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CSF Apo-E levels associate with cognitive decline and MRI changes

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Abstract

Apolipoprotein E (APOE) ε4 allele is the most important genetic risk factor for Alzheimer’s disease (AD) and it is thought to do so by modulating levels of its product, apolipoprotein E (Apo-E), and regulating amyloid-β (Aβ) clearance. However, information on clinical and biomarker correlates of Apo-E proteins is scarce. We examined the relationship of cerebrospinal fluid (CSF) and plasma Apo-E protein levels, and APOE genotype to cognition and AD biomarker changes in 311 AD neuroimaging initiative subjects with CSF Apo-E measurements and 565 subjects with plasma Apo-E measurements. At baseline, higher CSF Apo-E levels were associated with higher total and phosphorylated CSF tau levels. CSF Apo-E levels were associated with longitudinal cognitive decline, MCI conversion to dementia, and gray matter atrophy rate in total tau/Aβ1–42 ratio and APOE genotype-adjusted analyses. In analyses stratified by APOE genotype, our results were only significant in the group without the ε4 allele. Baseline CSF Apo-E levels did not predict longitudinal CSF Aβ or tau changes. Plasma Apo-E levels show a mild correlation with CSF Apo-E levels, but were not associated with longitudinal cognitive and MRI changes. Based on our analyses, we speculate that increased CSF Apo-E2 or -E3 levels might represent a protective response to injury in AD and may have neuroprotective effects by decreasing neuronal damage independent of tau and amyloid deposition in addition to its effects on amyloid clearance.

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References

  1. Aoki K, Uchihara T, Sanjo N, Nakamura A, Ikeda K, Tsuchiya K, Wakayama Y (2003) Increased expression of neuronal apolipoprotein E in human brain with cerebral infarction. Stroke 34(4):875–880. doi:10.1161/01.STR.0000064320.73388.C6

    Article  PubMed  CAS  Google Scholar 

  2. Baird GS, Nelson SK, Keeney TR, Stewart A, Williams S, Kraemer S, Peskind ER, Montine TJ (2012) Age-dependent changes in the cerebrospinal fluid proteome by slow off-rate modified aptamer array. Am J Pathol 180(2):446–456. doi:10.1016/j.ajpath.2011.10.024

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  3. Boschert U, Merlo-Pich E, Higgins G, Roses AD, Catsicas S (1999) Apolipoprotein E expression by neurons surviving excitotoxic stress. Neurobiol Dis 6(6):508–514. doi:10.1006/nbdi 1999.0251

    Article  PubMed  CAS  Google Scholar 

  4. Boyles JK, Pitas RE, Wilson E, Mahley RW, Taylor JM (1985) Apolipoprotein E associated with astrocytic glia of the central nervous system and with nonmyelinating glia of the peripheral nervous system. J Clin Invest 76(4):1501–1513. doi:10.1172/JCI112130

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  5. Bunce D, Fratiglioni L, Small BJ, Winblad B, Backman L (2004) APOE and cognitive decline in preclinical Alzheimer disease and non-demented aging. Neurology 63(5):816–821

    Article  PubMed  CAS  Google Scholar 

  6. Burnham SC, Faux NG, Wilson W, Laws SM, Ames D, Bedo J, Bush AI, Doecke JD, Ellis KA, Head R, Jones G, Kiiveri H, Martins RN, Rembach A, Rowe CC, Salvado O, Macaulay SL, Masters CL, Villemagne VL (2013) A blood-based predictor for neocortical Abeta burden in Alzheimer’s disease: results from the AIBL study. Mol Psychiatry. doi:10.1038/mp.2013.40

    Google Scholar 

  7. Castellano JM, Kim J, Stewart FR, Jiang H, DeMattos RB, Patterson BW, Fagan AM, Morris JC, Mawuenyega KG, Cruchaga C, Goate AM, Bales KR, Paul SM, Bateman RJ, Holtzman DM (2011) Human apoE isoforms differentially regulate brain amyloid-beta peptide clearance. Sci Transl Med 3(89):89ra57. doi:10.1126/scitranslmed.3002156

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  8. Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small GW, Roses AD, Haines JL, Pericak-Vance MA (1993) Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science 261(5123):921–923

    Article  PubMed  CAS  Google Scholar 

  9. Cosentino S, Scarmeas N, Helzner E, Glymour MM, Brandt J, Albert M, Blacker D, Stern Y (2008) APOE epsilon 4 allele predicts faster cognitive decline in mild Alzheimer disease. Neurology 70(19 Pt 2):1842–1849. doi:10.1212/01.wnl.0000304038.37421.cc

    PubMed Central  PubMed  CAS  Google Scholar 

  10. Cramer PE, Cirrito JR, Wesson DW, Lee CY, Karlo JC, Zinn AE, Casali BT, Restivo JL, Goebel WD, James MJ, Brunden KR, Wilson DA, Landreth GE (2012) ApoE-directed therapeutics rapidly clear beta-amyloid and reverse deficits in AD mouse models. Science 335(6075):1503–1506. doi:10.1126/science.1217697

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  11. Cruchaga C, Kauwe JS, Nowotny P, Bales K, Pickering EH, Mayo K, Bertelsen S, Hinrichs A, Fagan AM, Holtzman DM, Morris JC, Goate AM (2012) Cerebrospinal fluid APOE levels: an endophenotype for genetic studies for Alzheimer’s disease. Hum Mol Genet 21(20):4558–4571. doi:10.1093/hmg/dds296

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  12. Darreh-Shori T, Modiri N, Blennow K, Baza S, Kamil C, Ahmed H, Andreasen N, Nordberg A (2011) The apolipoprotein E epsilon4 allele plays pathological roles in AD through high protein expression and interaction with butyrylcholinesterase. Neurobiol Aging 32(7):1236–1248. doi:10.1016/j.neurobiolaging.2009.07.015

    Article  PubMed  CAS  Google Scholar 

  13. Doecke JD, Laws SM, Faux NG, Wilson W, Burnham SC, Lam CP, Mondal A, Bedo J, Bush AI, Brown B, De Ruyck K, Ellis KA, Fowler C, Gupta VB, Head R, Macaulay SL, Pertile K, Rowe CC, Rembach A, Rodrigues M, Rumble R, Szoeke C, Taddei K, Taddei T, Trounson B, Ames D, Masters CL, Martins RN (2012) Blood-based protein biomarkers for diagnosis of Alzheimer disease. Arch Neurol 69(10):1318–1325. doi:10.1001/archneurol2012.1282

    Article  PubMed  Google Scholar 

  14. Donkin JJ, Stukas S, Hirsch-Reinshagen V, Namjoshi D, Wilkinson A, May S, Chan J, Fan J, Collins J, Wellington CL (2010) ATP-binding cassette transporter A1 mediates the beneficial effects of the liver X receptor agonist GW3965 on object recognition memory and amyloid burden in amyloid precursor protein/presenilin 1 mice. J Biol Chem 285(44):34144–34154. doi:10.1074/jbc.M110.108100

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  15. Farrer LA, Cupples LA, Haines JL, Hyman B, Kukull WA, Mayeux R, Myers RH, Pericak-Vance MA, Risch N, van Duijn CM (1997) Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. A meta-analysis. APOE and Alzheimer Disease Meta Analysis Consortium. JAMA 278(16):1349–1356

    Article  PubMed  CAS  Google Scholar 

  16. Figurski MJ, Waligorska T, Toledo J, Vanderstichele H, Korecka M, Lee VM, Trojanowski JQ, Shaw LM (2012) Improved protocol for measurement of plasma beta-amyloid in longitudinal evaluation of Alzheimer’s disease neuroimaging initiative study patients. Alzheimers Dement 8(4):250–260. doi:10.1016/j.jalz.2012.01.001

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  17. Fitz NF, Cronican AA, Lefterov I, Koldamova R (2013) Comment on “ApoE-directed therapeutics rapidly clear beta-amyloid and reverse deficits in AD mouse models”. Science 340(6135):924-c. doi:10.1126/science.1235809

    Article  PubMed  Google Scholar 

  18. Foster JK, Albrecht MA, Savage G, Lautenschlager NT, Ellis KA, Maruff P, Szoeke C, Taddei K, Martins R, Masters CL, Ames D (2013) Lack of reliable evidence for a distinctive {varepsilon}4-related cognitive phenotype that is independent from clinical diagnostic status: findings from the Australian imaging, biomarkers and lifestyle study. Brain 136(Pt 7):2201–2216. doi:10.1093/brain/awt127

    Article  PubMed  Google Scholar 

  19. Fukuyama R, Mizuno T, Mori S, Yanagisawa K, Nakajima K, Fushiki S (2000) Age-dependent decline in the apolipoprotein E level in cerebrospinal fluid from control subjects and its increase in cerebrospinal fluid from patients with Alzheimer’s disease. Eur Neurol 43(3):161–169 (8157)

    Article  PubMed  CAS  Google Scholar 

  20. Gregg RE, Zech LA, Schaefer EJ, Stark D, Wilson D, Brewer HB Jr (1986) Abnormal in vivo metabolism of apolipoprotein E4 in humans. J Clin Invest 78(3):815–821. doi:10.1172/JCI112645

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  21. Gupta VB, Laws SM, Villemagne VL, Ames D, Bush AI, Ellis KA, Lui JK, Masters C, Rowe CC, Szoeke C, Taddei K, Martins RN (2011) Plasma apolipoprotein E and Alzheimer disease risk: the AIBL study of aging. Neurology 76(12):1091–1098. doi:10.1212/WNL.0b013e318211c352

    Article  PubMed  CAS  Google Scholar 

  22. Haag MD, Hofman A, Koudstaal PJ, Stricker BH, Breteler MM (2009) Statins are associated with a reduced risk of Alzheimer disease regardless of lipophilicity. The Rotterdam study. J Neurol Neurosurg Psychiatry 80(1):13–17. doi:10.1136/jnnp.2008.150433

    Article  PubMed  CAS  Google Scholar 

  23. Hong Z, Shi M, Chung KA, Quinn JF, Peskind ER, Galasko D, Jankovic J, Zabetian CP, Leverenz JB, Baird G, Montine TJ, Hancock AM, Hwang H, Pan C, Bradner J, Kang UJ, Jensen PH, Zhang J (2010) DJ-1 and alpha-synuclein in human cerebrospinal fluid as biomarkers of Parkinson’s disease. Brain 133(Pt 3):713–726. doi:10.1093/brain/awq008

    Article  PubMed Central  PubMed  Google Scholar 

  24. Hu WT, Holtzman DM, Fagan AM, Shaw LM, Perrin R, Arnold SE, Grossman M, Xiong C, Craig-Schapiro R, Clark CM, Pickering E, Kuhn M, Chen Y, Van Deerlin VM, McCluskey L, Elman L, Karlawish J, Chen-Plotkin A, Hurtig HI, Siderowf A, Swenson F, Lee VM, Morris JC, Trojanowski JQ, Soares H (2012) Plasma multianalyte profiling in mild cognitive impairment and Alzheimer disease. Neurology 79(9):897–905. doi:10.1212/WNL.0b013e318266fa70

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  25. Huang Y (2010) Abeta-independent roles of apolipoprotein E4 in the pathogenesis of Alzheimer’s disease. Trends Mol Med 16(6):287–294. doi:10.1016/j.molmed.2010.04.004

    Article  PubMed  CAS  Google Scholar 

  26. Huang Y, Liu XQ, Wyss-Coray T, Brecht WJ, Sanan DA, Mahley RW (2001) Apolipoprotein E fragments present in Alzheimer’s disease brains induce neurofibrillary tangle-like intracellular inclusions in neurons. Proc Natl Acad Sci USA 98(15):8838–8843. doi:10.1073/pnas.151254698

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  27. Jack CR Jr, Bernstein MA, Fox NC, Thompson P, Alexander G, Harvey D, Borowski B, Britson PJ, Whitwell JL, Ward C, Dale AM, Felmlee JP, Gunter JL, Hill DL, Killiany R, Schuff N, Fox-Bosetti S, Lin C, Studholme C, DeCarli CS, Krueger G, Ward HA, Metzger GJ, Scott KT, Mallozzi R, Blezek D, Levy J, Debbins JP, Fleisher AS, Albert M, Green R, Bartzokis G, Glover G, Mugler J, Weiner MW (2008) The Alzheimer’s disease neuroimaging initiative (ADNI): MRI methods. J Magn Reson Imaging 27(4):685–691. doi:10.1002/jmri.21049

    Article  PubMed Central  PubMed  Google Scholar 

  28. Jiang Q, Lee CY, Mandrekar S, Wilkinson B, Cramer P, Zelcer N, Mann K, Lamb B, Willson TM, Collins JL, Richardson JC, Smith JD, Comery TA, Riddell D, Holtzman DM, Tontonoz P, Landreth GE (2008) ApoE promotes the proteolytic degradation of Abeta. Neuron 58(5):681–693. doi:10.1016/j.neuron.2008.04.010

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  29. Kim S, Swaminathan S, Inlow M, Risacher SL, Nho K, Shen L, Foroud TM, Petersen RC, Aisen PS, Soares H, Toledo JB, Shaw LM, Trojanowski JQ, Weiner MW, McDonald BC, Farlow MR, Ghetti B, Saykin AJ (2013) Influence of genetic variation on plasma protein levels in older adults using a multi-analyte panel. PLoS One 8(7):e70269. doi:10.1371/journal.pone.0070269

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  30. Korff A, Liu C, Ginghina C, Shi M, Zhang J (2013) α-Synuclein in cerebrospinal fluid of Alzheimer’s disease and mild cognitive impairment. J Alzheimers Dis 36(4):679–688. doi:10.3233/JAD-130458

    Google Scholar 

  31. LaClair KD, Manaye KF, Lee DL, Allard JS, Savonenko AV, Troncoso JC, Wong PC (2013) Treatment with bexarotene, a compound that increases apolipoprotein-E, provides no cognitive benefit in mutant APP/PS1 mice. Mol Neurodegener 8:18. doi:10.1186/1750-1326-8-18

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  32. Landreth GE, Cramer PE, Lakner MM, Cirrito JR, Wesson DW, Brunden KR, Wilson DA (2013) Response to comments on “ApoE-directed therapeutics rapidly clear beta-amyloid and reverse deficits in AD mouse models”. Science 340(6135):924-g. doi:10.1126/science.1234114

    Article  PubMed  Google Scholar 

  33. Lehtimaki T, Pirttila T, Mehta PD, Wisniewski HM, Frey H, Nikkari T (1995) Apolipoprotein E (apoE) polymorphism and its influence on ApoE concentrations in the cerebrospinal fluid in Finnish patients with Alzheimer’s disease. Hum Genet 95(1):39–42

    PubMed  CAS  Google Scholar 

  34. Liu CC, Kanekiyo T, Xu H, Bu G (2013) Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy. Nat Rev Neurol 9(2):106–118. doi:10.1038/nrneurol.2012.263

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  35. Liu M, Kuhel DG, Shen L, Hui DY, Woods SC (2012) Apolipoprotein E does not cross the blood-cerebrospinal fluid barrier, as revealed by an improved technique for sampling CSF from mice. Am J Physiol Regul Integr Comp Physiol 303(9):R903–R908. doi:10.1152/ajpregu.00219.2012

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  36. Poirier J, Hess M, May PC, Finch CE (1991) Astrocytic apolipoprotein E mRNA and GFAP mRNA in hippocampus after entorhinal cortex lesioning. Brain Res Mol Brain Res 11(2):97–106

    Article  PubMed  CAS  Google Scholar 

  37. Price AR, Xu G, Siemienski ZB, Smithson LA, Borchelt DR, Golde TE, Felsenstein KM (2013) Comment on “ApoE-directed therapeutics rapidly clear beta-amyloid and reverse deficits in AD mouse models”. Science 340(6135):924-d. doi:10.1126/science.1234089

    Article  PubMed  Google Scholar 

  38. Reiman EM, Chen K, Liu X, Bandy D, Yu M, Lee W, Ayutyanont N, Keppler J, Reeder SA, Langbaum JB, Alexander GE, Klunk WE, Mathis CA, Price JC, Aizenstein HJ, DeKosky ST, Caselli RJ (2009) Fibrillar amyloid-beta burden in cognitively normal people at 3 levels of genetic risk for Alzheimer’s disease. Proc Natl Acad Sci USA 106(16):6820–6825. doi:10.1073/pnas.0900345106

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  39. Reuter M, Rosas HD, Fischl B (2010) Highly accurate inverse consistent registration: a robust approach. Neuroimage 53(4):1181–1196. doi:10.1016/j.neuroimage.2010.07.020

    Article  PubMed Central  PubMed  Google Scholar 

  40. Reuter M, Schmansky NJ, Rosas HD, Fischl B (2012) Within-subject template estimation for unbiased longitudinal image analysis. Neuroimage 61(4):1402–1418. doi:10.1016/j.neuroimage.2012.02.084

    Article  PubMed Central  PubMed  Google Scholar 

  41. Riddell DR, Zhou H, Atchison K, Warwick HK, Atkinson PJ, Jefferson J, Xu L, Aschmies S, Kirksey Y, Hu Y, Wagner E, Parratt A, Xu J, Li Z, Zaleska MM, Jacobsen JS, Pangalos MN, Reinhart PH (2008) Impact of apolipoprotein E (ApoE) polymorphism on brain ApoE levels. J Neurosci 28(45):11445–11453. doi:10.1523/JNEUROSCI.1972-08.2008

    Article  PubMed  CAS  Google Scholar 

  42. Roheim PS, Carey M, Forte T, Vega GL (1979) Apolipoproteins in human cerebrospinal fluid. Proc Natl Acad Sci USA 76(9):4646–4649

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  43. Shaw LM, Vanderstichele H, Knapik-Czajka M, Clark CM, Aisen PS, Petersen RC, Blennow K, Soares H, Simon A, Lewczuk P, Dean R, Siemers E, Potter W, Lee VM, Trojanowski JQ (2009) Cerebrospinal fluid biomarker signature in Alzheimer’s disease neuroimaging initiative subjects. Ann Neurol 65(4):403–413. doi:10.1002/ana.21610

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  44. Shaw LM, Vanderstichele H, Knapik-Czajka M, Figurski M, Coart E, Blennow K, Soares H, Simon AJ, Lewczuk P, Dean RA, Siemers E, Potter W, Lee VM, Trojanowski JQ (2011) Qualification of the analytical and clinical performance of CSF biomarker analyses in ADNI. Acta Neuropathol 121(5):597–609. doi:10.1007/s00401-011-0808-0

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  45. Shepardson NE, Shankar GM, Selkoe DJ (2011) Cholesterol level and statin use in Alzheimer disease: I. Review of epidemiological and preclinical studies. Arch Neurol 68(10):1239–1244. doi:10.1001/archneurol.2011.203

    Article  PubMed Central  PubMed  Google Scholar 

  46. Shepardson NE, Shankar GM, Selkoe DJ (2011) Cholesterol level and statin use in Alzheimer disease: II. Review of human trials and recommendations. Arch Neurol 68(11):1385–1392. doi:10.1001/archneurol.2011.242

    Article  PubMed Central  PubMed  Google Scholar 

  47. Soares HD, Potter WZ, Pickering E, Kuhn M, Immermann FW, Shera DM, Ferm M, Dean RA, Simon AJ, Swenson F, Siuciak JA, Kaplow J, Thambisetty M, Zagouras P, Koroshetz WJ, Wan HI, Trojanowski JQ, Shaw LM (2012) Plasma biomarkers associated with the apolipoprotein E genotype and Alzheimer disease. Arch Neurol 69(10):1310–1317. doi:10.1001/archneurol2012.1070

    Article  PubMed Central  PubMed  Google Scholar 

  48. Tesseur I, Lo AC, Roberfroid A, Dietvorst S, Van Broeck B, Borgers M, Gijsen H, Moechars D, Mercken M, Kemp J, D’Hooge R, De Strooper B (2013) Comment on “ApoE-directed therapeutics rapidly clear beta-amyloid and reverse deficits in AD mouse models”. Science 340(6135):924-e. doi:10.1126/science.1233937

    Article  PubMed  Google Scholar 

  49. Toledo JB, Arnold SE, Raible K, Brettschneider J, Xie SX, Grossman M, Monsell SE, Kukull WA, Trojanowski JQ (2013) Contribution of cerebrovascular disease in autopsy confirmed neurodegenerative disease cases in the National Alzheimer’s Coordinating Centre. Brain 136(Pt 9):2697–2706. doi:10.1093/brain/awt188

    Article  PubMed  Google Scholar 

  50. Toledo JB, Korff A, Shaw LM, Trojanowski JQ, Zhang J (2013) CSF alpha-synuclein improves diagnostic and prognostic performance of CSF tau and Abeta in Alzheimer’s disease. Acta Neuropathol 126(5):683–697. doi:10.1007/s00401-013-1148-z

    Article  PubMed  CAS  Google Scholar 

  51. Toledo JB, Shaw LM, Trojanowski JQ (2013) Plasma amyloid beta measurements—a desired but elusive Alzheimer’s disease biomarker. Alzheimers Res Ther 5(2):8. doi:10.1186/alzrt162

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  52. Toledo JB, Vanderstichele H, Figurski M, Aisen PS, Petersen RC, Weiner MW, Jack CR Jr, Jagust W, Decarli C, Toga AW, Toledo E, Xie SX, Lee VM, Trojanowski JQ, Shaw LM (2011) Factors affecting Abeta plasma levels and their utility as biomarkers in ADNI. Acta Neuropathol 122(4):401–413. doi:10.1007/s00401-011-0861-8

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  53. Toledo JB, Xie SX, Trojanowski JQ, Shaw LM (2013) Longitudinal change in CSF Tau and Abeta biomarkers for up to 48 months in ADNI. Acta Neuropathol 126(5):659–670. doi:10.1007/s00401-013-1151-4

    Article  PubMed  CAS  Google Scholar 

  54. Vanmierlo T, Rutten K, Dederen J, Bloks VW, van Vark-van der Zee LC, Kuipers F, Kiliaan A, Blokland A, Sijbrands EJ, Steinbusch H, Prickaerts J, Lutjohann D, Mulder M (2011) Liver X receptor activation restores memory in aged AD mice without reducing amyloid. Neurobiol Aging 32(7):1262–1272. doi:10.1016/j.neurobiolaging.2009.07.005

    Article  PubMed  CAS  Google Scholar 

  55. Veeraraghavalu K, Zhang C, Miller S, Hefendehl JK, Rajapaksha TW, Ulrich J, Jucker M, Holtzman DM, Tanzi RE, Vassar R, Sisodia SS (2013) Comment on “ApoE-directed therapeutics rapidly clear beta-amyloid and reverse deficits in AD mouse models”. Science 340(6135):924-f. doi:10.1126/science.1235505

    Article  PubMed  Google Scholar 

  56. Vijayaraghavan S, Maetzler W, Reimold M, Lithner CU, Liepelt-Scarfone I, Berg D, Darreh-Shori T (2013) High apolipoprotein E in cerebrospinal fluid of patients with Lewy body disorders is associated with dementia. Alzheimers Dement. doi:10.1016/j.jalz.2013.03.010

    PubMed  Google Scholar 

  57. Villemagne VL, Burnham S, Bourgeat P, Brown B, Ellis KA, Salvado O, Szoeke C, Macaulay SL, Martins R, Maruff P, Ames D, Rowe CC, Masters CL (2013) Amyloid beta deposition, neurodegeneration, and cognitive decline in sporadic Alzheimer’s disease: a prospective cohort study. Lancet Neurol 12(4):357–367. doi:10.1016/S1474-4422(13)70044-9

    Article  PubMed  CAS  Google Scholar 

  58. Wahrle SE, Shah AR, Fagan AM, Smemo S, Kauwe JS, Grupe A, Hinrichs A, Mayo K, Jiang H, Thal LJ, Goate AM, Holtzman DM (2007) Apolipoprotein E levels in cerebrospinal fluid and the effects of ABCA1 polymorphisms. Mol Neurodegener 2:7. doi:10.1186/1750-1326-2-7

    Article  PubMed Central  PubMed  Google Scholar 

  59. Weiner MW, Veitch DP, Aisen PS, Beckett LA, Cairns NJ, Green RC, Harvey D, Jack CR, Jagust W, Liu E, Morris JC, Petersen RC, Saykin AJ, Schmidt ME, Shaw L, Siuciak JA, Soares H, Toga AW, Trojanowski JQ (2012) The Alzheimer’s disease neuroimaging initiative: a review of papers published since its inception. Alzheimers Dement 8(1 Suppl):S1–S68. doi:10.1016/j.jalz.2011.09.172

    Article  PubMed Central  PubMed  Google Scholar 

  60. Weisgraber KH, Shinto LH (1991) Identification of the disulfide-linked homodimer of apolipoprotein E3 in plasma. Impact on receptor binding activity. J Biol Chem 266(18):12029–12034

    PubMed  CAS  Google Scholar 

  61. Winnock M, Letenneur L, Jacqmin-Gadda H, Dallongeville J, Amouyel P, Dartigues JF (2002) Longitudinal analysis of the effect of apolipoprotein E epsilon4 and education on cognitive performance in elderly subjects: the PAQUID study. J Neurol Neurosurg Psychiatry 72(6):794–797

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  62. Wolk DA, Dickerson BC (2010) Apolipoprotein E (APOE) genotype has dissociable effects on memory and attentional-executive network function in Alzheimer’s disease. Proc Natl Acad Sci USA 107(22):10256–10261. doi:10.1073/pnas.1001412107

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  63. Xu Q, Bernardo A, Walker D, Kanegawa T, Mahley RW, Huang Y (2006) Profile and regulation of apolipoprotein E (ApoE) expression in the CNS in mice with targeting of green fluorescent protein gene to the ApoE locus. J Neurosci 26(19):4985–4994. doi:10.1523/JNEUROSCI.5476-05.2006

    Article  PubMed  CAS  Google Scholar 

  64. Yaffe K, Cauley J, Sands L, Browner W (1997) Apolipoprotein E phenotype and cognitive decline in a prospective study of elderly community women. Arch Neurol 54(9):1110–1114

    Article  PubMed  CAS  Google Scholar 

  65. Yu L, Boyle PA, Leurgans S, Schneider JA, Bennett DA (2013) Disentangling the effects of age and APOE on neuropathology and late life cognitive decline. Neurobiol Aging. doi:10.1016/j.neurobiolaging.2013.10.074

    Google Scholar 

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Acknowledgments

Data collection and sharing for this project were funded by (ADNI (National Institutes of Health Grant U01 AG024904). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: Alzheimer’s Association; Alzheimer’s Drug Discovery Foundation; BioClinica, Inc.; Biogen Idec Inc.; Bristol-Myers Squibb Company; Eisai Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc.; GE Healthcare; Innogenetics, N·V.; IXICO Ltd.; Janssen Alzheimer Immunotherapy Research and Development, LLC.; Johnson & Johnson Pharmaceutical Research and Development LLC.; Medpace, Inc.; Merck & Co., Inc.; Meso Scale Diagnostics, LLC.; NeuroRx Research; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Servier; Synarc Inc.; and Takeda Pharmaceutical Company. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health (www.fnih.org). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer’s Disease Cooperative Study at the University of California, San Diego. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of California, Los Angeles. This research was also supported by NIH grants P30 AG010129 and K01 AG030514. JQT is the William Maul Measey-Truman G. Schnabel, Jr., Professor of Geriatric Medicine and Gerontology.

Conflict of interest

Dr. Arnold reports grants from NIH, the American Health Assistance Foundation and the Marian S Ware Alzheimer’s Programseveral pharmaceutical companies, other from Universities, pharmaceutical companies and advisory/speaking honoraria from Universities, pharmaceutical companies and law firms. Dr. Trojanowski reports grants from NIH, Bristol Myer Squib, Astra Zeneca and several non-profits, outside the submitted work; In addition, Dr. Trojanowski has a patent Modified avidin–biotin technique, Method of stabilizing microtubules to treat Alzheimer’s disease, Method of detecting abnormally phosphorylated tau, Method of screening for Alzheimer’s disease or disease associated with the accumulation of paired helical filaments, Compositions and methods for producing and using homogeneous neuronal cell transplants, Rat comprising straight filaments in its brain, Compositions and methods for producing and using homogeneous neuronal cell transplants to treat neurodegenerative disorders and brain and spinal cord injuries, Diagnostic methods for Alzheimer’s disease by detection of multiple MRNAs, Methods and compositions for determining lipid peroxidation levels in oxidant stress syndromes and diseases, Compositions and methods for producing and using homogenous neuronal cell transplants, Method of identifying, diagnosing and treating alpha-synuclein positive neurodegenerative disorders, Mutation-specific functional impairments in distinct tau isoforms of hereditary frontotemporal dementia and parkinsonism linked to chromosome-17: genotype predicts phenotype, Microtubule stabilizing therapies for neurodegenerative disorders, and Treatment of Alzheimer’s and related diseases with an antibody pending, and a patent Amyloid plaque aggregation inhibitors and diagnostic imaging agents sold to Avid to Eli Lily. Dr. Weiner reports stock/stock options from Elan, Synarc, travel expenses from Novartis, Tohoku University, Fundacio Ace, Travel eDreams, MCI Group, NSAS, Danone Trading, ANT Congress, NeuroVigil, CHRU-Hopital Roger Salengro, Siemens, AstraZeneca, Geneva University Hospitals, Lilly, University of California, San Diego—ADNI, Paris University, Institut Catala de Neurociencies Aplicades, University of New Mexico School of Medicine, Ipsen, Clinical Trials on Alzheimer’s Disease, Pfizer, AD PD meeting, Paul Sabatier University, board membership for Lilly, Araclon, Institut Catala de Neurociencies Aplicades, Gulf War Veterans Illnesses Advisory Committee, VACO, Biogen Idec, Pfizer, consultancy from AstraZeneca, Araclon, Medivation/Pfizer, Ipsen, TauRx Therapeutics, Bayer Healthcare, Biogen Idec, ExonHit Therapeutics, Servier, Synarc, Pfizer, Janssen, honoraria from NeuroVigil, Insitut Catala de Neurociencies Aplicades, PMDA/Japanese Ministry of Health, Labour, and Welfare, Tohoku University, commercial research support from Merck, Avid; government research support, DOD, VA, outside the submitted work. Other authors report no conflicts of interest.

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Authors and Affiliations

  1. Department of Pathology and Laboratory Medicine, Institute on Aging, Center for Neurodegenerative Disease Research, University of Pennsylvania School of Medicine, HUP, Maloney 3rd, 36th and Spruce Streets, Philadelphia, PA, 19104-4283, USA

    Jon B. Toledo, Leslie M. Shaw & John Q. Trojanowski

  2. Section of Biomedical Image Analysis, Department of Radiology, University of Pennsylvania, Philadelphia, PA, USA

    Xiao Da & Christos Davatzikos

  3. Department of Radiology, Center for Imaging of Neurodegenerative Diseases, San Francisco VA Medical Center/University of California San Francisco, San Francisco, USA

    Michael W. Weiner

  4. Department of Neurology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, USA

    David A. Wolk & Steven E. Arnold

  5. Department of Biostatistics and Epidemiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, USA

    Sharon X. Xie

  6. Department of Psychiatry, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, USA

    Steven E. Arnold

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  1. Jon B. Toledo
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  2. Xiao Da
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  9. John Q. Trojanowski
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Correspondence to John Q. Trojanowski.

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Toledo, J.B., Da, X., Weiner, M.W. et al. CSF Apo-E levels associate with cognitive decline and MRI changes. Acta Neuropathol 127, 621–632 (2014). https://doi.org/10.1007/s00401-013-1236-0

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