Korean J Physiol Pharmacol.  2014 Dec;18(6):447-456. 10.4196/kjpp.2014.18.6.447.

Role of Cerebrospinal Fluid Biomarkers in Clinical Trials for Alzheimer's Disease Modifying Therapies

• Kang JH
• Ryoo NY
• Shin DW
• Trojanowski JQ
• Shaw LM

• KMID: 2285545
• DOI: http://doi.org/10.4196/kjpp.2014.18.6.447

Abstract

Until now, a disease-modifying therapy (DMT) that has an ability to slow or arrest Alzheimer's disease (AD) progression has not been developed, and all clinical trials involving AD patients enrolled by clinical assessment alone also have not been successful. Given the growing consensus that the DMT is likely to require treatment initiation well before full-blown dementia emerges, the early detection of AD will provide opportunities to successfully identify new drugs that slow the course of AD pathology. Recent advances in early detection of AD and prediction of progression of the disease using various biomarkers, including cerebrospinal fluid (CSF) Abeta1-42, total tau and p-tau181 levels, and imagining biomarkers, are now being actively integrated into the designs of AD clinical trials. In terms of therapeutic mechanisms, monitoring these markers may be helpful for go/no-go decision making as well as surrogate markers for disease severity or progression. Furthermore, CSF biomarkers can be used as a tool to enrich patients for clinical trials with prospect of increasing statistical power and reducing costs in drug development. However, the standardization of technical aspects of analysis of these biomarkers is an essential prerequisite to the clinical uses. To accomplish this, global efforts are underway to standardize CSF biomarker measurements and a quality control program supported by the Alzheimer's Association. The current review summarizes therapeutic targets of developing drugs in AD pathophysiology, and provides the most recent advances in the

Keyword

Alzheimer's disease; Abeta1-42; Cerebrospinal fluid biomarker; Clinical trial; Tau

MeSH Terms

Alzheimer Disease*
Biomarkers*
Cerebrospinal Fluid*
Consensus
Decision Making
Dementia
Humans
Pathology
Quality Control

Figure

• 

  Fig. 1 Chronological relationship among pathology, clinical symptoms and biomarkers. Based on biomarker studies, Ab accumulation appears to start more than 20 years before the onset of dementia. Amyloid positron emission tomography (PET) or a decrease in CSF Aβ1-42 levels may indicate Ab accumulation in the brain, even in preclinical stage of AD. Neocortical tau pathology correlates with the timing of symptom onset and start approximately 10 years before the onset of dementia. However, these findings need to be reconciled with reports that tau pathology is observed in the prior to Ab pathology. FDG, 2-[18F]-fluoro-2-deoxy-D-glucose; MCI, mild cognitive impairment. Reproduced from [Therapeutic strategies for tau mediated neurodegneration, Yoshiyama Y, Lee VM and Trojanowski JQ, J Neruol Neurosurg Psychiatry 84:784-795, 2013] with permission from BMJ Publishing Group Ltd.

• 

  Fig. 2 Sequential process of amyloid precursor protein (APP) metabolism and production of amyloid beta species. Transmembrane APP is cleaved by α-secretase followed by γ-secretase to produce non-toxic amyloid species (non-amyloidogenic pathway, left blue thick arrow), while, through the amyloidogenic pathway (right red thick arrow), toxic Aβ species are generated by β-and γ-secretase. The toxic Aβ species including Aβ1-42 and Aβ1-40 are easily aggregated and produce highly toxic Aβ oligomers. Both processes produce soluble ectodomains [soluble APPα (sAPPα) and sAPPβ] and identical intracellular C-terminal fragment of APP (AICD). RAGE and LRP-1 located in bloodbrain barrier (BBB) are involved in the transport of the Ab between the brain and peripheral blood.

• 

  Fig. 3 Schematic presentation of tau mediated neurodegeneration. Phosphorylation and dephosphorylation of tau control the stability of microtubule. Hyperphosphorylation of tau induces disassembly of mitrotubules, causing axonal transport failure. Unbound tau produces oligomers or aggregates which congest axonal transport, and the tau pathology is synaptically transmitted. Reproduced from [Therapeutic strategies for tau mediated neurodegneration, Yoshiyama Y, Lee VM and Trojanowski JQ, J Neruol Neurosurg Psychiatry 84:784-795, 2013] with permission from BMJ Publishing Group Ltd.

Reference

1. Dubois B, Feldman HH, Jacova C, Dekosky ST, Barberger-Gateau P, Cummings J, Delacourte A, Galasko D, Gauthier S, Jicha G, Meguro K, Obrien J, Pasquier F, Robert P, Rossor M, Salloway S, Stern Y, Visser PJ, Scheltens P. Research criteria for the diagnosis of Alzheimer's disease: revising the NINCDS-ADRDA criteria. Lancet Neurol. 2007; 6:734–746. PMID: 17616482.

2. Dubois B, Feldman HH, Jacova C, Cummings JL, Dekosky ST, Barberger-Gateau P, Delacourte A, Frisoni G, Fox NC, Galasko D, Gauthier S, Hampel H, Jicha GA, Meguro K, O'Brien J, Pasquier F, Robert P, Rossor M, Salloway S, Sarazin M, de Souza LC, Stern Y, Visser PJ, Scheltens P. Revising the definition of Alzheimer's disease: a new lexicon. Lancet Neurol. 2010; 9:1118–1127. PMID: 20934914.

3. Albert MS, DeKosky ST, Dickson D, Dubois B, Feldman HH, Fox NC, Gamst A, Holtzman DM, Jagust WJ, Petersen RC, Snyder PJ, Carrillo MC, Thies B, Phelps CH. The diagnosis of mild cognitive impairment due to Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement. 2011; 7:270–279. PMID: 21514249.

4. McKhann GM, Knopman DS, Chertkow H, Hyman BT, Jack CR Jr, Kawas CH, Klunk WE, Koroshetz WJ, Manly JJ, Mayeux R, Mohs RC, Morris JC, Rossor MN, Scheltens P, Carrillo MC, Thies B, Weintraub S, Phelps CH. The diagnosis of dementia due to Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement. 2011; 7:263–269. PMID: 21514250.

5. Hansson O, Zetterberg H, Buchhave P, Londos E, Blennow K, Minthon L. Association between CSF biomarkers and incipient Alzheimer's disease in patients with mild cognitive impairment: a follow-up study. Lancet Neurol. 2006; 5:228–234. PMID: 16488378.

6. Herukka SK, Helisalmi S, Hallikainen M, Tervo S, Soininen H, Pirttilä T. CSF Abeta42, Tau and phosphorylated Tau, APOE epsilon4 allele and MCI type in progressive MCI. Neurobiol Aging. 2007; 28:507–514. PMID: 16546302.

7. 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. Alzheimer's Disease Neuroimaging Initiative. Cerebrospinal fluid biomarker signature in Alzheimer's disease neuroimaging initiative subjects. Ann Neurol. 2009; 65:403–413. PMID: 19296504.

8. De Meyer G, Shapiro F, Vanderstichele H, Vanmechelen E, Engelborghs S, De Deyn PP, Coart E, Hansson O, Minthon L, Zetterberg H, Blennow K, Shaw L, Trojanowski JQ; Alzheimer's Disease Neuroimaging Initiative. Diagnosis-independent Alzheimer disease biomarker signature in cognitively normal elderly people. Arch Neurol. 2010; 67:949–956. PMID: 20697045.

9. Buchhave P, Minthon L, Zetterberg H, Wallin AK, Blennow K, Hansson O. Cerebrospinal fluid levels of β-amyloid 1-42, but not of tau, are fully changed already 5 to 10 years before the onset of Alzheimer dementia. Arch Gen Psychiatry. 2012; 69:98–106. PMID: 22213792.

10. Palmqvist S, Hertze J, Minthon L, Wattmo C, Zetterberg H, Blennow K, Londos E, Hansson O. Comparison of brief cognitive tests and CSF biomarkers in predicting Alzheimer's disease in mild cognitive impairment: six-year follow-up study. PLoS One. 2012; 7:e38639. PMID: 22761691.

11. Yoshiyama Y, Lee VM, Trojanowski JQ. Therapeutic strategies for tau mediated neurodegeneration. J Neurol Neurosurg Psychiatry. 2013; 84:784–795. PMID: 23085937.

12. Brookmeyer R, Johnson E, Ziegler-Graham K, Arrighi HM. Forecasting the global burden of Alzheimer's disease. Alzheimers Dement. 2007; 3:186–191. PMID: 19595937.

13. Scott TJ, O'Connor AC, Link AN, Beaulieu TJ. Economic analysis of opportunities to accelerate Alzheimer's disease research and development. Ann N Y Acad Sci. 2014; 1313:17–34. PMID: 24673372.

14. Doody RS, Raman R, Farlow M, Iwatsubo T, Vellas B, Joffe S, Kieburtz K, He F, Sun X, Thomas RG, Aisen PS; Alzheimer's Disease Cooperative Study Steering Committee, Siemers E, Sethuraman G, Mohs R; Semagacestat Study Group. A phase 3 trial of semagacestat for treatment of Alzheimer's disease. N Engl J Med. 2013; 369:341–350. PMID: 23883379.

15. Coric V, van Dyck CH, Salloway S, Andreasen N, Brody M, Richter RW, Soininen H, Thein S, Shiovitz T, Pilcher G, Colby S, Rollin L, Dockens R, Pachai C, Portelius E, Andreasson U, Blennow K, Soares H, Albright C, Feldman HH, Berman RM. Safety and tolerability of the γ-secretase inhibitor avagacestat in a phase 2 study of mild to moderate Alzheimer disease. Arch Neurol. 2012; 69:1430–1440. PMID: 22892585.

16. Dockens R, Wang JS, Castaneda L, Sverdlov O, Huang SP, Slemmon R, Gu H, Wong O, Li H, Berman RM, Smith C, Albright CF, Tong G. A placebo-controlled, multiple ascending dose study to evaluate the safety, pharmacokinetics and pharmacodynamics of avagacestat (BMS-708163) in healthy young and elderly subjects. Clin Pharmacokinet. 2012; 51:681–693. PMID: 23018531.

17. Tong G, Wang JS, Sverdlov O, Huang SP, Slemmon R, Croop R, Castaneda L, Gu H, Wong O, Li H, Berman RM, Smith C, Albright CF, Dockens RC. Multicenter, randomized, double-blind, placebo-controlled, single-ascending dose study of the oral γ-secretase inhibitor BMS-708163 (Avagacestat): tolerability profile, pharmacokinetic parameters, and pharmacodynamic markers. Clin Ther. 2012; 34:654–667. PMID: 22381714.

18. Yan Q, Zhang J, Liu H, Babu-Khan S, Vassar R, Biere AL, Citron M, Landreth G. Anti-inflammatory drug therapy alters beta-amyloid processing and deposition in an animal model of Alzheimer's disease. J Neurosci. 2003; 23:7504–7509. PMID: 12930788.

19. Escribano L, Simón AM, Gimeno E, Cuadrado-Tejedor M, López de Maturana R, García-Osta A, Ricobaraza A, Pérez-Mediavilla A, Del Río J, Frechilla D. Rosiglitazone rescues memory impairment in Alzheimer's transgenic mice: mechanisms involving a reduced amyloid and tau pathology. Neuropsychopharmacology. 2010; 35:1593–1604. PMID: 20336061.

20. Landreth G, Jiang Q, Mandrekar S, Heneka M. PPARgamma agonists as therapeutics for the treatment of Alzheimer's disease. Neurotherapeutics. 2008; 5:481–489. PMID: 18625459.

21. Risner ME, Saunders AM, Altman JF, Ormandy GC, Craft S, Foley IM, Zvartau-Hind ME, Hosford DA, Roses AD; Rosiglitazone in Alzheimer's Disease Study Group. Efficacy of rosiglitazone in a genetically defined population with mild-to-moderate Alzheimer's disease. Pharmacogenomics J. 2006; 6:246–254. PMID: 16446752.

22. Gold M, Alderton C, Zvartau-Hind M, Egginton S, Saunders AM, Irizarry M, Craft S, Landreth G, Linnamägi U, Sawchak S. Rosiglitazone monotherapy in mild-to-moderate Alzheimer's disease: results from a randomized, double-blind, placebo-controlled phase III study. Dement Geriatr Cogn Disord. 2010; 30:131–146. PMID: 20733306.

23. Tzimopoulou S, Cunningham VJ, Nichols TE, Searle G, Bird NP, Mistry P, Dixon IJ, Hallett WA, Whitcher B, Brown AP, Zvartau-Hind M, Lotay N, Lai RY, Castiglia M, Jeter B, Matthews JC, Chen K, Bandy D, Reiman EM, Gold M, Rabiner EA, Matthews PM. A multi-center randomized proof-of-concept clinical trial applying [¹⁸F]FDG-PET for evaluation of metabolic therapy with rosiglitazone XR in mild to moderate Alzheimer's disease. J Alzheimers Dis. 2010; 22:1241–1256. PMID: 20930300.

24. Harrington C, Sawchak S, Chiang C, Davies J, Donovan C, Saunders AM, Irizarry M, Jeter B, Zvartau-Hind M, van Dyck CH, Gold M. Rosiglitazone does not improve cognition or global function when used as adjunctive therapy to AChE inhibitors in mild-to-moderate Alzheimer's disease: two phase 3 studies. Curr Alzheimer Res. 2011; 8:592–606. PMID: 21592048.

25. Geldmacher DS1, Fritsch T, McClendon MJ, Landreth G. A randomized pilot clinical trial of the safety of pioglitazone in treatment of patients with Alzheimer disease. Arch Neurol. 2011; 68:45–50. PMID: 20837824.

26. Sato T, Hanyu H, Hirao K, Kanetaka H, Sakurai H, Iwamoto T. Efficacy of PPAR-γ agonist pioglitazone in mild Alzheimer disease. Neurobiol Aging. 2011; 32:1626–1633. PMID: 19923038.

27. Klein WL, Krafft GA, Finch CE. Targeting small Abeta oligomers: the solution to an Alzheimer's disease conundrum? Trends Neurosci. 2001; 24:219–224. PMID: 11250006.

28. Hardy J, Selkoe DJ. The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science. 2002; 297:353–356. PMID: 12130773.

29. Aisen PS, Gauthier S, Ferris SH, Saumier D, Haine D, Garceau D, Duong A, Suhy J, Oh J, Lau WC, Sampalis J. Tramiprosate in mild-to-moderate Alzheimer's disease - a randomized, double-blind, placebo-controlled, multi-centre study (the Alphase Study). Arch Med Sci. 2011; 7:102–111. PMID: 22291741.

30. Adlard PA, Cherny RA, Finkelstein DI, Gautier E, Robb E, Cortes M, Volitakis I, Liu X, Smith JP, Perez K, Laughton K, Li QX, Charman SA, Nicolazzo JA, Wilkins S, Deleva K, Lynch T, Kok G, Ritchie CW, Tanzi RE, Cappai R, Masters CL, Barnham KJ, Bush AI. Rapid restoration of cognition in Alzheimer's transgenic mice with 8-hydroxy quinoline analogs is associated with decreased interstitial Abeta. Neuron. 2008; 59:43–55. PMID: 18614028.

31. Lannfelt L, Blennow K, Zetterberg H, Batsman S, Ames D, Harrison J, Masters CL, Targum S, Bush AI, Murdoch R, Wilson J, Ritchie CW; PBT2-201-EURO study group. Safety, efficacy, and biomarker findings of PBT2 in targeting Abeta as a modifying therapy for Alzheimer's disease: a phase IIa, double-blind, randomised, placebo-controlled trial. Lancet Neurol. 2008; 7:779–786. PMID: 18672400.

32. McLaurin J, Kierstead ME, Brown ME, Hawkes CA, Lambermon MH, Phinney AL, Darabie AA, Cousins JE, French JE, Lan MF, Chen F, Wong SS, Mount HT, Fraser PE, Westaway D, St George-Hyslop P. Cyclohexanehexol inhibitors of Abeta aggregation prevent and reverse Alzheimer phenotype in a mouse model. Nat Med. 2006; 12:801–808. PMID: 16767098.

33. Hawkes CA, Deng LH, Shaw JE, Nitz M, McLaurin J. Small molecule beta-amyloid inhibitors that stabilize protofibrillar structures in vitro improve cognition and pathology in a mouse model of Alzheimer's disease. Eur J Neurosci. 2010; 31:203–213. PMID: 20074226.

34. Salloway S, Sperling R, Keren R, Porsteinsson AP, van Dyck CH, Tariot PN, Gilman S, Arnold D, Abushakra S, Hernandez C, Crans G, Liang E, Quinn G, Bairu M, Pastrak A, Cedarbaum JM; ELND005-AD201 Investigators. A phase 2 randomized trial of ELND005, scyllo-inositol, in mild to moderate Alzheimer disease. Neurology. 2011; 77:1253–1262. PMID: 21917766.

35. Fukumoto H, Tokuda T, Kasai T, Ishigami N, Hidaka H, Kondo M, Allsop D, Nakagawa M. High-molecular-weight beta-amyloid oligomers are elevated in cerebrospinal fluid of Alzheimer patients. FASEB J. 2010; 24:2716–2726. PMID: 20339023.

36. Yang T, Hong S, O'Malley T, Sperling RA, Walsh DM, Selkoe DJ. New ELISAs with high specificity for soluble oligomers of amyloid β-protein detect natural Aβ oligomers in human brain but not CSF. Alzheimer's Dement. 2013; 9:99–112. PMID: 23375565.

37. Savage MJ, Kalinina J, Wolfe A, Tugusheva K, Korn R, Cash-Mason T, Maxwell JW, Hatcher NG, Haugabook SJ, Wu G, Howell BJ, Renger JJ, Shughrue PJ, McCampbell A. A sensitive aβ oligomer assay discriminates Alzheimer's and aged control cerebrospinal fluid. J Neurosci. 2014; 34:2884–2897. PMID: 24553930.

38. Lame ME, Chambers EE, Blatnik M. Quantitation of amyloid beta peptides Aβ(1-38), Aβ(1-40), and Aβ(1-42) in human cerebrospinal fluid by ultra-performance liquid chromatography-tandem mass spectrometry. Anal Biochem. 2011; 419:133–139. PMID: 21888888.

39. Shibata M, Yamada S, Kumar SR, Calero M, Bading J, Frangione B, Holtzman DM, Miller CA, Strickland DK, Ghiso J, Zlokovic BV. Clearance of Alzheimer's amyloid-ss(1-40) peptide from brain by LDL receptor-related protein-1 at the blood-brain barrier. J Clin Invest. 2000; 106:1489–1499. PMID: 11120756.

40. Deane R, Du Yan S, Submamaryan RK, LaRue B, Jovanovic S, Hogg E, Welch D, Manness L, Lin C, Yu J, Zhu H, Ghiso J, Frangione B, Stern A, Schmidt AM, Armstrong DL, Arnold B, Liliensiek B, Nawroth P, Hofman F, Kindy M, Stern D, Zlokovic B. RAGE mediates amyloid-beta peptide transport across the blood-brain barrier and accumulation in brain. Nat Med. 2003; 9:907–913. PMID: 12808450.

41. Srikanth V, Maczurek A, Phan T, Steele M, Westcott B, Juskiw D, Münch G. Advanced glycation endproducts and their receptor RAGE in Alzheimer's disease. Neurobiol Aging. 2011; 32:763–777. PMID: 19464758.

42. Galasko D, Bell J, Mancuso JY, Kupiec JW, Sabbagh MN, van Dyck C, Thomas RG, Aisen PS; Alzheimer's Disease Cooperative Study. Clinical trial of an inhibitor of RAGE-Aβ interactions in Alzheimer disease. Neurology. 2014; 82:1536–1542. PMID: 24696507.

43. Miners JS, Barua N, Kehoe PG, Gill S, Love S. Aβ-degrading enzymes: potential for treatment of Alzheimer disease. J Neuropathol Exp Neurol. 2011; 70:944–959. PMID: 22002425.

44. Nalivaeva NN, Beckett C, Belyaev ND, Turner AJ. Are amyloid-degrading enzymes viable therapeutic targets in Alzheimer's disease? J Neurochem. 2012; 120(Suppl 1):167–185. PMID: 22122230.

45. Orgogozo JM, Gilman S, Dartigues JF, Laurent B, Puel M, Kirby LC, Jouanny P, Dubois B, Eisner L, Flitman S, Michel BF, Boada M, Frank A, Hock C. Subacute meningoencephalitis in a subset of patients with AD after Abeta42 immunization. Neurology. 2003; 61:46–54. PMID: 12847155.

46. Winblad B, Andreasen N, Minthon L, Floesser A, Imbert G, Dumortier T, Maguire RP, Blennow K, Lundmark J, Staufenbiel M, Orgogozo JM, Graf A. Safety, tolerability, and antibody response of active Aβ immunotherapy with CAD106 in patients with Alzheimer's disease: randomised, double-blind, placebo-controlled, first-in-human study. Lancet Neurol. 2012; 11:597–604. PMID: 22677258.

47. Salloway S, Sperling R, Gilman S, Fox NC, Blennow K, Raskind M, Sabbagh M, Honig LS, Doody R, van Dyck CH, Mulnard R, Barakos J, Gregg KM, Liu E, Lieberburg I, Schenk D, Black R, Grundman M; Bapineuzumab 201 Clinical Trial Investigators. A phase 2 multiple ascending dose trial of bapineuzumab in mild to moderate Alzheimer disease. Neurology. 2009; 73:2061–2070. PMID: 19923550.

48. Blennow K, Zetterberg H, Rinne JO, Salloway S, Wei J, Black R, Grundman M, Liu E; AAB-001 201/202 Investigators. Effect of immunotherapy with bapineuzumab on cerebrospinal fluid biomarker levels in patients with mild to moderate Alzheimer disease. Arch Neurol. 2012; 69:1002–1010. PMID: 22473769.

49. Rinne JO, Brooks DJ, Rossor MN, Fox NC, Bullock R, Klunk WE, Mathis CA, Blennow K, Barakos J, Okello AA, Rodriguez Martinez de Liano S, Liu E, Koller M, Gregg KM, Schenk D, Black R, Grundman M. 11C-PiB PET assessment of change in fibrillar amyloid-beta load in patients with Alzheimer's disease treated with bapineuzumab: a phase 2, double-blind, placebo-controlled, ascending-dose study. Lancet Neurol. 2010; 9:363–372. PMID: 20189881.

50. Salloway S, Sperling R, Fox NC, Blennow K, Klunk W, Raskind M, Sabbagh M, Honig LS, Porsteinsson AP, Ferris S, Reichert M, Ketter N, Nejadnik B, Guenzler V, Miloslavsky M, Wang D, Lu Y, Lull J, Tudor IC, Liu E, Grundman M, Yuen E, Black R, Brashear HR; Bapineuzumab 301 and 302 Clinical Trial Investigators. Two phase 3 trials of bapineuzumab in mild-to-moderate Alzheimer's disease. N Engl J Med. 2014; 370:322–333. PMID: 24450891.

51. Farlow M, Arnold SE, van Dyck CH, Aisen PS, Snider BJ, Porsteinsson AP, Friedrich S, Dean RA, Gonzales C, Sethuraman G, DeMattos RB, Mohs R, Paul SM, Siemers ER. Safety and biomarker effects of solanezumab in patients with Alzheimer's disease. Alzheimers Dement. 2012; 8:261–271. PMID: 22672770.

52. Doody RS, Thomas RG, Farlow M, Iwatsubo T, Vellas B, Joffe S, Kieburtz K, Raman R, Sun X, Aisen PS, Siemers E, Liu-Seifert H, Mohs R; Alzheimer's Disease Cooperative Study Steering Committee; Solanezumab Study Group. Phase 3 trials of solanezumab for mild-to-moderate Alzheimer's disease. N Engl J Med. 2014; 370:311–321. PMID: 24450890.

53. Bateman RJ, Xiong C, Benzinger TL, Fagan AM, Goate A, Fox NC, Marcus DS, Cairns NJ, Xie X, Blazey TM, Holtzman DM, Santacruz A, Buckles V, Oliver A, Moulder K, Aisen PS, Ghetti B, Klunk WE, McDade E, Martins RN, Masters CL, Mayeux R, Ringman JM, Rossor MN, Schofield PR, Sperling RA, Salloway S, Morris JC; Dominantly Inherited Alzheimer Network. Clinical and biomarker changes in dominantly inherited Alzheimer's disease. N Engl J Med. 2012; 367:795–804. PMID: 22784036.

54. Worley S. After disappointments, Alzheimer's researchers seek out new paths: biomarkers and combination therapies may lead to disease-modifying treatments, experts say. P T. 2014; 39:365–374. PMID: 24883009.

55. National Institute on Aging. Preventing Alzheimer's disease; What do we know? http://www.nia.nih.gov/alzheimers/publication/preventing-alzheimers-disease/introduction.

56. Dodel RC, Du Y, Depboylu C, Hampel H, Frölich L, Haag A, Hemmeter U, Paulsen S, Teipel SJ, Brettschneider S, Spottke A, Nölker C, Möller HJ, Wei X, Farlow M, Sommer N, Oertel WH. Intravenous immunoglobulins containing antibodies against beta-amyloid for the treatment of Alzheimer's disease. J Neurol Neurosurg Psychiatry. 2004; 75:1472–1474. PMID: 15377700.

57. Fillit H, Hess G, Hill J, Bonnet P, Toso C. IV immunoglobulin is associated with a reduced risk of Alzheimer disease and related disorders. Neurology. 2009; 73:180–185. PMID: 19620605.

58. Relkin NR, Szabo P, Adamiak B, Burgut T, Monthe C, Lent RW, Younkin S, Younkin L, Schiff R, Weksler ME. 18-Month study of intravenous immunoglobulin for treatment of mild Alzheimer disease. Neurobiol Aging. 2009; 30:1728–1736. PMID: 18294736.

59. Dodel R, Rominger A, Bartenstein P, Barkhof F, Blennow K, Förster S, Winter Y, Bach JP, Popp J, Alferink J, Wiltfang J, Buerger K, Otto M, Antuono P, Jacoby M, Richter R, Stevens J, Melamed I, Goldstein J, Haag S, Wietek S, Farlow M, Jessen F. Intravenous immunoglobulin for treatment of mild-to-moderate Alzheimer's disease: a phase 2, randomised, double-blind, placebo-controlled, dose-finding trial. Lancet Neurol. 2013; 12:233–243. PMID: 23375965.

60. Weill Cornell Medical College. Updated results from phase 3 trial of IVIG for Alzheimer's disease. http://www.sciencedaily.com/releases/2013l07/130716092743.htm.

61. Knight EM, Gandy S. Immunomodulation and AD--down but not out. J Clin Immunol. 2014; 34(Suppl 1):S70–S73. PMID: 24781637.

62. Lee VM, Brunden KR, Hutton M, Trojanowski JQ. Developing therapeutic approaches to tau, selected kinases, and related neuronal protein targets. Cold Spring Harb Perspect Med. 2011; 1:a006437. PMID: 22229117.

63. Hanger DP, Anderton BH, Noble W. Tau phosphorylation: the therapeutic challenge for neurodegenerative disease. Trends Mol Med. 2009; 15:112–119. PMID: 19246243.

64. Jin N, Kovács AD, Sui Z, Dewhurst S, Maggirwar SB. Opposite effects of lithium and valproic acid on trophic factor deprivation-induced glycogen synthase kinase-3 activation, c-Jun expression and neuronal cell death. Neuropharmacology. 2005; 48:576–583. PMID: 15755485.

65. Profenno LA, Jakimovich L, Holt CJ, Porsteinsson A, Tariot PN. A randomized, double-blind, placebo-controlled pilot trial of safety and tolerability of two doses of divalproex sodium in outpatients with probable Alzheimer's disease. Curr Alzheimer Res. 2005; 2:553–558. PMID: 16375658.

66. Hampel H, Ewers M, Bürger K, Annas P, Mörtberg A, Bogstedt A, Frölich L, Schröder J, Schönknecht P, Riepe MW, Kraft I, Gasser T, Leyhe T, Möller HJ, Kurz A, Basun H. Lithium trial in Alzheimer's disease: a randomized, single-blind, placebocontrolled, multicenter 10-week study. J Clin Psychiatry. 2009; 70:922–931. PMID: 19573486.

67. Forlenza OV, Diniz BS, Radanovic M, Santos FS, Talib LL, Gattaz WF. Disease-modifying properties of long-term lithium treatment for amnestic mild cognitive impairment: randomised controlled trial. Br J Psychiatry. 2011; 198:351–356. PMID: 21525519.

68. Serenó L, Coma M, Rodríguez M, Sánchez-Ferrer P, Sánchez MB, Gich I, Agulló JM, Pérez M, Avila J, Guardia-Laguarta C, Clarimón J, Lleó A, Gómez-Isla T. A novel GSK-3beta inhibitor reduces Alzheimer's pathology and rescues neuronal loss in vivo. Neurobiol Dis. 2009; 35:359–367. PMID: 19523516.

69. del Ser T, Steinwachs KC, Gertz HJ, Andrés MV, Gómez-Carrillo B, Medina M, Vericat JA, Redondo P, Fleet D, León T. Treatment of Alzheimer's disease with the GSK-3 inhibitor tideglusib: a pilot study. J Alzheimers Dis. 2013; 33:205–215. PMID: 22936007.

70. Wischik CM, Bentham P, Wischik DJ, Seng KM. Tau aggregation inhibitor (TAI) therapy with remberTM arrests disease progression in mild and moderate Alzheimer's disease over 50 weeks. Alzheimers Dement. 2008; 4(Suppl 2):T167.

71. Schmechelemail DE, Gerard G, Vatakis NG, Harper L, Ross JS, Bari M, Walling D, Stedman M, Winston JL, Morimoto B, Keith JR. A phase 2, double-blind, placebo-controlled study to evaluate the safety, tolerability, and effect on cognitive function of AL-108 after 12 weeks of intranasal administration in subjects with mild cognitive impairment. Alzheimer's Dement. 2008; 4(4 Suppl 2):T483.

72. Kang JH, Korecka M, Toledo JB, Trojanowski JQ, Shaw LM. Clinical utility and analytical challenges in measurement of cerebrospinal fluid amyloid-β(1-42) and τ proteins as Alzheimer disease biomarkers. Clin Chem. 2013; 59:903–916. PMID: 23519967.

73. 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; Alzheimer's Disease Neuroimaging Initiative. Qualification of the analytical and clinical performance of CSF biomarker analyses in ADNI. Acta Neuropathol. 2011; 121:597–609. PMID: 21311900.

74. 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, Shen L, Siuciak JA, Soares H, Toga AW, Trojanowski JQ; Alzheimer's Disease Neuroimaging Initiative. The Alzheimer's Disease Neuroimaging Initiative: a review of papers published since its inception. Alzheimer's Dement. 2013; 9:e111–e194. PMID: 23932184.

75. Cui Y, Liu B, Luo S, Zhen X, Fan M, Liu T, Zhu W, Park M, Jiang T, Jin JS; Alzheimer's Disease Neuroimaging Initiative. Identification of conversion from mild cognitive impairment to Alzheimer's disease using multivariate predictors. PLoS One. 2011; 6:e21896. PMID: 21814561.

76. Hinrichs C, Singh V, Xu G, Johnson SC; Alzheimers Disease Neuroimaging Initiative. Predictive markers for AD in a multi-modality framework: an analysis of MCI progression in the ADNI population. Neuroimage. 2011; 55:574–589. PMID: 21146621.

77. Zhang D, Shen D; Alzheimer's Disease Neuroimaging Initiative. Predicting future clinical changes of MCI patients using longitudinal and multimodal biomarkers. PLoS One. 2012; 7:e33182. PMID: 22457741.

78. Lista S, Garaci FG, Ewers M, Teipel S, Zetterberg H, Blennow K, Hampel H. CSF Aβ1-42 combined with neuroimaging biomarkers in the early detection, diagnosis and prediction of Alzheimer's disease. Alzheimers Dement. 2014; 10:381–392. PMID: 23850330.

79. Mattsson N, Zetterberg H. What is a certified reference material? Biomark Med. 2012; 6:369–370. PMID: 22917138.

80. Mattsson N, Andreasson U, Persson S, Carrillo MC, Collins S, Chalbot S, Cutler N, Dufour-Rainfray D, Fagan AM, Heegaard NH, Robin Hsiung GY, Hyman B, Iqbal K, Lachno DR, Lleó A, Lewczuk P, Molinuevo JL, Parchi P, Regeniter A, Rissman R, Rosenmann H, Sancesario G, Schröder J, Shaw LM, Teunissen CE, Trojanowski JQ, Vanderstichele H, Vandijck M, Verbeek MM, Zetterberg H, Blennow K, Käser SA; Alzheimer's Association QC Program Work Group. CSF biomarker variability in the Alzheimer's Association quality control program. Alzheimers Dement. 2013; 9:251–261. PMID: 23622690.

81. Jack CR Jr, Knopman DS, Jagust WJ, Shaw LM, Aisen PS, Weiner MW, Petersen RC, Trojanowski JQ. Hypothetical model of dynamic biomarkers of the Alzheimer's pathological cascade. Lancet Neurol. 2010; 9:119–128. PMID: 20083042.

82. Fox NC, Black RS, Gilman S, Rossor MN, Griffith SG, Jenkins L, Koller M; AN1792(QS-21)-201 Study. QS-21)-201 Study. Effects of Abeta immunization (AN1792) on MRI measures of cerebral volume in Alzheimer disease. Neurology. 2005; 64:1563–1572. PMID: 15883317.

83. Holmes C, Boche D, Wilkinson D, Yadegarfar G, Hopkins V, Bayer A, Jones RW, Bullock R, Love S, Neal JW, Zotova E, Nicoll JA. Long-term effects of Abeta42 immunisation in Alzheimer's disease: follow-up of a randomised, placebocontrolled phase I trial. Lancet. 2008; 372:216–223. PMID: 18640458.

84. Vellas B, Black R, Thal LJ, Fox NC, Daniels M, McLennan G, Tompkins C, Leibman C, Pomfret M, Grundman M; AN1792 (QS-21)-251 Study Team. Long-term follow-up of patients immunized with AN1792: reduced functional decline in antibody responders. Curr Alzheimer Res. 2009; 6:144–151. PMID: 19355849.

85. Ereshefsky L, Jhee SS, Yen M, Moran SV. The role for CSF dynabridging studies in developing new therapies for Alzheimer's disease. Alzheimers Dement. 2009; 5(Suppl 4):P414–P415.

86. Jicha GA, Parisi JE, Dickson DW, Johnson K, Cha R, Ivnik RJ, Tangalos EG, Boeve BF, Knopman DS, Braak H, Petersen RC. Neuropathologic outcome of mild cognitive impairment following progression to clinical dementia. Arch Neurol. 2006; 63:674–681. PMID: 16682537.

87. Okonkwo OC, Mielke MM, Griffith HR, Moghekar AR, O'Brien RJ, Shaw LM, Trojanowski JQ, Albert MS; Alzheimer's Disease Neuroimaging Initiative. Cerebrospinal fluid profiles and prospective course and outcome in patients with amnestic mild cognitive impairment. Arch Neurol. 2011; 68:113–119. PMID: 21220682.

88. van Rossum IA, Vos S, Handels R, Visser PJ. Biomarkers as predictors for conversion from mild cognitive impairment to Alzheimer-type dementia: implications for trial design. J Alzheimer's Dis. 2010; 20:881–891. PMID: 20413876.

89. Holland D, McEvoy LK, Desikan RS, Dale AM; Alzheimer's Disease Neuroimaging Initiative. Enrichment and stratification for predementia Alzheimer disease clinical trials. PLoS One. 2012; 7:e47739. PMID: 23082203.

90. Mattsson N, Zetterberg H, Hansson O, Andreasen N, Parnetti L, Jonsson M, Herukka SK, van der Flier WM, Blankenstein MA, Ewers M, Rich K, Kaiser E, Verbeek M, Tsolaki M, Mulugeta E, Rosén E, Aarsland D, Visser PJ, Schröder J, Marcusson J, de Leon M, Hampel H, Scheltens P, Pirttilä T, Wallin A, Jönhagen ME, Minthon L, Winblad B, Blennow K. CSF biomarkers and incipient Alzheimer disease in patients with mild cognitive impairment. JAMA. 2009; 302:385–393. PMID: 19622817.