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

Na Zhao; Yingxue Ren; Yu Yamazaki; Wenhui Qiao; Fuyao Li; Lindsey M. Felton; Siamak Mahmoudiandehkordi; Alexandra Kueider-Paisley; Berkiye Sonoustoun; Matthias Arnold; Francis Shue; Jiaying Zheng; Olivia N. Attrebi; Yuka A. Martens; Zonghua Li; Ligia Bastea; Axel D. Meneses; Kai Chen; J. Will Thompson; Lisa St John-Williams; Masaya Tachibana; Tomonori Aikawa; Hiroshi Oue; Lucy Job; Akari Yamazaki; Chia Chen Liu; Peter Storz; Yan W. Asmann; Nilüfer Ertekin-Taner; Takahisa Kanekiyo; Rima Kaddurah-Daouk; Guojun Bu

doi:10.1016/j.neuron.2020.02.034

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

Na Zhao, Yingxue Ren, Yu Yamazaki, Wenhui Qiao, Fuyao Li, Lindsey M. Felton, Siamak Mahmoudiandehkordi, Alexandra Kueider-Paisley, Berkiye Sonoustoun, Matthias Arnold, Francis Shue, Jiaying Zheng, Olivia N. Attrebi, Yuka A. Martens, Zonghua Li, Ligia Bastea, Axel D. Meneses, Kai Chen, J. Will Thompson, Lisa St John-WilliamsMasaya Tachibana, Tomonori Aikawa, Hiroshi Oue, Lucy Job, Akari Yamazaki, Chia Chen Liu, Peter Storz, Yan W. Asmann, Nilüfer Ertekin-Taner, Takahisa Kanekiyo, Rima Kaddurah-Daouk, Guojun Bu

Research output: Contribution to journal › Article › peer-review

17 Scopus citations

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.

Original language	English (US)
Pages (from-to)	727-742.e6
Journal	Neuron
Volume	106
Issue number	5
DOIs	https://doi.org/10.1016/j.neuron.2020.02.034
State	Published - Jun 3 2020

Keywords

APOE
Alzheimer's disease
Serpina3
age
extracellular vesicles
inflammation
lipid metabolism
metabolomics
sex
transcriptomics

ASJC Scopus subject areas

Neuroscience(all)

Access to Document

10.1016/j.neuron.2020.02.034

Cite this

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., ... Bu, G. (2020). Alzheimer's Risk Factors Age, APOE Genotype, and Sex Drive Distinct Molecular Pathways. Neuron, 106(5), 727-742.e6. https://doi.org/10.1016/j.neuron.2020.02.034

Zhao, N , Ren, Y, Yamazaki, Y, Qiao, W, Li, F, Felton, LM, Mahmoudiandehkordi, S, Kueider-Paisley, A, Sonoustoun, B, Arnold, M, Shue, F, Zheng, J, Attrebi, ON, Martens, YA, Li, Z, Bastea, L, Meneses, AD, Chen, K, Thompson, JW, St John-Williams, L, Tachibana, M, Aikawa, T, Oue, H, Job, L, Yamazaki, A, Liu, CC , Storz, P , Asmann, YW , Ertekin-Taner, N , Kanekiyo, T, Kaddurah-Daouk, R & Bu, G 2020, 'Alzheimer's Risk Factors Age, APOE Genotype, and Sex Drive Distinct Molecular Pathways', Neuron, vol. 106, no. 5, pp. 727-742.e6. https://doi.org/10.1016/j.neuron.2020.02.034

@article{42e1c4e704214520aad61ed4e75c306b,

title = "Alzheimer's Risk Factors Age, APOE Genotype, and Sex Drive Distinct Molecular Pathways",

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.",

keywords = "APOE, Alzheimer's disease, Serpina3, age, extracellular vesicles, inflammation, lipid metabolism, metabolomics, sex, transcriptomics",

author = "Na Zhao and Yingxue Ren and Yu Yamazaki and Wenhui Qiao and Fuyao Li and Felton, {Lindsey M.} and Siamak Mahmoudiandehkordi and Alexandra Kueider-Paisley and Berkiye Sonoustoun and Matthias Arnold and Francis Shue and Jiaying Zheng and Attrebi, {Olivia N.} and Martens, {Yuka A.} and Zonghua Li and Ligia Bastea and Meneses, {Axel D.} and Kai Chen and Thompson, {J. Will} and {St John-Williams}, Lisa and Masaya Tachibana and Tomonori Aikawa and Hiroshi Oue and Lucy Job and Akari Yamazaki and Liu, {Chia Chen} and Peter Storz and Asmann, {Yan W.} and Nil{\"u}fer Ertekin-Taner and Takahisa Kanekiyo and Rima Kaddurah-Daouk and Guojun Bu",

note = "Funding Information: We thank Dr. Patrick Sullivan (Duke University Medical Center, Durham, NC) for developing and contributing the apoE-TR mice. We are grateful to Monica Castanedes-Casey for histologic and immunohistochemical support. This work was supported by NIA grants RF1 AG051504 (to G.B. and N.E.-T.); RF1 AG057181, R37 AG027924, R01 AG035355, and RF1 AG046205 (to G.B.); RF1 AG062110 (to C.-C.L.); R21 AG052423 (to T.K.); and BrightFocus Foundation Fellowship A2018777F (to N.Z.). The Mayo Clinic human RNA-seq dataset were provided by the following sources: The Mayo Clinic Alzheimer's Disease Genetic Studies, led by Dr. Nil{\"u}fer Ertekin-Taner and Dr. Steven G. Younkin, Mayo Clinic, Jacksonville, FL using samples from the Mayo Clinic Study of Aging, the Mayo Clinic Alzheimer's Disease Research Center, and the Mayo Clinic Brain Bank. Data collection was supported through funding by NIA grants P50 AG016574, R01 AG032990, U01 AG046139, R01 AG018023, U01 AG006576, U01 AG006786, R01 AG025711, R01 AG017216, R01 AG003949, NINDS grant R01 NS080820, Club Foundation, and support from Mayo Foundation. Study data include samples collected through the Sun Health Research Institute Brain and Body Donation Program of Sun City, Arizona. The Brain and Body Donation Program is supported by the National Institute of Neurological Disorders and Stroke (U24 NS072026 National Brain and Tissue Resource for Parkinson's Disease and Related Disorders), the National Institute on Aging (P30 AG19610 Arizona Alzheimer's Disease Core Center), the Arizona Department of Health Services (contract 211002, Arizona Alzheimer's Research Center), the Arizona Biomedical Research Commission (contracts 4001, 0011, 05-901, and 1001 to the Arizona Parkinson's Disease Consortium), and the Michael J. Fox Foundation for Parkinson's Research. The Religious Orders Study and Rush Memory and Aging Project (ROSMAP) was supported by the NIA grants P30 AG10161, R01 AG15819, R01 AG17917, and U01 AG51356. Support for the metabolomics sample processing, assays, and analytics reported here was provided by grants from the NIA, which supported the Alzheimer's Disease Metabolomics Consortium led by Rima Kaddurah-Daouk at Duke University, part of NIA's national initiatives AMP-AD and M2OVE-AD (R01 AG046171, RF1 AG051550). N.Z. Y.Y. T.K. and G.B. developed the research concept and designed the experiments; N.Z. Y.Y. and L.F. prepared the animals and tissues for RNA-seq and metabolomics; M.T. T.A. H.O. Y.A.M. A.Y. and C.-C.L. helped with the animal and tissue preparation; Y.R. W.Q. Y.A. and N.Z. performed the statistical and bioinformatics analysis; F.L. B.S. A.D.M. and K.C. prepared the animals and performed the experiments for validation; J.Z. O.N.A. and L.J. helped with the qPCR for RNA-seq data validation; Z.L. L.B. and P.S. performed the in situ hybridization experiment; F.S. established the website; J.W.T. and L.S.J.-W. performed serum metabolomics assay; S.M. A.K.-P. M.A. and R.K.-D. performed serum metabolomics data analysis; N.E.-T. provided the Mayo Clinic human brain datasets; N.Z. Y.R. and G.B. wrote the manuscript with critical input and edits by the co-authors. M.A. is co-inventor on patent WO2018049268 in this field. The other authors declare no competing interests. Funding Information: We thank Dr. Patrick Sullivan (Duke University Medical Center, Durham, NC) for developing and contributing the apoE-TR mice. We are grateful to Monica Castanedes-Casey for histologic and immunohistochemical support. This work was supported by NIA grants RF1 AG051504 (to G.B. and N.E.-T.); RF1 AG057181 , R37 AG027924 , R01 AG035355 , and RF1 AG046205 (to G.B.); RF1 AG062110 (to C.-C.L.); R21 AG052423 (to T.K.); and BrightFocus Foundation Fellowship A2018777F (to N.Z.). The Mayo Clinic human RNA-seq dataset were provided by the following sources: The Mayo Clinic Alzheimer{\textquoteright}s Disease Genetic Studies, led by Dr. Nil{\"u}fer Ertekin-Taner and Dr. Steven G. Younkin, Mayo Clinic, Jacksonville, FL using samples from the Mayo Clinic Study of Aging , the Mayo Clinic Alzheimer{\textquoteright}s Disease Research Center , and the Mayo Clinic Brain Bank . Data collection was supported through funding by NIA grants P50 AG016574 , R01 AG032990 , U01 AG046139 , R01 AG018023 , U01 AG006576 , U01 AG006786 , R01 AG025711 , R01 AG017216 , R01 AG003949 , NINDS grant R01 NS080820 , Club Foundation , and support from Mayo Foundation . Study data include samples collected through the Sun Health Research Institute Brain and Body Donation Program of Sun City, Arizona. The Brain and Body Donation Program is supported by the National Institute of Neurological Disorders and Stroke ( U24 NS072026 National Brain and Tissue Resource for Parkinson{\textquoteright}s Disease and Related Disorder s), the National Institute on Aging ( P30 AG19610 Arizona Alzheimer{\textquoteright}s Disease Core Center ), the Arizona Department of Health Services (contract 211002 , Arizona Alzheimer{\textquoteright}s Research Center ), the Arizona Biomedical Research Commission (contracts 4001 , 0011 , 05-901 , and 1001 to the Arizona Parkinson{\textquoteright}s Disease Consortium ), and the Michael J. Fox Foundation for Parkinson's Research . The Religious Orders Study and Rush Memory and Aging Project (ROSMAP) was supported by the NIA grants P30 AG10161 , R01 AG15819 , R01 AG17917 , and U01 AG51356 . Support for the metabolomics sample processing, assays, and analytics reported here was provided by grants from the NIA , which supported the Alzheimer{\textquoteright}s Disease Metabolomics Consortium led by Rima Kaddurah-Daouk at Duke University, part of NIA{\textquoteright}s national initiatives AMP-AD and M2OVE-AD ( R01 AG046171 , RF1 AG051550 ). Publisher Copyright: {\textcopyright} 2020 Elsevier Inc.",

year = "2020",

month = jun,

day = "3",

doi = "10.1016/j.neuron.2020.02.034",

language = "English (US)",

volume = "106",

pages = "727--742.e6",

journal = "Neuron",

issn = "0896-6273",

publisher = "Cell Press",

number = "5",

}

TY - JOUR

T1 - Alzheimer's Risk Factors Age, APOE Genotype, and Sex Drive Distinct Molecular Pathways

AU - Zhao, Na

AU - Ren, Yingxue

AU - Yamazaki, Yu

AU - Qiao, Wenhui

AU - Li, Fuyao

AU - Felton, Lindsey M.

AU - Mahmoudiandehkordi, Siamak

AU - Kueider-Paisley, Alexandra

AU - Sonoustoun, Berkiye

AU - Arnold, Matthias

AU - Shue, Francis

AU - Zheng, Jiaying

AU - Attrebi, Olivia N.

AU - Martens, Yuka A.

AU - Li, Zonghua

AU - Bastea, Ligia

AU - Meneses, Axel D.

AU - Chen, Kai

AU - Thompson, J. Will

AU - St John-Williams, Lisa

AU - Tachibana, Masaya

AU - Aikawa, Tomonori

AU - Oue, Hiroshi

AU - Job, Lucy

AU - Yamazaki, Akari

AU - Liu, Chia Chen

AU - Storz, Peter

AU - Asmann, Yan W.

AU - Ertekin-Taner, Nilüfer

AU - Kanekiyo, Takahisa

AU - Kaddurah-Daouk, Rima

AU - Bu, Guojun

N1 - Funding Information: We thank Dr. Patrick Sullivan (Duke University Medical Center, Durham, NC) for developing and contributing the apoE-TR mice. We are grateful to Monica Castanedes-Casey for histologic and immunohistochemical support. This work was supported by NIA grants RF1 AG051504 (to G.B. and N.E.-T.); RF1 AG057181, R37 AG027924, R01 AG035355, and RF1 AG046205 (to G.B.); RF1 AG062110 (to C.-C.L.); R21 AG052423 (to T.K.); and BrightFocus Foundation Fellowship A2018777F (to N.Z.). The Mayo Clinic human RNA-seq dataset were provided by the following sources: The Mayo Clinic Alzheimer's Disease Genetic Studies, led by Dr. Nilüfer Ertekin-Taner and Dr. Steven G. Younkin, Mayo Clinic, Jacksonville, FL using samples from the Mayo Clinic Study of Aging, the Mayo Clinic Alzheimer's Disease Research Center, and the Mayo Clinic Brain Bank. Data collection was supported through funding by NIA grants P50 AG016574, R01 AG032990, U01 AG046139, R01 AG018023, U01 AG006576, U01 AG006786, R01 AG025711, R01 AG017216, R01 AG003949, NINDS grant R01 NS080820, Club Foundation, and support from Mayo Foundation. Study data include samples collected through the Sun Health Research Institute Brain and Body Donation Program of Sun City, Arizona. The Brain and Body Donation Program is supported by the National Institute of Neurological Disorders and Stroke (U24 NS072026 National Brain and Tissue Resource for Parkinson's Disease and Related Disorders), the National Institute on Aging (P30 AG19610 Arizona Alzheimer's Disease Core Center), the Arizona Department of Health Services (contract 211002, Arizona Alzheimer's Research Center), the Arizona Biomedical Research Commission (contracts 4001, 0011, 05-901, and 1001 to the Arizona Parkinson's Disease Consortium), and the Michael J. Fox Foundation for Parkinson's Research. The Religious Orders Study and Rush Memory and Aging Project (ROSMAP) was supported by the NIA grants P30 AG10161, R01 AG15819, R01 AG17917, and U01 AG51356. Support for the metabolomics sample processing, assays, and analytics reported here was provided by grants from the NIA, which supported the Alzheimer's Disease Metabolomics Consortium led by Rima Kaddurah-Daouk at Duke University, part of NIA's national initiatives AMP-AD and M2OVE-AD (R01 AG046171, RF1 AG051550). N.Z. Y.Y. T.K. and G.B. developed the research concept and designed the experiments; N.Z. Y.Y. and L.F. prepared the animals and tissues for RNA-seq and metabolomics; M.T. T.A. H.O. Y.A.M. A.Y. and C.-C.L. helped with the animal and tissue preparation; Y.R. W.Q. Y.A. and N.Z. performed the statistical and bioinformatics analysis; F.L. B.S. A.D.M. and K.C. prepared the animals and performed the experiments for validation; J.Z. O.N.A. and L.J. helped with the qPCR for RNA-seq data validation; Z.L. L.B. and P.S. performed the in situ hybridization experiment; F.S. established the website; J.W.T. and L.S.J.-W. performed serum metabolomics assay; S.M. A.K.-P. M.A. and R.K.-D. performed serum metabolomics data analysis; N.E.-T. provided the Mayo Clinic human brain datasets; N.Z. Y.R. and G.B. wrote the manuscript with critical input and edits by the co-authors. M.A. is co-inventor on patent WO2018049268 in this field. The other authors declare no competing interests. Funding Information: We thank Dr. Patrick Sullivan (Duke University Medical Center, Durham, NC) for developing and contributing the apoE-TR mice. We are grateful to Monica Castanedes-Casey for histologic and immunohistochemical support. This work was supported by NIA grants RF1 AG051504 (to G.B. and N.E.-T.); RF1 AG057181 , R37 AG027924 , R01 AG035355 , and RF1 AG046205 (to G.B.); RF1 AG062110 (to C.-C.L.); R21 AG052423 (to T.K.); and BrightFocus Foundation Fellowship A2018777F (to N.Z.). The Mayo Clinic human RNA-seq dataset were provided by the following sources: The Mayo Clinic Alzheimer’s Disease Genetic Studies, led by Dr. Nilüfer Ertekin-Taner and Dr. Steven G. Younkin, Mayo Clinic, Jacksonville, FL using samples from the Mayo Clinic Study of Aging , the Mayo Clinic Alzheimer’s Disease Research Center , and the Mayo Clinic Brain Bank . Data collection was supported through funding by NIA grants P50 AG016574 , R01 AG032990 , U01 AG046139 , R01 AG018023 , U01 AG006576 , U01 AG006786 , R01 AG025711 , R01 AG017216 , R01 AG003949 , NINDS grant R01 NS080820 , Club Foundation , and support from Mayo Foundation . Study data include samples collected through the Sun Health Research Institute Brain and Body Donation Program of Sun City, Arizona. The Brain and Body Donation Program is supported by the National Institute of Neurological Disorders and Stroke ( U24 NS072026 National Brain and Tissue Resource for Parkinson’s Disease and Related Disorder s), the National Institute on Aging ( P30 AG19610 Arizona Alzheimer’s Disease Core Center ), the Arizona Department of Health Services (contract 211002 , Arizona Alzheimer’s Research Center ), the Arizona Biomedical Research Commission (contracts 4001 , 0011 , 05-901 , and 1001 to the Arizona Parkinson’s Disease Consortium ), and the Michael J. Fox Foundation for Parkinson's Research . The Religious Orders Study and Rush Memory and Aging Project (ROSMAP) was supported by the NIA grants P30 AG10161 , R01 AG15819 , R01 AG17917 , and U01 AG51356 . Support for the metabolomics sample processing, assays, and analytics reported here was provided by grants from the NIA , which supported the Alzheimer’s Disease Metabolomics Consortium led by Rima Kaddurah-Daouk at Duke University, part of NIA’s national initiatives AMP-AD and M2OVE-AD ( R01 AG046171 , RF1 AG051550 ). Publisher Copyright: © 2020 Elsevier Inc.

PY - 2020/6/3

Y1 - 2020/6/3

N2 - 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.

AB - 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.

KW - APOE

KW - Alzheimer's disease

KW - Serpina3

KW - age

KW - extracellular vesicles

KW - inflammation

KW - lipid metabolism

KW - metabolomics

KW - sex

KW - transcriptomics

UR - http://www.scopus.com/inward/record.url?scp=85082824401&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85082824401&partnerID=8YFLogxK

U2 - 10.1016/j.neuron.2020.02.034

DO - 10.1016/j.neuron.2020.02.034

M3 - Article

C2 - 32199103

AN - SCOPUS:85082824401

SN - 0896-6273

VL - 106

SP - 727-742.e6

JO - Neuron

JF - Neuron

IS - 5

ER -

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

Abstract

Keywords

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this