Application of metabolomics in Alzheimer's disease

Frontiers in Neurology

Volumn 8, Issue JAN, 2018, Pages

  Wilkins, Jordan Maximillian ^a   Trushina, Eugenia ^a,b  

^a MAYO CLINIC   (United States)

^b MAYO GRADUATE SCHOOL   (United States)

Author keywords

Alzheimer's disease; Animal models of Alzheimer's disease; Biomarkers; Lipidomics; Metabolomics

Indexed keywords

BREVISCAPINE; CAD 31; GLUCOSE; LIPID; LYSINE; MEMANTINE; NEUROPROTECTIVE AGENT; PANTETHINE; SCUTELLARIN; TAU PROTEIN; UNCLASSIFIED DRUG;

ALZHEIMER DISEASE; AMINO ACID METABOLISM; AMYLOID PLAQUE; AUTOPSY; BLOOD ANALYSIS; CITRIC ACID CYCLE; DIAGNOSTIC ACCURACY; DISEASE EXACERBATION; DOSE RESPONSE; DRUG EFFECT; GLUCOSE UTILIZATION; HUMAN; LIPID METABOLISM; MASS SPECTROMETRY; METABOLITE; METABOLOME; METABOLOMICS; MILD COGNITIVE IMPAIRMENT; NEUROFIBRILLARY TANGLE; NEUROPROTECTION; NONHUMAN; NUCLEAR MAGNETIC RESONANCE IMAGING; NUCLEAR MAGNETIC RESONANCE SPECTROSCOPY; PATHOGENESIS; REVIEW; SALIVA ANALYSIS;

EID: 85040456972     PISSN: None     EISSN: 16642295     Source Type: Journal    
DOI: 10.3389/fneur.2017.00719     Document Type: Review

References (200)

1. Lane CA, Hardy J, Schott JM. Alzheimer's disease. Eur J Neurol (2017) 25:59-70. doi:10.1111/ene.13439
2. Bertram L, Tanzi RE. Thirty years of Alzheimer's disease genetics: the implications of systematic meta-analyses. Nat Rev Neurosci (2008) 9(10):768-78. doi:10.1038/nrn2494
3. Hardy JA, Higgins GA. Alzheimer's disease: the amyloid cascade hypothesis. Science (1992) 256(5054):184-5. doi:10.1126/science.1566067
4. Hardy J, Selkoe DJ. The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science (2002) 297(5580):353-6. doi:10.1126/science.1072994
5. Huang Y, Mucke L. Alzheimer mechanisms and therapeutic strategies. Cell (2012) 148(6):1204-22. doi:10.1016/j.cell.2012.02.040
6. Haass C, Kaether C, Thinakaran G, Sisodia S. Trafficking and proteolytic processing of APP. Cold Spring Harb Perspect Med (2012) 2(5):a006270. doi:10.1101/cshperspect.a006270
7. Liu CC, Kanekiyo T, Xu H, Bu G. Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy. Nat Rev Neurol (2013) 9(2):106-18. doi:10.1038/nrneurol.2012.263
8. Alzheimer's Association. Genetic Testing. (2014). Available from: http://alz.org
9. Burke SL, Maramaldi P, Cadet T, Kukull W. Associations between depression, sleep disturbance, and apolipoprotein E in the development of Alzheimer's disease: dementia. Int Psychogeriatr (2016) 28(9):1409-24. doi:10.1017/S1041610216000405
10. Alzheimer's Association. Alzheimer's Disease Facts and Figures. (2017). Available from: http://alz.org/facts
11. Altmann A, Tian L, Henderson VW, Greicius MD. Alzheimer's disease neuroimaging initiative I. Sex modifies the APOE-related risk of developing Alzheimer disease. Ann Neurol (2014) 75(4):563-73. doi:10.1002/ana.24135
12. Xing Y, Tang Y, Jia J. Sex differences in neuropsychiatric symptoms of Alzheimer's disease: the modifying effect of apolipoprotein E epsilon4 status. Behav Neurol (2015) 2015:275256. doi:10.1155/2015/275256
13. Cummings JL, Morstorf T, Zhong K. Alzheimer's disease drug-development pipeline: few candidates, frequent failures. Alzheimers Res Ther (2014) 6(4):37. doi:10.1186/alzrt269
14. Pimplikar SW, Nixon RA, Robakis NK, Shen J, Tsai LH. Amyloid-independent mechanisms in Alzheimer's disease pathogenesis. J Neurosci (2010) 30(45):14946-54. doi:10.1523/JNEUROSCI.4305-10.2010
15. Tonnies E, Trushina E. Oxidative stress, synaptic dysfunction, and Alzheimer's disease. J Alzheimers Dis (2017) 57(4):1105-21. doi:10.3233/JAD-161088
16. Pagani M, Nobili F, Morbelli S, Arnaldi D, Giuliani A, Oberg J, et al. Early identification of MCI converting to AD: a FDG PET study. Eur J Nucl Med Mol Imaging (2017) 44(12):2042-52. doi:10.1007/s00259-017-3761-x
17. Patel L, Grossberg GT. Combination therapy for Alzheimer's disease. Drugs Aging (2011) 28(7):539-46. doi:10.2165/11591860-000000000-00000
18. Toledo JB, Arnold M, Kastenmuller G, Chang R, Baillie RA, Han X, et al. Metabolic network failures in Alzheimer's disease-a biochemical road map. Alzheimers Dement (2017) 13(9):965-84. doi:10.1016/j.jalz.2017.01.020
19. Nemutlu E, Zhang S, Juranic NO, Terzic A, Macura S, Dzeja P. 18O-assisted dynamic metabolomics for individualized diagnostics and treatment of human diseases. Croat Med J (2012) 53(6):529-34. doi:10.3325/cmj.2012.53.529
20. Oliver SG, Winson MK, Kell DB, Baganz F. Systematic functional analysis of the yeast genome. Trends Biotechnol (1998) 16(9):373-8. doi:10.1016/S0167-7799(98)01214-1
21. Flicker C, Ferris SH, Reisberg B. Mild cognitive impairment in the elderly: predictors of dementia. Neurology (1991) 41(7):1006-9. doi:10.1212/WNL.41.7.1006
22. Kidd PM. Alzheimer's disease, amnestic mild cognitive impairment, and age-associated memory impairment: current understanding and progress toward integrative prevention. Altern Med Rev (2008) 13(2):85-115
23. Mosconi L, Andrews RD, Matthews DC. Comparing brain amyloid deposition, glucose metabolism, and atrophy in mild cognitive impairment with and without a family history of dementia. J Alzheimers Dis (2013) 35(3):509-24. doi:10.3233/JAD-121867
24. Mosconi L, Pupi A, De Leon MJ. Brain glucose hypometabolism and oxidative stress in preclinical Alzheimer's disease. Ann N Y Acad Sci (2008) 1147:180-95. doi:10.1196/annals.1427.007
25. Mergenthaler P, Lindauer U, Dienel GA, Meisel A. Sugar for the brain: the role of glucose in physiological and pathological brain function. Trends Neurosci (2013) 36(10):587-97. doi:10.1016/j.tins.2013.07.001
26. Heininger K. A unifying hypothesis of Alzheimer's disease. IV. Causation and sequence of events. Rev Neurosci (2000) 11:213-328. doi:10.1515/REVNEURO.2000.11.S1.213
27. Klosinski L, Yao J, Yin F, Fonteh A, Harrington M, Christensen T, et al. White matter lipids as a ketogenic fuel supply in aging female brain: implications for Alzheimer's disease. EBioMedicine (2015) 2(12):1888-904. doi:10.1016/j.ebiom.2015.11.002
28. Ding F, Yao J, Rettberg JR, Chen S, Brinton RD. Early decline in glucose transport and metabolism precedes shift to ketogenic system in female aging and Alzheimer's mouse brain: implication for bioenergetic intervention. PLoS One (2013) 8(11):e79977. doi:10.1371/journal.pone.0079977
29. Koppel SJ, Swerdlow RH. Neuroketotherapeutics: a modern review of a century-old therapy. Neurochem Int (2017). doi:10.1016/j.neuint.2017.05.019
30. Trushina E, Dutta T, Persson XM, Mielke MM, Petersen RC. Identification of altered metabolic pathways in plasma and CSF in mild cognitive impairment and Alzheimer's disease using metabolomics. PLoS One (2013) 8(5):e63644. doi:10.1371/journal.pone.0063644
31. Kaddurah-Daouk R, Zhu H, Sharma S, Bogdanov M, Rozen SG, Matson W, et al. Alterations in metabolic pathways and networks in Alzheimer's disease. Transl Psychiatry (2013) 3:e244. doi:10.1038/tp.2013.18
32. Han X, Rozen S, Boyle SH, Hellegers C, Cheng H, Burke JR, et al. Metabolomics in early Alzheimer's disease: identification of altered plasma sphingolipidome using shotgun lipidomics. PLoS One (2011) 6(7):e21643. doi:10.1371/journal.pone.0021643
33. Trushina E, Nemutlu E, Zhang S, Christensen T, Camp J, Mesa J, et al. Defects in mitochondrial dynamics and metabolomic signatures of evolving energetic stress in mouse models of familial Alzheimer's disease. PLoS One (2012) 7(2):e32737. doi:10.1371/journal.pone.0032737
34. Godyn J, Jonczyk J, Panek D, Malawska B. Therapeutic strategies for Alzheimer's disease in clinical trials. Pharmacol Rep (2016) 68(1):127-38. doi:10.1016/j.pharep.2015.07.006
35. Patti GJ, Yanes O, Siuzdak G. Innovation: metabolomics: the apogee of the omics trilogy. Nat Rev Mol Cell Biol (2012) 13(4):263-9. doi:10.1038/nrm3314
36. Charidemou E, Ashmore T, Griffin JL. The use of stable isotopes in the study of human pathophysiology. Int J Biochem Cell Biol (2017) 93:102-9. doi:10.1016/j.biocel.2017.07.012
37. Triebl A, Trotzmuller M, Hartler J, Stojakovic T, Kofeler HC. Lipidomics by ultrahigh performance liquid chromatography-high resolution mass spectrometry and its application to complex biological samples. J Chromatogr B Analyt Technol Biomed Life Sci (2017) 1053:72-80. doi:10.1016/j.jchromb.2017.03.027
38. Wishart DS. Current progress in computational metabolomics. Brief Bioinform (2007) 8(5):279-93. doi:10.1093/bib/bbm030
39. Markley JL, Bruschweiler R, Edison AS, Eghbalnia HR, Powers R, Raftery D, et al. The future of NMR-based metabolomics. Curr Opin Biotechnol (2017) 43:34-40. doi:10.1016/j.copbio.2016.08.001
40. Wishart DS, Jewison T, Guo AC, Wilson M, Knox C, Liu Y, et al. HMDB 3.0-the human metabolome database in 2013. Nucleic Acids Res (2013) 41(Database issue):D801-7. doi:10.1093/nar/gks1065
41. Smolinska A, Blanchet L, Buydens LM, Wijmenga SS. NMR and pattern recognition methods in metabolomics: from data acquisition to biomarker discovery: a review. Anal Chim Acta (2012) 750:82-97. doi:10.1016/j.aca.2012.05.049
42. Jansson J, Willing B, Lucio M, Fekete A, Dicksved J, Halfvarson J, et al. Metabolomics reveals metabolic biomarkers of Crohn's disease. PLoS One (2009) 4(7):e6386. doi:10.1371/journal.pone.0006386
43. Kentgens AP, Bart J, van Bentum PJ, Brinkmann A, van Eck ER, Gardeniers JG, et al. High-resolution liquid-and solid-state nuclear magnetic resonance of nanoliter sample volumes using microcoil detectors. J Chem Phys (2008) 128(5):052202. doi:10.1063/1.2833560
44. Felli IC, Brutscher B. Recent advances in solution NMR: fast methods and heteronuclear direct detection. Chemphyschem (2009) 10(9-10):1356-68. doi:10.1002/cphc.200900133
45. Garcia A, Barbas C. Gas chromatography-mass spectrometry (GC-MS)-based metabolomics. Methods Mol Biol (2011) 708:191-204. doi:10.1007/978-1-61737-985-7_11
46. Trushina E. LC-MS-based metabolomics in understanding the mechanisms of Alzheimer's disease and biomarker discovery. In: Han J, Parker CE, Borchers CH, editors. Advanced LC-MS Applications in Metabolomics. London, UK: Future Science (2015). p. 40-57
47. Zhou B, Xiao JF, Tuli L, Ressom HW. LC-MS-based metabolomics. Mol Biosyst (2012) 8(2):470-81. doi:10.1039/c1mb05350g
48. Nassar AF, Wu T, Nassar SF, Wisnewski AV. UPLC-MS for metabolomics: a giant step forward in support of pharmaceutical research. Drug Discov Today (2017) 22(2):463-70. doi:10.1016/j.drudis.2016.11.020
49. Sun X, Lin L, Liu X, Zhang F, Chi L, Xia Q, et al. Capillary electrophoresis-mass spectrometry for the analysis of heparin oligosaccharides and low molecular weight heparin. Anal Chem (2016) 88(3):1937-43. doi:10.1021/acs.analchem.5b04405
50. Baker MJ, Trevisan J, Bassan P, Bhargava R, Butler HJ, Dorling KM, et al. Using Fourier transform IR spectroscopy to analyze biological materials. Nat Protoc (2014) 9(8):1771-91. doi:10.1038/nprot.2014.110
51. Ghaste M, Mistrik R, Shulaev V. Applications of Fourier transform ion cyclotron resonance (FT-ICR) and orbitrap based high resolution mass spectrometry in metabolomics and lipidomics. Int J Mol Sci (2016) 17(6):E816. doi:10.3390/ijms17060816
52. Bedair M, Sumner LW. Current and emerging mass-spectrometry technologies for metabolomics. Trends Anal Chem (2008) 27(3):238-50. doi:10.1016/j.trac.2008.01.006
53. Sellick CA, Knight D, Croxford AS, Maqsood AR, Stephens GM, Goodacre R, et al. Evaluation of extraction processes for intracellular metabolite profiling of mammalian cells: matching extraction approaches to cell type and metabolite targets. Metabolomics (2010) 6(3):427-38. doi:10.1007/s11306-010-0216-9
54. Snyder HM, Carrillo MC, Grodstein F, Henriksen K, Jeromin A, Lovestone S, et al. Developing novel blood-based biomarkers for Alzheimer's disease. Alzheimers Dement (2014) 10(1):109-14. doi:10.1016/j.jalz.2013.10.007
55. Galasko D, Golde TE. Biomarkers for Alzheimer's disease in plasma, serum and blood-conceptual and practical problems. Alzheimers Res Ther (2013) 5(2):10. doi:10.1186/alzrt164
56. McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM. Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease. Neurology (1984) 34(7):939-44. doi:10.1212/WNL.34.7.939
57. Trushina E, Mielke MM. Recent advances in the application of metabolomics to Alzheimer's disease. Biochim Biophys Acta (2014) 1842(8):1232-9. doi:10.1016/j.bbadis.2013.06.014
58. Paglia G, Stocchero M, Cacciatore S, Lai S, Angel P, Alam MT, et al. Unbiased metabolomic investigation of Alzheimer's disease brain points to dysregulation of mitochondrial aspartate metabolism. J Proteome Res (2016) 15(2):608-18. doi:10.1021/acs.jproteome.5b01020
59. Snowden SG, Ebshiana AA, Hye A, An Y, Pletnikova O, O'Brien R, et al. Association between fatty acid metabolism in the brain and Alzheimer disease neuropathology and cognitive performance: a nontargeted metabolomic study. PLoS Med (2017) 14(3):e1002266. doi:10.1371/journal.pmed.1002266
60. Koal T, Klavins K, Seppi D, Kemmler G, Humpel C. Sphingomyelin SM(d18:1/18:0) is significantly enhanced in cerebrospinal fluid samples dichotomized by pathological amyloid-beta42, tau, and phospho-tau-181 levels. J Alzheimers Dis (2015) 44(4):1193-201. doi:10.3233/JAD-142319
61. Guiraud SP, Montoliu I, Da Silva L, Dayon L, Galindo AN, Corthesy J, et al. High-throughput and simultaneous quantitative analysis of homocysteine-methionine cycle metabolites and co-factors in blood plasma and cerebrospinal fluid by isotope dilution LC-MS/MS. Anal Bioanal Chem (2017) 409(1):295-305. doi:10.1007/s00216-016-0003-1
62. Graham SF, Chevallier OP, Elliott CT, Holscher C, Johnston J, McGuinness B, et al. Untargeted metabolomic analysis of human plasma indicates differentially affected polyamine and l-arginine metabolism in mild cognitive impairment subjects converting to Alzheimer's disease. PLoS One (2015) 10(3):e0119452. doi:10.1371/journal.pone.0119452
63. Proitsi P, Kim M, Whiley L, Pritchard M, Leung R, Soininen H, et al. Plasma lipidomics analysis finds long chain cholesteryl esters to be associated with Alzheimer's disease. Transl Psychiatry (2015) 5:e494. doi:10.1038/tp.2014.127
64. Kim M, Nevado-Holgado A, Whiley L, Snowden SG, Soininen H, Kloszewska I, et al. Association between plasma ceramides and phosphatidylcholines and hippocampal brain volume in late onset Alzheimer's disease. J Alzheimers Dis (2017) 60(3):809-17. doi:10.3233/JAD-160645
65. Proitsi P, Kim M, Whiley L, Simmons A, Sattlecker M, Velayudhan L, et al. Association of blood lipids with Alzheimer's disease: a comprehensive lipidomics analysis. Alzheimers Dement (2017) 13(2):140-51. doi:10.1016/j.jalz.2016.08.003
66. Mapstone M, Cheema AK, Fiandaca MS, Zhong X, Mhyre TR, Macarthur LH, et al. Plasma phospholipids identify antecedent memory impairment in older adults. Nat Med (2014) 20(4):415-8. doi:10.1038/nm.3466
67. Fiandaca MS, Zhong X, Cheema AK, Orquiza MH, Chidambaram S, Tan MT, et al. Plasma 24-metabolite panel predicts preclinical transition to clinical stages of Alzheimer's disease. Front Neurol (2015) 6:237. doi:10.3389/fneur.2015.00237
68. Mapstone M, Lin F, Nalls MA, Cheema AK, Singleton AB, Fiandaca MS, et al. What success can teach us about failure: the plasma metabolome of older adults with superior memory and lessons for Alzheimer's disease. Neurobiol Aging (2017) 51:148-55. doi:10.1016/j.neurobiolaging.2016.11.007
69. Yilmaz A, Geddes T, Han B, Bahado-Singh RO, Wilson GD, Imam K, et al. Diagnostic biomarkers of Alzheimer's disease as identified in saliva using 1H NMR-based metabolomics. J Alzheimers Dis (2017) 58(2):355-9. doi:10.3233/JAD-161226
70. Liang Q, Liu H, Zhang T, Jiang Y, Xing H, Zhang A-H. Metabolomics-based screening of salivary biomarkers for early diagnosis of Alzheimer's disease. RSC Adv (2015) 5(116):96074-9. doi:10.1039/C5RA19094K
71. Moffett JR, Ross B, Arun P, Madhavarao CN, Namboodiri AM. N-Acetylaspartate in the CNS: from neurodiagnostics to neurobiology. Prog Neurobiol (2007) 81(2):89-131. doi:10.1016/j.pneurobio.2006.12.003
72. Hur JY, Welander H, Behbahani H, Aoki M, Franberg J, Winblad B, et al. Active gamma-secretase is localized to detergent-resistant membranes in human brain. FEBS J (2008) 275(6):1174-87. doi:10.1111/j.1742-4658.2008.06278.x
73. Fontecave M, Atta M, Mulliez E. S-Adenosylmethionine: nothing goes to waste. Trends Biochem Sci (2004) 29(5):243-9. doi:10.1016/j.tibs.2004.03.007
74. Skovierova H, Vidomanova E, Mahmood S, Sopkova J, Drgova A, Cervenova T, et al. The molecular and cellular effect of homocysteine metabolism imbalance on human health. Int J Mol Sci (2016) 17(10):E1733. doi:10.3390/ijms17101733
75. Ravaglia G, Forti P, Maioli F, Martelli M, Servadei L, Brunetti N, et al. Homocysteine and folate as risk factors for dementia and Alzheimer disease. Am J Clin Nutr (2005) 82(3):636-43
76. Obeid R, Schadt A, Dillmann U, Kostopoulos P, Fassbender K, Herrmann W. Methylation status and neurodegenerative markers in Parkinson disease. Clin Chem (2009) 55(10):1852-60. doi:10.1373/clinchem.2009.125021
77. Tapia-Rojas C, Lindsay CB, Montecinos-Oliva C, Arrazola MS, Retamales RM, Bunout D, et al. Is l-methionine a trigger factor for Alzheimer's-like neurodegeneration? Changes in Abeta oligomers, tau phosphorylation, synaptic proteins, Wnt signaling and behavioral impairment in wild-type mice. Mol Neurodegener (2015) 10:62. doi:10.1186/s13024-015-0057-0
78. Lunnon K, Smith R, Hannon E, De Jager PL, Srivastava G, Volta M, et al. Methylomic profiling implicates cortical deregulation of ANK1 in Alzheimer's disease. Nat Neurosci (2014) 17(9):1164-70. doi:10.1038/nn.3782
79. Bakulski KM, Dolinoy DC, Sartor MA, Paulson HL, Konen JR, Lieberman AP, et al. Genome-wide DNA methylation differences between late-onset Alzheimer's disease and cognitively normal controls in human frontal cortex. J Alzheimers Dis (2012) 29(3):571-88. doi:10.3233/JAD-2012-111223
80. De Jager PL, Srivastava G, Lunnon K, Burgess J, Schalkwyk LC, Yu L, et al. Alzheimer's disease: early alterations in brain DNA methylation at ANK1, BIN1, RHBDF2 and other loci. Nat Neurosci (2014) 17(9):1156-63. doi:10.1038/nn.3786
81. Skinner J, Carvalho JO, Potter GG, Thames A, Zelinski E, Crane PK, et al. Alzheimer's disease neuroimaging I. The Alzheimer's Disease Assessment Scale-Cognitive-Plus (ADAS-Cog-Plus): an expansion of the ADAS-Cog to improve responsiveness in MCI. Brain Imaging Behav (2012) 6(4):489-501. doi:10.1007/s11682-012-9166-3
82. Jack CR Jr, Holtzman DM. Biomarker modeling of Alzheimer's disease. Neuron (2013) 80(6):1347-58. doi:10.1016/j.neuron.2013.12.003
83. Davatzikos C, Bhatt P, Shaw LM, Batmanghelich KN, Trojanowski JQ. Prediction of MCI to AD conversion, via MRI, CSF biomarkers, and pattern classification. Neurobiol Aging (2011) 32(12):2322.e19-27. doi:10.1016/j.neurobiolaging.2010.05.023
84. Bender DA. The metabolism of 'surplus' amino acids. Br J Nutr (2012) 108(Suppl 2):S113-21. doi:10.1017/S0007114512002292
85. Vural H, Sirin B, Yilmaz N, Eren I, Delibas N. The role of arginine-nitric oxide pathway in patients with Alzheimer disease. Biol Trace Elem Res (2009) 129(1-3):58-64. doi:10.1007/s12011-008-8291-8
86. Maxwell AJ, Anderson B, Zapien MP, Cooke JP. Endothelial dysfunction in hypercholesterolemia is reversed by a nutritional product designed to enhance nitric oxide activity. Cardiovasc Drugs Ther (2000) 14(3):309-16. doi:10.1023/A:1007886725480
87. Esch F, Lin KI, Hills A, Zaman K, Baraban JM, Chatterjee S, et al. Purification of a multipotent antideath activity from bovine liver and its identification as arginase: nitric oxide-independent inhibition of neuronal apoptosis. J Neurosci (1998) 18(11):4083-95
88. Becker-Catania SG, Gregory TL, Yang Y, Gau CL, de Vellis J, Cederbaum SD, et al. Loss of arginase I results in increased proliferation of neural stem cells. J Neurosci Res (2006) 84(4):735-46. doi:10.1002/jnr.20964
89. Kan MJ, Lee JE, Wilson JG, Everhart AL, Brown CM, Hoofnagle AN, et al. Arginine deprivation and immune suppression in a mouse model of Alzheimer's disease. J Neurosci (2015) 35(15):5969-82. doi:10.1523/JNEUROSCI.4668-14.2015
90. Minois N, Carmona-Gutierrez D, Madeo F. Polyamines in aging and disease. Aging (2011) 3(8):716-32. doi:10.18632/aging.100361
91. Williams K, Dawson VL, Romano C, Dichter MA, Molinoff PB. Characterization of polyamines having agonist, antagonist, and inverse agonist effects at the polyamine recognition site of the NMDA receptor. Neuron (1990) 5(2):199-208. doi:10.1016/0896-6273(90)90309-4
92. Ito K, Makino M, Okado K, Tomita T. Memantine inhibits beta-amyloid aggregation and disassembles preformed beta-amyloid aggregates. Biochem Biophys Res Commun (2017) 493(1):158-63. doi:10.1016/j.bbrc.2017.09.058
93. Gonzalez-Dominguez R, Garcia-Barrera T, Gomez-Ariza JL. Combination of metabolomic and phospholipid-profiling approaches for the study of Alzheimer's disease. J Proteomics (2014) 104:37-47. doi:10.1016/j.jprot.2014.01.014
94. Whiley L, Sen A, Heaton J, Proitsi P, Garcia-Gomez D, Leung R, et al. Evidence of altered phosphatidylcholine metabolism in Alzheimer's disease. Neurobiol Aging (2014) 35(2):271-8. doi:10.1016/j.neurobiolaging.2013.08.001
95. Di Paolo G, Kim TW. Linking lipids to Alzheimer's disease: cholesterol and beyond. Nat Rev Neurosci (2011) 12(5):284-96. doi:10.1038/nrn3012
96. Morgado I, Garvey M. Lipids in Amyloid-beta processing, aggregation, and toxicity. Adv Exp Med Biol (2015) 855:67-94. doi:10.1007/978-3-319-17344-3_3
97. Lim WL, Martins IJ, Martins RN. The involvement of lipids in Alzheimer's disease. J Genet Genomics (2014) 41(5):261-74. doi:10.1016/j.jgg.2014.04.003
98. Sibal L, Agarwal SC, Home PD, Boger RH. The role of asymmetric dimethylarginine (ADMA) in endothelial dysfunction and cardiovascular disease. Curr Cardiol Rev (2010) 6(2):82-90. doi:10.2174/157340310791162659
99. Park NJ, Zhou H, Elashoff D, Henson BS, Kastratovic DA, Abemayor E, et al. Salivary microRNA: discovery, characterization, and clinical utility for oral cancer detection. Clin Cancer Res (2009) 15(17):5473-7. doi:10.1158/1078-0432.CCR-09-0736
100. Gorr SU. Antimicrobial peptides in periodontal innate defense. Front Oral Biol (2012) 15:84-98. doi:10.1159/000329673
101. Denny P, Hagen FK, Hardt M, Liao L, Yan W, Arellanno M, et al. The proteomes of human parotid and submandibular/sublingual gland salivas collected as the ductal secretions. J Proteome Res (2008) 7(5):1994-2006. doi:10.1021/pr700764j
102. Takeda I, Stretch C, Barnaby P, Bhatnager K, Rankin K, Fu H, et al. Understanding the human salivary metabolome. NMR Biomed (2009) 22(6):577-84. doi:10.1002/nbm.1369
103. Loo JA, Yan W, Ramachandran P, Wong DT. Comparative human salivary and plasma proteomes. J Dent Res (2010) 89(10):1016-23. doi:10.1177/0022034510380414
104. Strassnig M, Ganguli M. About a peculiar disease of the cerebral cortex: Alzheimer's original case revisited. Psychiatry (Edgmont) (2005) 2(9):30-3
105. Alzheimer A. über eine eigenartige Erkrankung der Hirnrinde. Vortrag in der Versammlung Südwestdeutscher Irrenärzte in Tübingen am 3. Allg Z Psychiatr Psych Gerichtl Med (1907) 1907:146-8
106. Kang J, Lemaire HG, Unterbeck A, Salbaum JM, Masters CL, Grzeschik KH, et al. The precursor of Alzheimer's disease amyloid A4 protein resembles a cell-surface receptor. Nature (1987) 325(6106):733-6. doi:10.1038/325733a0
107. Glenner GG, Wong CW. Alzheimer's disease and Down's syndrome: sharing of a unique cerebrovascular amyloid fibril protein. Biochem Biophys Res Commun (1984) 122(3):1131-5. doi:10.1016/0006-291X(84)91209-9
108. Divry P, Florkin M. Sur les proprietes optiques de l'amyloide. C R Seances Soc Biol Fil (Paris) (1927) 97:1808-10
109. Sherrington R, Rogaev EI, Liang Y, Rogaeva EA, Levesque G, Ikeda M, et al. Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease. Nature (1995) 375(6534):754-60. doi:10.1038/375754a0
110. Levy-Lahad E, Wasco W, Poorkaj P, Romano DM, Oshima J, Pettingell WH, et al. Candidate gene for the chromosome 1 familial Alzheimer's disease locus. Science (1995) 269(5226):973-7. doi:10.1126/science.7638621
111. Kitazawa M, Medeiros R, Laferla FM. Transgenic mouse models of Alzheimer disease: developing a better model as a tool for therapeutic interventions. Curr Pharm Des (2012) 18(8):1131-47. doi:10.2174/138161212799315786
112. Hamanaka H, Katoh-Fukui Y, Suzuki K, Kobayashi M, Suzuki R, Motegi Y, et al. Altered cholesterol metabolism in human apolipoprotein E4 knock-in mice. Hum Mol Genet (2000) 9(3):353-61. doi:10.1093/hmg/9.3.353
113. Tai LM, Youmans KL, Jungbauer L, Yu C, Ladu MJ. Introducing human APOE into Abeta transgenic mouse models. Int J Alzheimers Dis (2011) 2011:810981. doi:10.4061/2011/810981
114. Hsiao K, Chapman P, Nilsen S, Eckman C, Harigaya Y, Younkin S, et al. Correlative memory deficits, Abeta elevation, and amyloid plaques in transgenic mice. Science (1996) 274(5284):99-102. doi:10.1126/science.274.5284.99
115. Frautschy SA, Yang F, Irrizarry M, Hyman B, Saido TC, Hsiao K, et al. Microglial response to amyloid plaques in APPsw transgenic mice. Am J Pathol (1998) 152(1):307-17
116. Duff K, Eckman C, Zehr C, Yu X, Prada CM, Perez-tur J, et al. Increased amyloid-beta42(43) in brains of mice expressing mutant presenilin 1. Nature (1996) 383(6602):710-3. doi:10.1038/383710a0
117. Holcomb L, Gordon MN, McGowan E, Yu X, Benkovic S, Jantzen P, et al. Accelerated Alzheimer-type phenotype in transgenic mice carrying both mutant amyloid precursor protein and presenilin 1 transgenes. Nat Med (1998) 4(1):97-100. doi:10.1038/nm0198-097
118. Gordon MN, Holcomb LA, Jantzen PT, DiCarlo G, Wilcock D, Boyett KW, et al. Time course of the development of Alzheimer-like pathology in the doubly transgenic PS1+APP mouse. Exp Neurol (2002) 173(2):183-95. doi:10.1006/exnr.2001.7754
119. Stover KR, Campbell MA, Van Winssen CM, Brown RE. Early detection of cognitive deficits in the 3xTg-AD mouse model of Alzheimer's disease. Behav Brain Res (2015) 289:29-38. doi:10.1016/j.bbr.2015.04.012
120. Oddo S, Caccamo A, Shepherd JD, Murphy MP, Golde TE, Kayed R, et al. Triple-transgenic model of Alzheimer's disease with plaques and tangles: intracellular Abeta and synaptic dysfunction. Neuron (2003) 39(3):409-21. doi:10.1016/S0896-6273(03)00434-3
121. Billings LM, Oddo S, Green KN, McGaugh JL, LaFerla FM. Intraneuronal Abeta causes the onset of early Alzheimer's disease-related cognitive deficits in transgenic mice. Neuron (2005) 45(5):675-88. doi:10.1016/j.neuron.2005.01.040
122. Oakley H, Cole SL, Logan S, Maus E, Shao P, Craft J, et al. Intraneuronal beta-amyloid aggregates, neurodegeneration, and neuron loss in transgenic mice with five familial Alzheimer's disease mutations: potential factors in amyloid plaque formation. J Neurosci (2006) 26(40):10129-40. doi:10.1523/JNEUROSCI.1202-06.2006
123. Kimura R, Ohno M. Impairments in remote memory stabilization precede hippocampal synaptic and cognitive failures in 5XFAD Alzheimer mouse model. Neurobiol Dis (2009) 33(2):229-35. doi:10.1016/j.nbd.2008.10.006
124. Knouff C, Hinsdale ME, Mezdour H, Altenburg MK, Watanabe M, Quarfordt SH, et al. Apo E structure determines VLDL clearance and atherosclerosis risk in mice. J Clin Invest (1999) 103(11):1579-86. doi:10.1172/JCI6172
125. Youmans KL, Tai LM, Nwabuisi-Heath E, Jungbauer L, Kanekiyo T, Gan M, et al. APOE4-specific changes in Abeta accumulation in a new transgenic mouse model of Alzheimer disease. J Biol Chem (2012) 287(50):41774-86. doi:10.1074/jbc.M112.407957
126. Rosenthal N, Brown S. The mouse ascending: perspectives for human-disease models. Nat Cell Biol (2007) 9(9):993-9. doi:10.1038/ncb437
127. Lv X, Li W, Luo Y, Wang D, Zhu C, Huang ZX, et al. Exploring the differences between mouse mAbeta(1-42) and human hAbeta(1-42) for Alzheimer's disease related properties and neuronal cytotoxicity. Chem Commun (Camb) (2013) 49(52):5865-7. doi:10.1039/c3cc40779a
128. Gonzalez-Dominguez R, Garcia-Barrera T, Vitorica J, Gomez-Ariza JL. Metabolomic screening of regional brain alterations in the APP/PS1 transgenic model of Alzheimer's disease by direct infusion mass spectrometry. J Pharm Biomed Anal (2015) 102:425-35. doi:10.1016/j.jpba.2014.10.009
129. Gonzalez-Dominguez R, Garcia-Barrera T, Vitorica J, Gomez-Ariza JL. Application of metabolomics based on direct mass spectrometry analysis for the elucidation of altered metabolic pathways in serum from the APP/PS1 transgenic model of Alzheimer's disease. J Pharm Biomed Anal (2015) 107:378-85. doi:10.1016/j.jpba.2015.01.025
130. Pan X, Nasaruddin MB, Elliott CT, McGuinness B, Passmore AP, Kehoe PG, et al. Alzheimer's disease-like pathology has transient effects on the brain and blood metabolome. Neurobiol Aging (2016) 38:151-63. doi:10.1016/j.neurobiolaging.2015.11.014
131. Pan X, Elliott CT, McGuinness B, Passmore P, Kehoe PG, Holscher C, et al. Metabolomic profiling of bile acids in clinical and experimental samples of Alzheimer's disease. Metabolites (2017) 7(2):28-39. doi:10.3390/metabo7020028
132. Yu J, Kong L, Zhang A, Han Y, Liu Z, Sun H, et al. High-throughput metabolomics for discovering potential metabolite biomarkers and metabolic mechanism from the APPswe/PS1dE9 transgenic model of Alzheimer's disease. J Proteome Res (2017) 4:7467. doi:10.1021/acs.jproteome.7b00206
133. Kimball BA, Wilson DA, Wesson DW. Alterations of the volatile metabolome in mouse models of Alzheimer's disease. Sci Rep (2016) 6:19495. doi:10.1038/srep19495
134. Daugherty D, Goldberg J, Fischer W, Dargusch R, Maher P, Schubert D. A novel Alzheimer's disease drug candidate targeting inflammation and fatty acid metabolism. Alzheimers Res Ther (2017) 9(1):50. doi:10.1186/s13195-017-0277-3
135. Xia H, Wu L, Chu M, Feng H, Lu C, Wang Q, et al. Effects of breviscapine on amyloid beta 1-42 induced Alzheimer's disease mice: a HPLC-QTOF-MS based plasma metabonomics study. J Chromatogr B Analyt Technol Biomed Life Sci (2017) 1057:92-100. doi:10.1016/j.jchromb.2017.05.003
136. van Gijsel-Bonnello M, Baranger K, Benech P, Rivera S, Khrestchatisky M, de Reggi M, et al. Metabolic changes and inflammation in cultured astrocytes from the 5xFAD mouse model of Alzheimer's disease: alleviation by pantethine. PLoS One (2017) 12(4):e0175369. doi:10.1371/journal.pone.0175369
137. Ulland TK, Song WM, Huang SC, Ulrich JD, Sergushichev A, Beatty WL, et al. TREM2 maintains microglial metabolic fitness in Alzheimer's disease. Cell (2017) 170(4):649-63.e13. doi:10.1016/j.cell.2017.07.023
138. Martorana A, Koch G. Is dopamine involved in Alzheimer's disease? Front Aging Neurosci (2014) 6:252. doi:10.3389/fnagi.2014.00252
139. Nobili A, Latagliata EC, Viscomi MT, Cavallucci V, Cutuli D, Giacovazzo G, et al. Dopamine neuronal loss contributes to memory and reward dysfunction in a model of Alzheimer's disease. Nat Commun (2017) 8:14727. doi:10.1038/ncomms14727
140. Mattson MP. Pathways towards and away from Alzheimer's disease. Nature (2004) 430(7000):631-9. doi:10.1038/nature02621
141. De Strooper B, Karran E. The cellular phase of Alzheimer's disease. Cell (2016) 164(4):603-15. doi:10.1016/j.cell.2015.12.056
142. de la Monte SM, Tong M. Brain metabolic dysfunction at the core of Alzheimer's disease. Biochem Pharmacol (2014) 88(4):548-59. doi:10.1016/j.bcp.2013.12.012
143. Dennis EA, Norris PC. Eicosanoid storm in infection and inflammation. Nat Rev Immunol (2015) 15(8):511-23. doi:10.1038/nri3859
144. Herbst-Robinson KJ, Liu L, James M, Yao Y, Xie SX, Brunden KR. Inflammatory eicosanoids increase amyloid precursor protein expression via activation of multiple neuronal receptors. Sci Rep (2015) 5:18286. doi:10.1038/srep18286
145. Hensley K. Neuroinflammation in Alzheimer's disease: mechanisms, pathologic consequences, and potential for therapeutic manipulation. J Alzheimers Dis (2010) 21(1):1-14. doi:10.3233/JAD-2010-1414
146. Thomas C, Pellicciari R, Pruzanski M, Auwerx J, Schoonjans K. Targeting bile-acid signalling for metabolic diseases. Nat Rev Drug Discov (2008) 7(8):678-93. doi:10.1038/nrd2619
147. Festa C, De Marino S, Carino A, Sepe V, Marchiano S, Cipriani S, et al. Targeting bile acid receptors: discovery of a potent and selective farnesoid X receptor agonist as a new lead in the pharmacological approach to liver diseases. Front Pharmacol (2017) 8:162. doi:10.3389/fphar.2017.00162
148. Schroeder BO, Backhed F. Signals from the gut microbiota to distant organs in physiology and disease. Nat Med (2016) 22(10):1079-89. doi:10.1038/nm.4185
149. Sola S, Castro RE, Laires PA, Steer CJ, Rodrigues CM. Tauroursodeoxycholic acid prevents amyloid-beta peptide-induced neuronal death via a phosphatidylinositol 3-kinase-dependent signaling pathway. Mol Med (2003) 9(9-12):226-34. doi:10.2119/2003-00042.Rodrigues
150. Lo AC, Callaerts-Vegh Z, Nunes AF, Rodrigues CM, D'Hooge R. Tauroursodeoxycholic acid (TUDCA) supplementation prevents cognitive impairment and amyloid deposition in APP/PS1 mice. Neurobiol Dis (2013) 50:21-9. doi:10.1016/j.nbd.2012.09.003
151. Ackerman HD, Gerhard GS. Bile acids in neurodegenerative disorders. Front Aging Neurosci (2016) 8:263. doi:10.3389/fnagi.2016.00263
152. Nunes AF, Amaral JD, Lo AC, Fonseca MB, Viana RJ, Callaerts-Vegh Z, et al. TUDCA, a bile acid, attenuates amyloid precursor protein processing and amyloid-beta deposition in APP/PS1 mice. Mol Neurobiol (2012) 45(3):440-54. doi:10.1007/s12035-012-8256-y
153. Keene CD, Rodrigues CM, Eich T, Chhabra MS, Steer CJ, Low WC. Tauroursodeoxycholic acid, a bile acid, is neuroprotective in a transgenic animal model of Huntington's disease. Proc Natl Acad Sci U S A (2002) 99(16):10671-6. doi:10.1073/pnas.162362299
154. Camilleri M, Gores GJ. Therapeutic targeting of bile acids. Am J Physiol Gastrointest Liver Physiol (2015) 309(4):G209-15. doi:10.1152/ajpgi.00121.2015
155. Amaral JD, Viana RJ, Ramalho RM, Steer CJ, Rodrigues CM. Bile acids: regulation of apoptosis by ursodeoxycholic acid. J Lipid Res (2009) 50(9):1721-34. doi:10.1194/jlr.R900011-JLR200
156. Ridlon JM, Harris SC, Bhowmik S, Kang DJ, Hylemon PB. Consequences of bile salt biotransformations by intestinal bacteria. Gut Microbes (2016) 7(1):22-39. doi:10.1080/19490976.2015.1127483
157. Kim HY, Kim HV, Yoon JH, Kang BR, Cho SM, Lee S, et al. Taurine in drinking water recovers learning and memory in the adult APP/PS1 mouse model of Alzheimer's disease. Sci Rep (2014) 4:7467. doi:10.1038/srep07467
158. Kema IP, Schellings AM, Meiborg G, Hoppenbrouwers CJ, Muskiet FA. Influence of a serotonin-and dopamine-rich diet on platelet serotonin content and urinary excretion of biogenic amines and their metabolites. Clin Chem (1992) 38(9):1730-6
159. Meltzer CC, Smith G, DeKosky ST, Pollock BG, Mathis CA, Moore RY, et al. Serotonin in aging, late-life depression, and Alzheimer's disease: the emerging role of functional imaging. Neuropsychopharmacology (1998) 18(6):407-30. doi:10.1016/S0893-133X(97)00194-2
160. Geldenhuys WJ, Van der Schyf CJ. Role of serotonin in Alzheimer's disease: a new therapeutic target? CNS Drugs (2011) 25(9):765-81. doi:10.2165/11590190-000000000-00000
161. Pype S, Moechars D, Dillen L, Mercken M. Characterization of amyloid beta peptides from brain extracts of transgenic mice overexpressing the London mutant of human amyloid precursor protein. J Neurochem (2003) 84(3):602-9. doi:10.1046/j.1471-4159.2003.01556.x
162. Chishti MA, Yang DS, Janus C, Phinney AL, Horne P, Pearson J, et al. Early-onset amyloid deposition and cognitive deficits in transgenic mice expressing a double mutant form of amyloid precursor protein 695. J Biol Chem (2001) 276(24):21562-70. doi:10.1074/jbc.M100710200
163. Inamdar AA, Hossain MM, Bernstein AI, Miller GW, Richardson JR, Bennett JW. Fungal-derived semiochemical 1-octen-3-ol disrupts dopamine packaging and causes neurodegeneration. Proc Natl Acad Sci U S A (2013) 110(48):19561-6. doi:10.1073/pnas.1318830110
164. Hung SY, Fu WM. Drug candidates in clinical trials for Alzheimer's disease. J Biomed Sci (2017) 24(1):47. doi:10.1186/s12929-017-0355-7
165. Prior M, Goldberg J, Chiruta C, Farrokhi C, Kopynets M, Roberts AJ, et al. Selecting for neurogenic potential as an alternative for Alzheimer's disease drug discovery. Alzheimers Dement (2016) 12(6):678-86. doi:10.1016/j.jalz.2016.03.016
166. Chen Q, Prior M, Dargusch R, Roberts A, Riek R, Eichmann C, et al. A novel neurotrophic drug for cognitive enhancement and Alzheimer's disease. PLoS One (2011) 6(12):e27865. doi:10.1371/journal.pone.0027865
167. Lim GP, Chu T, Yang F, Beech W, Frautschy SA, Cole GM. The curry spice curcumin reduces oxidative damage and amyloid pathology in an Alzheimer transgenic mouse. J Neurosci (2001) 21(21):8370-7
168. Ewers M, Sperling RA, Klunk WE, Weiner MW, Hampel H. Neuroimaging markers for the prediction and early diagnosis of Alzheimer's disease dementia. Trends Neurosci (2011) 34(8):430-42. doi:10.1016/j.tins.2011.05.005
169. Yao J, Rettberg JR, Klosinski LP, Cadenas E, Brinton RD. Shift in brain metabolism in late onset Alzheimer's disease: implications for biomarkers and therapeutic interventions. Mol Aspects Med (2011) 32(4-6):247-57. doi:10.1016/j.mam.2011.10.005
170. Kano M, Ohno-Shosaku T, Hashimotodani Y, Uchigashima M, Watanabe M. Endocannabinoid-mediated control of synaptic transmission. Physiol Rev (2009) 89(1):309-80. doi:10.1152/physrev.00019.2008
171. Chen R, Zhang J, Wu Y, Wang D, Feng G, Tang YP, et al. Monoacylglycerol lipase is a therapeutic target for Alzheimer's disease. Cell Rep (2012) 2(5):1329-39. doi:10.1016/j.celrep.2012.09.030
172. Maaloe T, Schmidt EB, Svensson M, Aardestrup IV, Christensen JH. The effect of n-3 polyunsaturated fatty acids on leukotriene B(4) and leukotriene B(5) production from stimulated neutrophil granulocytes in patients with chronic kidney disease. Prostaglandins Leukot Essent Fatty Acids (2011) 85(1):37-41. doi:10.1016/j.plefa.2011.04.004
173. Lutz CS, Cornett AL. Regulation of genes in the arachidonic acid metabolic pathway by RNA processing and RNA-mediated mechanisms. Wiley Interdiscip Rev RNA (2013) 4(5):593-605. doi:10.1002/wrna.1183
174. Chouinard F, Lefebvre JS, Navarro P, Bouchard L, Ferland C, Lalancette-Hebert M, et al. The endocannabinoid 2-arachidonoyl-glycerol activates human neutrophils: critical role of its hydrolysis and de novo leukotriene B4 biosynthesis. J Immunol (2011) 186(5):3188-96. doi:10.4049/jimmunol.1002853
175. Gao J, Chen G, He H, Liu C, Xiong X, Li J, et al. Therapeutic effects of breviscapine in cardiovascular diseases: a review. Front Pharmacol (2017) 8:289. doi:10.3389/fphar.2017.00289
176. Zhu JT, Choi RC, Li J, Xie HQ, Bi CW, Cheung AW, et al. Estrogenic and neuroprotective properties of scutellarin from Erigeron breviscapus: a drug against postmenopausal symptoms and Alzheimer's disease. Planta Med (2009) 75(14):1489-93. doi:10.1055/s-0029-1185776
177. Wyss-Coray T, Rogers J. Inflammation in Alzheimer disease-a brief review of the basic science and clinical literature. Cold Spring Harb Perspect Med (2012) 2(1):a006346. doi:10.1101/cshperspect.a006346
178. Penet MF, Abou-Hamdan M, Coltel N, Cornille E, Grau GE, de Reggi M, et al. Protection against cerebral malaria by the low-molecular-weight thiol pantethine. Proc Natl Acad Sci U S A (2008) 105(4):1321-6. doi:10.1073/pnas.0706867105
179. Kavian N, Marut W, Servettaz A, Nicco C, Chereau C, Lemarechal H, et al. Pantethine prevents murine systemic sclerosis through the inhibition of microparticle shedding. Arthritis Rheumatol (2015) 67(7):1881-90. doi:10.1002/art.39121
180. Rana A, Seinen E, Siudeja K, Muntendam R, Srinivasan B, van der Want JJ, et al. Pantethine rescues a Drosophila model for pantothenate kinase-associated neurodegeneration. Proc Natl Acad Sci U S A (2010) 107(15):6988-93. doi:10.1073/pnas.0912105107
181. Cornille E, Abou-Hamdan M, Khrestchatisky M, Nieoullon A, de Reggi M, Gharib B. Enhancement of l-3-hydroxybutyryl-CoA dehydrogenase activity and circulating ketone body levels by pantethine. Relevance to dopaminergic injury. BMC Neurosci (2010) 11:51. doi:10.1186/1471-2202-11-51
182. Brunetti D, Dusi S, Giordano C, Lamperti C, Morbin M, Fugnanesi V, et al. Pantethine treatment is effective in recovering the disease phenotype induced by ketogenic diet in a pantothenate kinase-associated neurodegeneration mouse model. Brain (2014) 137(Pt 1):57-68. doi:10.1093/brain/awt325
183. Paloneva J, Manninen T, Christman G, Hovanes K, Mandelin J, Adolfsson R, et al. Mutations in two genes encoding different subunits of a receptor signaling complex result in an identical disease phenotype. Am J Hum Genet (2002) 71(3):656-62. doi:10.1086/342259
184. Guerreiro R, Hardy J. Genetics of Alzheimer's disease. Neurotherapeutics (2014) 11(4):732-7. doi:10.1007/s13311-014-0295-9
185. Wang Y, Cella M, Mallinson K, Ulrich JD, Young KL, Robinette ML, et al. TREM2 lipid sensing sustains the microglial response in an Alzheimer's disease model. Cell (2015) 160(6):1061-71. doi:10.1016/j.cell.2015.01.049
186. Shimobayashi M, Hall MN. Making new contacts: the mTOR network in metabolism and signalling crosstalk. Nat Rev Mol Cell Biol (2014) 15(3):155-62. doi:10.1038/nrm3757
187. Walker JB. Creatine: biosynthesis, regulation, and function. Adv Enzymol Relat Areas Mol Biol (1979) 50:177-242
188. Huang YA, Zhou B, Wernig M, Sudhof TC. ApoE2, ApoE3, and ApoE4 differentially stimulate APP transcription and Abeta secretion. Cell (2017) 168(3):427-41.e21. doi:10.1016/j.cell.2016.12.044
189. Hattori C, Asai M, Onishi H, Sasagawa N, Hashimoto Y, Saido TC, et al. BACE1 interacts with lipid raft proteins. J Neurosci Res (2006) 84(4):912-7. doi:10.1002/jnr.20981
190. Grimm MO, Mett J, Grimm HS, Hartmann T. APP function and lipids: a bidirectional link. Front Mol Neurosci (2017) 10:63. doi:10.3389/fnmol.2017.00063
191. Eckert GP, Muller WE. Presenilin 1 modifies lipid raft composition of neuronal membranes. Biochem Biophys Res Commun (2009) 382(4):673-7. doi:10.1016/j.bbrc.2009.03.070
192. Hagen N, Hans M, Hartmann D, Swandulla D, van Echten-Deckert G. Sphingosine-1-phosphate links glycosphingolipid metabolism to neurodegeneration via a calpain-mediated mechanism. Cell Death Differ (2011) 18(8):1356-65. doi:10.1038/cdd.2011.7
193. Elbaum-Garfinkle S, Ramlall T, Rhoades E. The role of the lipid bilayer in tau aggregation. Biophys J (2010) 98(11):2722-30. doi:10.1016/j.bpj.2010.03.013
194. Xi B, Gu H, Baniasadi H, Raftery D. Statistical analysis and modeling of mass spectrometry-based metabolomics data. Methods Mol Biol (2014) 1198:333-53. doi:10.1007/978-1-4939-1258-2_22
195. Van Cauwenberghe C, Van Broeckhoven C, Sleegers K. The genetic landscape of Alzheimer disease: clinical implications and perspectives. Genet Med (2016) 18(5):421-30. doi:10.1038/gim.2015.117
196. Willette A. Does metabolic syndrome impact cognition and emotion in Alzheimer's disease? Eur J Neurol (2016) 23(2):237-8. doi:10.1111/ene.12879
197. Wang XF, Lin X, Li DY, Zhou R, Greenbaum J, Chen YC, et al. Linking Alzheimer's disease and type 2 diabetes: novel shared susceptibility genes detected by cFDR approach. J Neurol Sci (2017) 380:262-72. doi:10.1016/j.jns.2017.07.044
198. Rios JA, Cisternas P, Arrese M, Barja S, Inestrosa NC. Is Alzheimer's disease related to metabolic syndrome? A Wnt signaling conundrum. Prog Neurobiol (2014) 121:125-46. doi:10.1016/j.pneurobio.2014.07.004
199. Pistollato F, Sumalla Cano S, Elio I, Masias Vergara M, Giampieri F, Battino M. Role of gut microbiota and nutrients in amyloid formation and pathogenesis of Alzheimer disease. Nutr Rev (2016) 74(10):624-34. doi:10.1093/nutrit/nuw023
200. Demetrius LA, Driver J. Alzheimer's as a metabolic disease. Biogerontology (2013) 14(6):641-9. doi:10.1007/s10522-013-9479-7