APOE genotype influences on the brain metabolome of aging mice – role for mitochondrial energetics in mechanisms of resilience in APOE2 genotype

Farrer LA, Cupples LA, Haines JL, Hyman B, Kukull WA, Mayeux R, Myers RH, Pericak-Vance MA, Risch N, van Duijn CM. Effects of age, sex, and ethnicity on the association between Apolipoprotein E genotype and alzheimer disease: A Meta-analysis. JAMA. 1997;278(16):1349–56. https://doi.org/10.1001/jama.1997.03550160069041.

Article  PubMed  CAS  Google Scholar 

Coon KD, Myers AJ, Craig DW, Webster JA, Pearson JV, Lince DH, Zismann VL, Beach TG, Leung D, Bryden L. A high-density whole-genome association study reveals that APOE is the major susceptibility gene for sporadic late-onset alzheimer’s disease. J Clin Psychiatry. 2007;68(4):8183.

Google Scholar 

Reiman EM, Arboleda-Velasquez JF, Quiroz YT, Huentelman MJ, Beach TG, Caselli RJ, Chen Y, Su Y, Myers AJ, Hardy J. Exceptionally low likelihood of alzheimer’s dementia in APOE2 homozygotes from a 5,000-person neuropathological study. Nat Commun. 2020;11(1):667.

PubMed  PubMed Central  CAS  Google Scholar 

Lopresti BJ, Campbell EM, Yu Z, Anderson SJ, Cohen AD, Minhas DS, Snitz BE, Royse SK, Becker CR, Aizenstein HJ, Mathis CA, Lopez OL, Klunk WE, Tudorascu DL. Influence of apolipoprotein-E genotype on brain amyloid load and longitudinal trajectories. Neurobiol Aging. 2020;94:111–20. https://doi.org/10.1016/j.neurobiolaging.2020.05.012.

Article  PubMed  PubMed Central  CAS  Google Scholar 

Farfel JM, Yu L, De Jager PL, Schneider JA, Bennett DA. Association of APOE with tau-tangle pathology with and without β-amyloid. Neurobiol Aging. 2016;37:19–25. https://doi.org/10.1016/j.neurobiolaging.2015.09.011.

Article  PubMed  CAS  Google Scholar 

Schuff N, Woerner N, Boreta L, Kornfield T, Shaw L, Trojanowski J, Thompson P, Jack C Jr, Weiner M. Alzheimer’s, initiative DN. MRI of hippocampal volume loss in early alzheimer’s disease in relation to ApoE genotype and biomarkers. Brain. 2009;132(4):1067–77.

PubMed  PubMed Central  CAS  Google Scholar 

Salvadó GA-O, Ferreira DA-O, Operto GA-O, Cumplido-Mayoral IA-O, Arenaza-Urquijo EA-O, Cacciaglia RA-OX, Falcon CA-O, Vilor-Tejedor NA-O, Minguillon CA-O, Groot CA-O, van der Flier WA-O, Barkhof FA-O, Scheltens PA-O, Ossenkoppele RA-O, Kern S, Zettergren A, Skoog IA-O, Hort J, Stomrud EA-O, van Westen DA-O, Hansson OA-O, Molinuevo JA-O, Wahlund LA-O, Westman EA-O, Gispert JA-O. The protective gene dose effect of the APOE ε2 allele on gray matter volume in cognitively unimpaired individuals(1552–5279 (Electronic)).

Qian J, Betensky RA, Hyman BT, Serrano-Pozo A. Association of APOE genotype with heterogeneity of cognitive decline rate in alzheimer disease. Neurology. 2021;96(19):e2414–28.

PubMed  PubMed Central  CAS  Google Scholar 

Rawle MJ, Davis D, Bendayan R, Wong A, Kuh D, Richards M. Apolipoprotein-E (Apoe) ε4 and cognitive decline over the adult life course. Translational Psychiatry. 2018;8(1):18.

PubMed  PubMed Central  Google Scholar 

Arnold M, Nho K, Kueider-Paisley A, Massaro T, Huynh K, Brauner B, MahmoudianDehkordi S, Louie G, Moseley MA, Thompson JW, John-Williams LS, Tenenbaum JD, Blach C, Chang R, Brinton RD, Baillie R, Han X, Trojanowski JQ, Shaw LM, Martins R, Weiner MW, Trushina E, Toledo JB, Meikle PJ, Bennett DA, Krumsiek J, Doraiswamy PM, Saykin AJ, Kaddurah-Daouk R, Kastenmuller G. Sex and APOE epsilon4 genotype modify the alzheimer’s disease serum metabolome. Nat Commun. 2020;11(1):1148. https://doi.org/10.1038/s41467-020-14959-w. PubMed PMID: 32123170; PMCID: PMC7052223.

Article  PubMed  PubMed Central  CAS  Google Scholar 

Arnold M, Buyukozkan M, Doraiswamy PM, Nho K, Wu T, Gudnason V, Launer LJ, Wang-Sattler R, Adamski J, Initiative AsDN. Individual bioenergetic capacity as a potential source of resilience to Alzheimer’s disease. MedRxiv. 2024:2024.01. 23.23297820.

Borkowski K, Pedersen TL, Seyfried NT, Lah JJ, Levey AI, Hales CM, Dammer EB, Blach C, Louie G, Kaddurah-Daouk R, Newman JW. Alzheimer’s disease metabolomics C. Association of plasma and CSF cytochrome P450, soluble epoxide hydrolase, and ethanolamide metabolism with alzheimer’s disease. Alzheimers Res Ther. 2021;13(1):149. https://doi.org/10.1186/s13195-021-00893-6.

Article  PubMed  PubMed Central  CAS  Google Scholar 

Borkowski K, Seyfried NT, Arnold M, Lah JJ, Levey AI, Hales CM, Dammer EB, Blach C, Louie G, Kaddurah-Daouk R. Integration of plasma and CSF metabolomics with CSF proteomic reveals novel associations between lipid mediators and central nervous system vascular and energy metabolism. Sci Rep. 2023;13(1):13752.

PubMed  PubMed Central  CAS  Google Scholar 

Wörheide MA, Krumsiek J, Nataf S, Nho K, Greenwood AK, Wu T, Huynh K, Weinisch P, Römisch-Margl W, Lehner N, Consortium TAMPAD, Initiative TADN, Consortium TADM, Baumbach J, Meikle PJ, Saykin AJ, Doraiswamy PM, Duijn C, Suhre K, Kaddurah-Daouk R, Kastenmüller G, Arnold M. An integrated molecular atlas of alzheimer’s disease. medRxiv, 2021 2021/09/22/. Report No.

Batra R, Arnold M, Wörheide MA, Allen M, Wang X, Blach C, Levey AI, Seyfried NT, Ertekin-Taner N, Bennett DA. The landscape of metabolic brain alterations in alzheimer’s disease. Alzheimer’s Dement. 2023;19(3):980–98.

Google Scholar 

Batra R, Arnold M, Worheide MA, Allen M, Wang X, Blach C, Levey AI, Seyfried NT, Ertekin-Taner N, Bennett DA, Kastenmuller G, Kaddurah-Daouk RF, Krumsiek J. Alzheimer’s disease metabolomics C. The landscape of metabolic brain alterations in alzheimer’s disease. Alzheimers Dement. 2022. https://doi.org/10.1002/alz.12714. PubMed PMID: 35829654; PMCID: PMC9837312.

Article  PubMed  Google Scholar 

Toledo JB, Arnold M, Kastenmuller G, Chang R, Baillie RA, Han X, Thambisetty M, Tenenbaum JD, Suhre K, Thompson JW, John-Williams LS, MahmoudianDehkordi S, Rotroff DM, Jack JR, Motsinger-Reif A, Risacher SL, Blach C, Lucas JE, Massaro T, Louie G, Zhu H, Dallmann G, Klavins K, Koal T, Kim S, Nho K, Shen L, Casanova R, Varma S, Legido-Quigley C, Moseley MA, Zhu K, van der Henrion MYR, Harms AC, Demirkan A, Hankemeier T, van Duijn CM, Trojanowski JQ, Shaw LM, Saykin AJ, Weiner MW, Doraiswamy PM. Kaddurah-Daouk R, alzheimer’s disease neuroimaging I, the alzheimer disease metabolomics C. Metabolic network failures in alzheimer’s disease: A biochemical road map. Alzheimers Dement. 2017;13(9):965–84. https://doi.org/10.1016/j.jalz.2017.01.020. PubMed PMID: 28341160; PMCID: PMC5866045.

Article  PubMed  Google Scholar 

Borkowski K, Pedersen TL, Seyfried NT, Lah JJ, Levey AI, Hales CM, Dammer EB, Blach C, Louie G, Kaddurah-Daouk R, Newman JW. Alzheimer’s disease metabolomics C. Association of plasma and CSF cytochrome P450, soluble epoxide hydrolase, and ethanolamide metabolism with alzheimer’s disease. Alzheimers Res Ther. 2021;13(1):149. https://doi.org/10.1186/s13195-021-00893-6. PubMed PMID: 34488866; PMCID: PMC8422756.

Article  PubMed  PubMed Central  CAS  Google Scholar 

Borkowski Kea. Serum metabolomic biomarkers of perceptual speed in cognitively normal and mildly impaired subjects with fasting state stratification. 2020. https://doi.org/10.1101/2020.09.03.282343

Baloni P, Arnold M, Buitrago L, Nho K, Moreno H, Huynh K, Brauner B, Louie G, Kueider-Paisley A, Suhre K, Saykin AJ, Ekroos K, Meikle PJ, Hood L, Price ND, Alzheimer’s Disease, Metabolomics C, Doraiswamy PM, Funk CC, Hernandez AI, Kastenmuller G, Baillie R, Han X, Kaddurah-Daouk R. Multi-Omic analyses characterize the ceramide/sphingomyelin pathway as a therapeutic target in Alzheimer’s disease. Commun Biol. 2022;5(1):1074. https://doi.org/10.1038/s42003-022-04011-6. PubMed PMID: 36209301; PMCID: PMC9547905.

Chen T, Wang L, Xie G, Kristal BS, Zheng X, Sun T, Arnold M, Louie G, Li M, Wu L, Mahmoudiandehkordi S, Sniatynski MJ, Borkowski K, Guo Q, Kuang J, Wang J, Nho K, Ren Z, Kueider-Paisley A, Blach C, Kaddurah-Daouk R, Jia W. Alzheimer’s disease neuroimaging I, the alzheimer disease metabolomics C. Serum bile acids improve prediction of alzheimer’s progression in a Sex-Dependent manner. Adv Sci (Weinh). 2024;11(9):e2306576. https://doi.org/10.1002/advs.202306576. PubMed PMID: 38093507; PMCID: PMC10916590.

Article  PubMed  CAS  Google Scholar 

Wang T, Huynh K, Giles C, Mellett NA, Duong T, Nguyen A, Lim WLF, Smith AA, Olshansky G, Cadby G, Hung J, Hui J, Beilby J, Watts GF, Chatterjee P, Martins I, Laws SM, Bush AI, Rowe CC, Villemagne VL, Ames D, Masters CL, Taddei K, Dore V, Fripp J, Arnold M, Kastenmuller G, Nho K, Saykin AJ, Baillie R, Han X, Martins RN, Moses EK, Kaddurah-Daouk R, Meikle PJ. APOE epsilon2 resilience for alzheimer’s disease is mediated by plasma lipid species: analysis of three independent cohort studies. Alzheimers Dement. 2022;18(11):2151–66. https://doi.org/10.1002/alz.12538. PubMed PMID: 35077012; PMCID: PMC9787288.

Article  PubMed  CAS  Google Scholar 

Jun Liu NA, Sproviero W, Arnold M, Batra R, Bonnechere B, Chiou Y-J, Fernandes M, Krumsiek J, Newby D, Nho K, Kim JP, Saykin AJ, Shi L, Winchester L, Yang Y, Nevado-Holgado AJ, Kastenmüller G, Rima F, Kaddurah-Daouk, Cornelia M, van Duijn. Longitudinal analysis of UK Biobank participants suggests age and APOE-dependent alterations of energy metabolism in development of dementia. medRxiv.https://doi.org/10.1101/2022.02.25.22271530

Bhatia S, Rawal R, Sharma P, Singh T, Singh M, Singh V. Mitochondrial dysfunction in alzheimer’s disease: opportunities for drug development. Curr Neuropharmacol. 2022;20(4):675–92. https://doi.org/10.2174/1570159X19666210517114016. PubMed PMID: 33998995; PMCID: PMC9878959.

Article  PubMed  PubMed Central  CAS  Google Scholar 

Arnold M, Buyukozkan M, Doraiswamy PM, Nho K, Wu T, Gudnason V, Launer LJ, Wang-Sattler R, Adamski J, Alzheimer’s Disease Neuroimaging I, Alzheimer’s Disease Metabolomics C, De Jager PL, Ertekin-Taner N, Bennett DA, Saykin AJ, Peters A, Suhre K, Kaddurah-Daouk R, Kastenmuller G, Krumsiek J. Individual bioenergetic capacity as a potential source of resilience to alzheimer’s disease. MedRxiv. 2024. https://doi.org/10.1101/2024.01.23.23297820. PubMed PMID: 38313266; PMCID: PMC10836119.

Article  PubMed  PubMed Central  Google Scholar 

Stempler S, Yizhak K, Ruppin E. Integrating transcriptomics with metabolic modeling predicts biomarkers and drug targets for alzheimer’s disease. PLoS ONE. 2014;9(8):e105383. https://doi.org/10.1371/journal.pone.0105383. PubMed PMID: 25127241; PMCID: PMC4134302.

Article  PubMed  PubMed Central  CAS  Google Scholar 

Batra R, Arnold M, Worheide MA, Allen M, Wang X, Blach C, Levey AI, Seyfried NT, Ertekin-Taner N, Bennett DA, Kastenmuller G, Kaddurah-Daouk RF, Krumsiek J. Alzheimer’s disease metabolomics C. The landscape of metabolic brain alterations in alzheimer’s disease. Alzheimers Dement. 2023;19(3):980–98. 12714. PubMed PMID: 35829654; PMCID: PMC9837312.

PubMed  Google Scholar 

Jang J, Kim SR, Lee JE, Lee S, Son HJ, Choe W, Yoon KS, Kim SS, Yeo EJ, Kang I. Molecular mechanisms of neuroprotection by ketone bodies and ketogenic diet in cerebral ischemia and neurodegenerative diseases. Int J Mol Sci. 2023;25(1). https://doi.org/10.3390/ijms25010124. PubMed PMID: 38203294; PMCID: PMC10779133.

Li Z, Shue F, Zhao N, Shinohara M, Bu G. APOE2: protective mechanism and therapeutic implications for alzheimer’s disease. Mol Neurodegeneration. 2020;15(1):63. https://doi.org/10.1186/s13024-020-00413-4.

Article  CAS  Google Scholar 

Oblak AL, Forner S, Territo PR, Sasner M, Carter GW, Howell GR, Sukoff-Rizzo SJ, Logsdon BA, Mangravite LM, Mortazavi A, Baglietto-Vargas D, Green KN, MacGregor GR, Wood MA, Tenner AJ, LaFerla FM, Lamb BT, and The M-A, Consortium. Model organism developmentevaluation for late-onset Alzheimer’s disease: MODEL-AD. Alzheimers Dement (N Y). 2020;6(1):e12110. https://doi.org/10.1002/trc2.12110. PubMed PMID: 33283040; PMCID: PMC7683958.

Sullivan PM, Mezdour H, Aratani Y, Knouff C, Najib J, Reddick RL, Quarfordt SH, Maeda N. Targeted replacement of the mouse Apolipoprotein E gene with the common human APOE3 allele enhances diet-induced hypercholesterolemia and atherosclerosis. J Biol Chem. 1997;272(29):17972–80. https://doi.org/10.1074/jbc.272.29.17972. PubMed PMID: 9218423.

Article  PubMed  CAS  Google Scholar 

Comments (0)

No login
gif