alzheimer’s disease, apolipoprotein E4, and gender. JAMA 271, 1316– 1317. 8158809
  46. Perez-Nievas BG, and Serrano-Pozo A (2018). Deciphering the Astrocyte Reaction in Alzheimer’s Disease. Front Aging Neurosci 10, 114. 29922147 PMC5996928
  47. Ping L, Duong DM, Yin L, Gearing M, Lah JJ, Levey AI, and Seyfried NT (2018). Global quantitative analysis of the human brain proteome in Alzheimer’s and Parkinson’s Disease. Sci Data 5, 180036. 29533394 PMC5848788
  48. Pitale PM, Gorbatyuk O, and Gorbatyuk M (2017). Neurodegeneration: Keeping ATF4 on a Tight Leash. Front Cell Neurosci 11, 410. 29326555 PMC5736573
  49. Rangaraju S, Dammer EB, Raza SA, Rathakrishnan P, Xiao H, Gao T, Duong DM, Pennington MW, Lah JJ, Seyfried NT, (2018). Identification and therapeutic modulation of a pro-inflammatory subset of disease-associated-microglia in Alzheimer’s disease. Molecular neurodegeneration 13, 24. 29784049 PMC5963076
  50. Rasmussen KL, Tybjaerg-Hansen A, Nordestgaard BG, and Frikke-Schmidt R (2015). Plasma levels of apolipoprotein E and risk of dementia in the general population. Ann Neurol 77, 301– 311. 25469919
  51. Scheper W, and Hoozemans JJ (2015). The unfolded protein response in neurodegenerative diseases: a neuropathological perspective. Acta Neuropathol 130, 315– 331. 26210990 PMC4541706
  52. Schneider WJ, Kovanen PT, Brown MS, Goldstein JL, Utermann G, Weber W, Havel RJ, Kotite L, Kane JP, Innerarity TL, (1981). Familial dysbetalipoproteinemia. Abnormal binding of mutant apoprotein E to low density lipoprotein receptors of human fibroblasts and membranes from liver and adrenal of rats, rabbits, and cows. J Clin Invest 68, 1075– 1085. 6270194 PMC370895
  53. Shinohara M, Kanekiyo T, Yang L, Linthicum D, Shinohara M, Fu Y, Price L, Frisch-Daiello JL, Han X, Fryer JD, (2016). APOE2 eases cognitive decline during Aging: Clinical and preclinical evaluations. Ann Neurol 79, 758– 774. 26933942 PMC5010530
  54. St John-Williams L, Blach C, Toledo JB, Rotroff DM, Kim S, Klavins K, Baillie R, Han X, Mahmoudiandehkordi S, Jack J, (2017). Targeted metabolomics and medication classification data from participants in the ADNI1 cohort. Sci Data 4, 170140. 29039849 PMC5644370
  55. Uddin MS, Stachowiak A, Mamun AA, Tzvetkov NT, Takeda S, Atanasov AG, Bergantin LB, Abdel-Daim MM, and Stankiewicz AM (2018). Autophagy and Alzheimer’s Disease: From Molecular Mechanisms to Therapeutic Implications. Front Aging Neurosci 10, 04. 29441009 PMC5797541
  56. Walker DG, and Lue LF (2015). Immune phenotypes of microglia in human neurodegenerative disease: challenges to detecting microglial polarization in human brains. Alzheimers Res Ther 7, 56. 26286145 PMC4543480
  57. Walter P, and Ron D (2011). The unfolded protein response: from stress pathway to homeostatic regulation. Science 334, 1081– 1086. 22116877
  58. Wang L, Wang S, and Li W (2012). RSeQC: quality control of RNA-seq experiments. Bioinformatics 28, 2184– 2185. 22743226
  59. Yamazaki Y, and Kanekiyo T (2017). Blood-Brain Barrier Dysfunction and the Pathogenesis of Alzheimer’s Disease. Int J Mol Sci 18. PMC5618614 28902142
  60. Yamazaki Y, Zhao N, Caulfield TR, Liu CC, and Bu G (2019). Apolipoprotein E and Alzheimer disease: pathobiology and targeting strategies. Nat Rev Neurol 15, 501– 518. 31367008 PMC7055192
  61. Zamanian JL, Xu L, Foo LC, Nouri N, Zhou L, Giffard RG, and Barres BA (2012). Genomic analysis of reactive astrogliosis. J Neurosci 32, 6391– 6410. 22553043 PMC3480225
  62. Zhang B, Gaiteri C, Bodea LG, Wang Z, McElwee J, Podtelezhnikov AA, Zhang C, Xie T, Tran L, Dobrin R, (2013). Integrated systems approach identifies genetic nodes and networks in late-onset Alzheimer’s disease. Cell 153, 707– 720. 23622250 PMC3677161
  63. Zhang B, and Horvath S (2005). A general framework for weighted gene co-expression network analysis. Stat Appl Genet Mol Biol 4, Article17. 16646834
  64. Zhao N, Attrebi ON, Ren Y, Qiao W, Sonustun B, Martens YA, Meneses AD, Li F, Shue F, Zheng J, (2020). APOE4 exacerbates alpha-synuclein pathology and related toxicity independent of amyloid. Sci Transl Med 12. PMC8309690 32024798
  65. Zhao N, Liu CC, Qiao W, and Bu G (2018a). Apolipoprotein E, Receptors, and Modulation of Alzheimer’s Disease. Biol Psychiatry 83, 347– 357. 28434655 PMC5599322
  66. Zhao QR, Lei YY, Li J, Jiang N, and Shi JP (2017b). Association between apolipoprotein E polymorphisms and premature coronary artery disease: a meta-analysis. Clin Chem Lab Med 55, 284– 298. 27394044

Authors
Zhao, N., Ren, Y., Yamazaki, Y., Qiao, W., Li, F., Felton, L. M., Mahmoudiandehkordi, S., Kueider-Paisley, A., Sonoustoun, B., Arnold, M., Shue, F., Zheng, J., Attrebi, O. N., Martens, Y. A., Li, Z., Bastea, L., Meneses, A. D., Chen, K., Thompson, J. W., St John-Williams, L., Tachibana, M., Aikawa, T., Oue, H., Job, L., Yamazaki, A., Liu, C.-C., Storz, P., Asmann, Y. W., Ertekin-Taner, N., Kanekiyo, T., Kaddurah-Daouk, R., & Bu, G.
Affiliations
  • Mayo Clinic (US)
  • Duke University (US)
  • Mayo Clinic in Florida (US)
Corresponding author
  • Zhao, Na
  • Bu, Guojun
ORCID
Venue
Neuron
Publisher
Elsevier BV
Published
2020-06
Volume
106
Issue
5
Pages
727-742.e6
ISSN
0896-6273 (ISSN-L)
DOI
10.1016/j.neuron.2020.02.034
PMC
PMC7388065
OpenAlex
W3011658331
Cited by
225
References
101
Citations by year
2026: 17 · 2025: 24 · 2024: 33 · 2023: 50 · 2022: 51 · 2021: 39 · 2020: 10
FWCI
22.56
Type
journal article
Language
en
Open access
Licence
Locations
  • Neuron (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • Rare & Special e-Zone (The Hong Kong University of Science and Technology) (submittedVersion)
  • PuSH - Publication Server of Helmholtz Zentrum München (submittedVersion)
Funders
  • National Institute of Neurological Disorders and Stroke (R01 NS080820, U24 NS072026)
  • Arizona Department of Health Services (211002)
  • National Institute on Aging (P30 AG19610, RF1 AG062110, RF1 AG051504, R37 AG027924, R21 AG052423, RF1 AG057181, RF1 AG046205, R01 AG035355)
  • BrightFocus Foundation (A2018777F, R01 AG032990, R01 AG017216, R01 AG018023, P50 AG016574, U01 AG006576, U01 AG006786, R01 AG025711, U01 AG046139, R01 AG003949)
  • Club Foundation
  • Mayo Foundation for Medical Education and Research
  • Mayo Clinic
  • Michael J. Fox Foundation for Parkinson's Research (WO2018049268, U01 AG51356, RF1 AG051550, R01 AG046171, R01 AG15819, R01 AG17917, P30 AG10161)
  • Arizona Biomedical Research Commission (1001, 0011, 05-901, 4001)
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
Alzheimer's disease, APOE genotype, APOE ε4, APOE2, APOE3, age, sex differences, brain transcriptome, blood metabolome, TREM2, TYROBP, alpha-1-antichymotrypsin, unfolded protein response, lipid metabolites
MeSH terms
Age Factors, Aging, Alzheimer Disease, Animals, Apolipoproteins E, Brain, Female, Genotype, Humans, Male, Membrane Glycoproteins, Membrane Proteins, Mice, Transgenic, Receptors, Immunologic, Risk Factors, Sex Factors, Serpins, Gene Expression, Gene Expression Profiling, Adaptor Proteins, Signal Transducing, Mice, Gene Regulatory Networks, Apolipoprotein E3, Apolipoprotein E4, Apolipoprotein E2, Metabolome, Unfolded Protein Response, Protective Factors

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