Skip to main content
SpringerLink
Log in

Use of Biomarkers in Clinical Trials of Alzheimer Disease

From Concept to Application

  • Current Opinion
  • Published:
Molecular Diagnosis & Therapy Aims and scope Submit manuscript

Abstract

Research progress during the last decades has resulted in an unprecedented accumulation of knowledge regarding the molecular pathogenesis of Alzheimer disease (AD). These important achievements toward clarifying the mechanistic processes underlying AD are being translated into ongoing development of biomarkers and their use in clinical trials.

AD biomarkers are biochemical and anatomical variables (e.g. cerebrospinal fluid, positron emission tomography, and structural MRI) that measure AD-related pathologic features (i.e. amyloid deposition and neurodegeneration) in vivo. Biomarkers are utilized as ‘diagnostic biomarkers’ and/or ‘endpoint biomarkers’ in symptomatic or disease-modifying clinical trials. Diagnostic biomarkers play an important role in population enrichment by refining selection criteria, stratifying populations, and increasing the statistical power of trials. Endpoint biomarkers may be used as outcome measures to monitor the rate of disease progression and detect treatment effects.

AD biomarkers do not reach abnormal levels or peak simultaneously, but do so in a time-dependent order. The choice of biomarkers for a clinical trial must take into consideration the type of therapeutic intervention, the clinical stage of AD, and the time dependence of biomarker changes during disease progression. The combination of amyloid and neurodegeneration biomarkers is highly desirable since they capture different aspects of the disease. Clinical trials for every clinical stage of AD would benefit from quantification and standardization of biomarkers. However, this is still a work in progress.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Table I
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Table II

Similar content being viewed by others

References

  1. Hebert LE, Scherr PA, Bienias JL, et al. Alzheimer disease in the US population: prevalence estimates using the 2000 census. Arch Neurol 2003 Aug; 60(8): 1119–22

    Article  PubMed  Google Scholar 

  2. Masters CL, Simms G, Weinman NA, et al. Amyloid plaque core protein in Alzheimer disease and Down syndrome. Proc Natl Acad Sci U S A 1985 Jun; 82(12): 4245–9

    Article  PubMed  CAS  Google Scholar 

  3. Hardy JA, Higgins GA. Alzheimer's disease: the amyloid cascade hypothesis. Science 1992 Apr 10; 256(5054): 184–5

    Article  PubMed  CAS  Google Scholar 

  4. Thal LJ, Kantarci K, Reiman EM, et al. The role of biomarkers in clinical trials for Alzheimer disease. Alzheimer Dis Assoc Disord 2006 Jan–Mar; 20(1): 6–15

    Article  PubMed  Google Scholar 

  5. Dubois B, Feldman HH, Jacova C, et al. Research criteria for the diagnosis of Alzheimer's disease: revising the NINCDS-ADRDA criteria. Lancet Neurol 2007 Aug; 6(8): 734–46

    Article  PubMed  Google Scholar 

  6. Dickerson BC, Sperling RA. Neuroimaging biomarkers for clinical trials of disease-modifying therapies in Alzheimer's disease. NeuroRx 2005 Apr; 2(2): 348–60

    Article  PubMed  Google Scholar 

  7. Price DL, Sisodia SS. Cellular and molecular biology of Alzheimer's disease and animal models. Annu Rev Med 1994; 45: 435–46

    Article  PubMed  CAS  Google Scholar 

  8. Mangialasche F, Solomon A, Winblad B, et al. Alzheimer's disease: clinical trials and drug development. Lancet Neurol 2010 Jul; 9(7): 702–16

    Article  PubMed  CAS  Google Scholar 

  9. Hardy J, Selkoe DJ. The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science 2002 Jul 19; 297(5580): 353–6

    Article  PubMed  CAS  Google Scholar 

  10. Mathis CA, Lopresti BJ, Klunk WE. Impact of amyloid imaging on drug development in Alzheimer's disease. Nuclear Med Biol 2007 Oct; 34(7): 809–22

    Article  CAS  Google Scholar 

  11. Iwatsubo T, Odaka A, Suzuki N, et al. Visualization of A beta 42(43) and A beta 40 in senile plaques with end-specific A beta monoclonals: evidence that an initially deposited species is A beta 42(43). Neuron 1994 Jul; 13(1): 45–53

    Article  PubMed  CAS  Google Scholar 

  12. Hardy J. Has the amyloid cascade hypothesis for Alzheimer's disease been proved? Curr Alzheimer Res 2006 Feb; 3(1): 71–3

    Article  PubMed  CAS  Google Scholar 

  13. Hardy J, Duff K, Hardy KG, et al. Genetic dissection of Alzheimer's disease and related dementias: amyloid and its relationship to tau. Nature Neurosci 1998 Sep; 1(5): 355–8

    Article  PubMed  CAS  Google Scholar 

  14. Feigin A. Evidence from biomarkers and surrogate endpoints. NeuroRx 2004 Jul; 1(3): 323–30

    Article  PubMed  Google Scholar 

  15. Jack Jr CR, Knopman DS, Jagust WJ, et al. Hypothetical model of dynamic biomarkers of the Alzheimer's pathological cascade. Lancet Neurol 2010 Jan; 9(1): 119–28

    Article  PubMed  CAS  Google Scholar 

  16. Hampel H, Shen Y, Walsh DM, et al. Biological markers of amyloid beta-related mechanisms in Alzheimer's disease. Exper Neurol 2010 Jun; 223(2): 334–46

    Article  CAS  Google Scholar 

  17. Strozyk D, Blennow K, White LR, et al. CSF Abeta 42 levels correlate with amyloid-neuropathology in a population-based autopsy study. Neurology 2003 Feb 25; 60(4): 652–6

    Article  PubMed  CAS  Google Scholar 

  18. Lopresti BJ, Klunk WE, Mathis CA, et al. Simplified quantification of Pittsburgh Compound B amyloid imaging PET studies: a comparative analysis. J Nucl Med 2005 Dec; 46(12): 1959–72

    PubMed  CAS  Google Scholar 

  19. Jack Jr CR, Lowe VJ, Senjem ML, et al. 1 1C PiB and structural MRI provide complementary information in imaging of Alzheimer's disease and amnestic mild cognitive impairment. Brain 2008 Mar; 131 (Pt 3): 665–80

    Article  PubMed  Google Scholar 

  20. Wong DF, Rosenberg PB, Zhou Y, et al. In vivo imaging of amyloid deposition in Alzheimer disease using the radioligand 18F-AV-45 (florbetapir [corrected] F 18). J Nucl Med 2010 Jun; 51(6): 913–20

    Article  PubMed  CAS  Google Scholar 

  21. Clark CM, Schneider JA, Bedell BJ, et al. Use of florbetapir-PET for imaging beta-amyloid pathology. JAMA 2011 Jan 19; 305(3): 275–83

    Article  PubMed  CAS  Google Scholar 

  22. Barthel H, Gertz HJ, Dresel S, et al. Cerebral amyloid-beta PET with florbetaben ((1)F) in patients with Alzheimer's disease and healthy controls: a multicentre phase 2 diagnostic study. Lancet Neurol 2011 May; 10(5): 424–35

    Article  PubMed  CAS  Google Scholar 

  23. Vandenberghe R, Van Laere K, Ivanoiu A, et al. 18F-flutemetamol amyloid imaging in Alzheimer disease and mild cognitive impairment: a phase 2 trial. Ann Neurol 2010 Sep; 68(3): 319–29

    Article  PubMed  Google Scholar 

  24. Buerger K, Ewers M, Pirttila T, et al. CSF phosphorylated tau protein correlates with neocortical neurofibrillary pathology in Alzheimer's disease. Brain 2006 Nov; 129 (Pt 11): 3035–41

    Article  PubMed  Google Scholar 

  25. Blennow K, Zetterberg H. Cerebrospinal fluid biomarkers for Alzheimer's disease. J Alzheimers Dis 2009; 18(2): 413–7

    PubMed  CAS  Google Scholar 

  26. Jagust W, Reed B, Mungas D, et al. What does fluorodeoxyglucose PET imaging add to a clinical diagnosis of dementia? Neurology 2007 Aug 28; 69(9): 871–7

    Article  PubMed  CAS  Google Scholar 

  27. Landau SM, Harvey D, Madison CM, et al. Comparing predictors of conversion and decline in mild cognitive impairment. Neurology 2010 Jul 20; 75(3): 230–8

    Article  PubMed  Google Scholar 

  28. Jack Jr CR, Wiste HJ, Vemuri P, et al. Brain beta-amyloid measures and magnetic resonance imaging atrophy both predict time-to-progression from mild cognitive impairment to Alzheimer's disease. Brain 2010 Nov; 133(11): 3336–48

    Article  PubMed  Google Scholar 

  29. Barnes J, Bartlett JW, van de Pol LA, et al. A meta-analysis of hippocampal atrophy rates in Alzheimer's disease. Neurobiol Aging 2009 Nov; 30(11): 1711–23

    Article  PubMed  Google Scholar 

  30. Stoub TR, Rogalski EJ, Leurgans S, et al. Rate of entorhinal and hippocampal atrophy in incipient and mild AD: relation to memory function. Neurobiol Aging 2010 Jul; 31(7): 1089–98

    Article  PubMed  CAS  Google Scholar 

  31. Sluimer JD, van der Flier WM, Karas GB, et al. Whole-brain atrophy rate and cognitive decline: longitudinal MR study of memory clinic patients. Radiology 2008 Aug; 248(2): 590–8

    Article  PubMed  Google Scholar 

  32. Habert MO, Horn JF, Sarazin M, et al. Brain perfusion SPECT with an automated quantitative tool can identify prodromal Alzheimer's disease among patients with mild cognitive impairment. Neurobiol Aging 2011 Jan; 32(1): 15–23

    Article  PubMed  Google Scholar 

  33. Chao LL, Buckley ST, Kornak J, et al. ASL perfusion MRI predicts cognitive decline and conversion from MCI to dementia. Alzheimer Dis Assoc Disord 2010 Jan–Mar; 24(1): 19–27

    Article  PubMed  Google Scholar 

  34. Dickerson BC, Salat DH, Greve DN, et al. Increased hippocampal activation in mild cognitive impairment compared to normal aging and AD. Neurology 2005 Aug 9; 65(3): 404–11

    Article  PubMed  CAS  Google Scholar 

  35. Greicius MD, Srivastava G, Reiss AL, et al. Default-mode network activity distinguishes Alzheimer's disease from healthy aging: evidence from functional MRI. Proc Natl Acad Sci U S A 2004 Mar 30; 101(13): 4637–42

    Article  PubMed  CAS  Google Scholar 

  36. Lorenzi M, Beltramello A, Mercuri NB, et al. Effect of memantine on resting state default mode network activity in Alzheimer's disease. Drugs Aging 2011 Mar 1; 28(3): 205–17

    Article  PubMed  CAS  Google Scholar 

  37. Kantarci K, Jack Jr CR, Xu YC, et al. Regional metabolic patterns in mild cognitive impairment and Alzheimer's disease: a 1H MRS study. Neurology 2000 Jul 25; 55(2): 210–7

    Article  PubMed  CAS  Google Scholar 

  38. Salat DH, Tuch DS, van der Kouwe AJ, et al. White matter pathology isolates the hippocampal formation in Alzheimer's disease. Neurobiol Aging 2010 Feb; 31(2): 244–56

    Article  PubMed  CAS  Google Scholar 

  39. Swardfager W, Lanctot K, Rothenburg L, et al. A meta-analysis of cytokines in Alzheimer's disease. Biol Psychiatry 2010 Nov 15; 68(10): 930–41

    Article  PubMed  CAS  Google Scholar 

  40. Yokokura M, Mori N, Yagi S, et al. In vivo changes in microglial activation and amyloid deposits in brain regions with hypometabolism in Alzheimer's disease. Eur J Nuclear Med Mol Imag 2011 Feb; 38(2): 343–51

    Article  CAS  Google Scholar 

  41. Okello A, Edison P, Archer HA, et al. Microglial activation and amyloid deposition in mild cognitive impairment: a PET study. Neurology 2009 Jan 6; 72(1): 56–62

    Article  PubMed  CAS  Google Scholar 

  42. Ringman JM, Younkin SG, Pratico D, et al. Biochemical markers in persons with preclinical familial Alzheimer disease. Neurology 2008 Jul 8; 71(2): 85–92

    Article  PubMed  CAS  Google Scholar 

  43. Herholz K, Weisenbach S, Zundorf G, et al. In vivo study of acetylcholine esterase in basal forebrain, amygdala, and cortex in mild to moderate Alzheimer disease. NeuroImage 2004 Jan; 21(1): 136–43

    Article  PubMed  CAS  Google Scholar 

  44. Albert MS, DeKosky ST, Dickson D, et al. The diagnosis of mild cognitive impairment due to Alzheimer's disease: recommendations from the National Institute on Aging and Alzheimer's Association Workgroup. Alzheimer's Dementia 2011 May; 7(3): 270–9

    Article  PubMed  Google Scholar 

  45. Nordberg A. Amyloid imaging in Alzheimer's disease. Neuropsychologia 2008; 46(6): 1636–41

    Article  PubMed  Google Scholar 

  46. Nordberg A. Molecular imaging markers in clinical trials in Alzheimer s disease. J Nutr Health Aging 2009 Apr; 13(4): 346–7

    Article  PubMed  CAS  Google Scholar 

  47. Forsberg A, Almkvist O, Engler H, et al. High PIB retention in Alzheimer's disease is an early event with complex relationship with CSF biomarkers and functional parameters. Curr Alzheimer Res 2010 Feb; 7(1): 56–66

    Article  PubMed  CAS  Google Scholar 

  48. Forsberg A, Engler H, Almkvist O, et al. PET imaging of amyloid deposition in patients with mild cognitive impairment. Neurobiol Aging 2008 Oct; 29(10): 1456–65

    Article  PubMed  CAS  Google Scholar 

  49. Morris JC, Roe CM, Grant EA, et al. Pittsburgh Compound B imaging and prediction of progression from cognitive normality to symptomatic Alzheimer disease. Arch Neurol 2009 Dec; 66(12): 1469–75

    Article  PubMed  Google Scholar 

  50. Choi SR, Golding G, Zhuang Z, et al. Preclinical properties of 18F-AV-45: a PET agent for Abeta plaques in the brain. J Nucl Med 2009 Nov; 50(11): 1887–94

    Article  PubMed  CAS  Google Scholar 

  51. Vemuri P, Wiste HJ, Weigand SD, et al. MRI and CSF biomarkers in normal, MCI, and AD subjects: diagnostic discrimination and cognitive correlations. Neurology 2009 Jul 28; 73(4): 287–93

    Article  PubMed  CAS  Google Scholar 

  52. Schoonenboom NS, van der Flier WM, Blankenstein MA, et al. CSF and MRI markers independently contribute to the diagnosis of Alzheimer's disease. Neurobiol Aging 2008 May; 29(5): 669–75

    Article  PubMed  CAS  Google Scholar 

  53. Clark CM, Xie S, Chittams J, et al. Cerebrospinal fluid tau and beta-amyloid: how well do these biomarkers reflect autopsy-confirmed dementia diagnoses? Arch Neurol 2003 Dec; 60(12): 1696–702

    Article  PubMed  Google Scholar 

  54. Fagan AM, Mintun MA, Mach RH, et al. Inverse relation between in vivo amyloid imaging load and cerebrospinal fluid Abeta42 in humans. Ann Neurol 2006 Mar; 59(3): 512–9

    Article  PubMed  CAS  Google Scholar 

  55. Fagan AM, Shaw LM, Xiong C, et al. Comparison of analytical platforms for cerebrospinal fluid measures of ta-amyloid 1-42, total tau, and p-tau181 for identifying Alzheimer disease amyloid plaque pathology. Arch Neurol 2011 Sep;68(9): 1137–44

    Article  PubMed  Google Scholar 

  56. Jagust WJ, Landau SM, Shaw LM, et al. Relationships between biomarkers in aging and dementia. Neurology 2009 Oct 13; 73(15): 1193–9

    Article  PubMed  CAS  Google Scholar 

  57. Weigand SD, Vemuri P, Wiste HJ, et al. Transforming cerebrospinal fluid Abeta42 measures into calculated Pittsburgh Compound B units of brain Abeta amyloid. Alzheimers Dement 2011 Mar; 7(2): 133–41

    Article  PubMed  CAS  Google Scholar 

  58. Bennett DA, Schneider JA, Wilson RS, et al. Neurofibrillary tangles mediate the association of amyloid load with clinical Alzheimer disease and level of cognitive function. Arch Neurol 2004 Mar; 61(3): 378–84

    Article  PubMed  Google Scholar 

  59. Savva GM, Wharton SB, Ince PG, et al. Age, neuropathology, and dementia. N Engl J Med 2009 May 28; 360(22): 2302–9

    Article  PubMed  CAS  Google Scholar 

  60. Blennow K, Hampel H. CSF markers for incipient Alzheimer's disease. Lancet Neurol 2003 Oct; 2(10): 605–13

    Article  PubMed  CAS  Google Scholar 

  61. Mattsson N, Blennow K, Zetterberg H. CSF biomarkers: pinpointing Alzheimer pathogenesis. Ann N Y Acad Sci 2009 Oct; 1180: 28–35

    Article  PubMed  CAS  Google Scholar 

  62. Hampel H, Burger K, Teipel SJ, et al. Core candidate neurochemical and imaging biomarkers of Alzheimer's disease. Alzheimers Dement 2008 Jan; 4(1): 38–48

    Article  PubMed  CAS  Google Scholar 

  63. Herholz K, Carter SF, Jones M. Positron emission tomography imaging in dementia. Br J Radiol 2007 Dec; 80(2): S160–7

    Article  PubMed  Google Scholar 

  64. Minoshima S, Giordani B, Berent S, et al. Metabolic reduction in the posterior cingulate cortex in very early Alzheimer's disease. Ann Neurol 1997 Jul; 42(1): 85–94

    Article  PubMed  CAS  Google Scholar 

  65. Hampel H, Wilcock G, Andrieu S, et al. Biomarkers for Alzheimer's disease therapeutic trials. Prog Neurobiol 2011 Dec; 95(4): 579–93

    Article  PubMed  CAS  Google Scholar 

  66. Killiany RJ, Moss MB, Albert MS, et al. Temporal lobe regions on magnetic resonance imaging identify patients with early Alzheimer's disease. Arch Neurol 1993 Sep; 50(9): 949–54

    Article  PubMed  CAS  Google Scholar 

  67. Vemuri P, Wiste HJ, Weigand SD, et al. Serial MRI and CSF biomarkers in normal aging, MCI, and AD. Neurology 2010 Jul 13; 75(2): 143–51

    Article  PubMed  Google Scholar 

  68. Jack Jr CR, Lowe VJ, Weigand SD, et al. Serial PIB and MRI in normal, mild cognitive impairment and Alzheimer's disease: implications for sequence of pathological events in Alzheimer's disease. Brain 2009 May; 132 (Pt 5): 1355–65

    Article  PubMed  Google Scholar 

  69. Fox NC, Scahill RI, Crum WR, et al. Correlation between rates of brain atrophy and cognitive decline in AD. Neurology 1999 May 12; 52(8): 1687–9

    Article  PubMed  CAS  Google Scholar 

  70. Whitwell JL, Josephs KA, Murray ME, et al. MRI correlates of neurofibrillary tangle pathology at autopsy: a voxel-based morphometry study. Neurology 2008 Sep 2; 71(10): 743–9

    Article  PubMed  CAS  Google Scholar 

  71. Hua X, Leow AD, Parikshak N, et al. Tensor-based morphometry as a neuroimaging biomarker for Alzheimer's disease: an MRI study of 676 AD, MCI, and normal subjects. NeuroImage 2008 Nov 15; 43(3): 458–69

    Article  PubMed  Google Scholar 

  72. Prince SE, Woo S, Doraiswamy PM, et al. Functional MRI in the early diagnosis of Alzheimer's disease: is it time to refocus? Expert Rev Neurother 2008 Feb; 8(2): 169–75

    Article  PubMed  Google Scholar 

  73. Kadir A, Darreh-Shori T, Almkvist O, et al. PET imaging of the in vivo brain acetylcholinesterase activity and nicotine binding in galantamine-treated patients with AD. Neurobiol Aging 2008 Aug; 29(8): 1204–17

    Article  PubMed  CAS  Google Scholar 

  74. Rabinovici GD, Jagust WJ. Amyloid imaging in aging and dementia: testing the amyloid hypothesis in vivo. Behav Neurol 2009; 21(1): 117–28

    PubMed  CAS  Google Scholar 

  75. Ingelsson M, Fukumoto H, Newell KL, et al. Early Abeta accumulation and progressive synaptic loss, gliosis, and tangle formation in AD brain. Neurology 2004 Mar 23; 62(6): 925–31

    Article  PubMed  CAS  Google Scholar 

  76. Petersen RC, Jack Jr CR. Imaging and biomarkers in early Alzheimer's disease and mild cognitive impairment. Clin Pharmacol Ther 2009 Oct; 86(4): 438–41

    Article  PubMed  CAS  Google Scholar 

  77. Sperling RA, Aisen PS, Beckett LA, et al. Toward defining the preclinical stages of Alzheimer's disease: recommendations from the National Institute on Aging and the Alzheimer's Association Workgroup. Alzheimer Dementia 2011 May; 7(3): 280–92

    Article  Google Scholar 

  78. Sunderland T, Hampel H, Takeda M, et al. Biomarkers in the diagnosis of Alzheimer's disease: are we ready? J Geriatric Psychiatry Neurol 2006 Sep; 19(3): 172–9

    Article  Google Scholar 

  79. Chertkow H, Black S. Imaging biomarkers and their role in dementia clinical trials. Can J Neurol Sci 2007 Mar; 34 Suppl. 1: S77–83

    Google Scholar 

  80. Hampel H, Mitchell A, Blennow K, et al. Core biological marker candidates of Alzheimer's disease — perspectives for diagnosis, prediction of outcome and reflection of biological activity. J Neural Transm 2004 Mar; 111(3): 247–72

    Article  PubMed  CAS  Google Scholar 

  81. Cedazo-Minguez A, Winblad B. Biomarkers for Alzheimer's disease and other forms of dementia: clinical needs, limitations and future aspects. Exper Gerontol 2010 Jan; 45(1): 5–14

    Article  CAS  Google Scholar 

  82. Vellas B, Andrieu S, Sampaio C, et al. Endpoints for trials in Alzheimer's disease: a European task force consensus. Lancet Neurol 2008 May; 7(5): 436–50

    Article  PubMed  CAS  Google Scholar 

  83. Vellas B, Andrieu S, Sampaio C, et al. Disease-modifying trials in Alzheimer's disease: a European task force consensus. Lancet Neurol 2007 Jan; 6(1): 56–62

    Article  PubMed  Google Scholar 

  84. Consensus report of the Working Group on Molecular and Biochemical Markers of Alzheimer's Disease. The Ronald and Nancy Reagan Research Institute of the Alzheimer's Association and the National Institute on Aging Working Group. Neurobiol Aging 1998 Mar–Apr; 19(2): 109–16

    Article  Google Scholar 

  85. Shaw LM, Vanderstichele H, Knapik-Czajka M, et al. Cerebrospinal fluid biomarker signature in Alzheimer's Disease Neuroimaging Initiative subjects. Ann Neurol 2009 Apr; 65(4): 403–13

    Article  PubMed  CAS  Google Scholar 

  86. Cummings JL. Biomarkers in Alzheimer's disease drug development. Alzheimers Dement 2011 May; 7(3): e1 3–44

    Article  CAS  Google Scholar 

  87. Katz R. Biomarkers and surrogate markers: an FDA perspective. NeuroRx 2004 Apr; 1(2): 189–95

    Article  PubMed  Google Scholar 

  88. Coley N, Andrieu S, Delrieu J, et al. Biomarkers in Alzheimer's disease: not yet surrogate endpoints. Ann N Y Acad Sci 2009 Oct; 1180: 119–24

    Article  PubMed  CAS  Google Scholar 

  89. Gauthier S, Scheltens P. Can we do better in developing new drugs for Alzheimer's disease? Alzheimers Dement 2009 Nov; 5(6): 489–91

    Article  PubMed  Google Scholar 

  90. Mintun MA, Larossa GN, Sheline YI, et al. [11C]PIB in a nondemented population: potential antecedent marker of Alzheimer disease. Neurology 2006 Aug 8; 67(3): 446–52

    Article  PubMed  CAS  Google Scholar 

  91. Pike KE, Savage G, Villemagne VL, et al. Beta-amyloid imaging and memory in non-demented individuals: evidence for preclinical Alzheimer's disease. Brain 2007 Nov; 130 (Pt 11): 2837–44

    Article  PubMed  Google Scholar 

  92. Andreasen N, Zetterberg H. Amyloid-related biomarkers for Alzheimer's disease. Curr Med Chem 2008; 15(8): 766–71

    Article  PubMed  CAS  Google Scholar 

  93. Okello A, Koivunen J, Edison P, et al. Conversion of amyloid positive and negative MCI to AD over 3 years: an 11C-PIB PET study. Neurology 2009 Sep 8; 73(10): 754–60

    Article  PubMed  CAS  Google Scholar 

  94. Kemppainen NM, Aalto S, Wilson IA, et al. PET amyloid ligand [11C]PIB uptake is increased in mild cognitive impairment. Neurology 2007 May 8; 68(19): 1603–6

    Article  PubMed  CAS  Google Scholar 

  95. Engler H, Forsberg A, Almkvist O, et al. Two-year follow-up of amyloid deposition in patients with Alzheimer's disease. Brain 2006 Nov; 129 (Pt 11): 2856–66

    Article  PubMed  Google Scholar 

  96. Sunderland T, Linker G, Mirza N, et al. Decreased beta-amyloid 1-42 and increased tau levels in cerebrospinal fluid of patients with Alzheimer disease. JAMA 2003 Apr 23–30; 289(16): 2094–103

    Article  PubMed  Google Scholar 

  97. Mulder C, Verwey NA, van der Flier WM, et al. Amyloid-beta(1–42), total tau, and phosphorylated tau as cerebrospinal fluid biomarkers for the diagnosis of Alzheimer disease. Clin Chem 2010 Feb; 56(2): 248–53

    Article  PubMed  CAS  Google Scholar 

  98. van der Vlies AE, Verwey NA, Bouwman FH, et al. CSF biomarkers in relationship to cognitive profiles in Alzheimer disease. Neurology 2009 Mar 24; 72(12): 1056–61

    Article  CAS  Google Scholar 

  99. Visser PJ, Verhey F, Knol DL, et al. Prevalence and prognostic value of CSF markers of Alzheimer's disease pathology in patients with subjective cognitive impairment or mild cognitive impairment in the DESCRIPA study: a prospective cohort study. Lancet Neurol 2009 Jul; 8(7): 619–27

    Article  PubMed  Google Scholar 

  100. Hansson O, Zetterberg H, Buchhave P, et al. Association between CSF biomarkers and incipient Alzheimer's disease in patients with mild cognitive impairment: a follow-up study. Lancet Neurol 2006 Mar; 5(3): 228–34

    Article  PubMed  CAS  Google Scholar 

  101. Mattsson N, Zetterberg H, Hansson O, et al. CSF biomarkers and incipient Alzheimer disease in patients with mild cognitive impairment. JAMA 2009 Jul 22; 302(4): 385–93

    Article  PubMed  CAS  Google Scholar 

  102. Wallin AK, Blennow K, Zetterberg H, et al. CSF biomarkers predict a more malignant outcome in Alzheimer disease. Neurology 2010 May 11; 74(19): 1531–7

    Article  PubMed  CAS  Google Scholar 

  103. Kester MI, van der Vlies AE, Blankenstein MA, et al. CSF biomarkers predict rate of cognitive decline in Alzheimer disease. Neurology 2009 Oct 27; 73(17): 1353–8

    Article  PubMed  CAS  Google Scholar 

  104. Langbaum JB, Chen K, Lee W, et al. Categorical and correlational analyses of baseline fluorodeoxyglucose positron emission tomography images from the Alzheimer's Disease Neuroimaging Initiative (ADNI). NeuroImage 2009 May 1;45(4): 1107–16

    Article  PubMed  Google Scholar 

  105. Teipel SJ, Drzezga A, Bartenstein P, et al. Effects of donepezil on cortical metabolic response to activation during (18)FDG-PET in Alzheimer's disease: a double-blind cross-over trial. Psychopharmacology 2006 Jul; 187(1): 86–94

    Article  PubMed  CAS  Google Scholar 

  106. Krishnan KR, Charles HC, Doraiswamy PM, et al. Randomized, placebocontrolled trial of the effects of donepezil on neuronal markers and hippocampal volumes in Alzheimer's disease. Am J Psychiatry 2003 Nov; 160(11): 2003–11

    Article  PubMed  Google Scholar 

  107. de Leon MJ, DeSanti S, Zinkowski R, et al. Longitudinal CSF and MRI biomarkers improve the diagnosis of mild cognitive impairment. Neurobiol Aging 2006 Mar; 27(3): 394–401

    Article  PubMed  CAS  Google Scholar 

  108. Braak H, Braak E. Evolution of neuronal changes in the course of Alzheimer's disease. J Neural Transmission 1998; 53: 127–40

    Article  CAS  Google Scholar 

  109. Querbes O, Aubry F, Pariente J, et al. Early diagnosis of Alzheimer's disease using cortical thickness: impact of cognitive reserve. Brain 2009 Aug; 132 (Pt 8): 2036–47

    Article  PubMed  Google Scholar 

  110. Jack Jr CR, Shiung MM, Gunter JL, et al. Comparison of different MRI brain atrophy rate measures with clinical disease progression in AD. Neurology 2004 Feb 24; 62(4): 591–600

    Article  PubMed  Google Scholar 

  111. Jack Jr CR, Shiung MM, Weigand SD, et al. Brain atrophy rates predict subsequent clinical conversion in normal elderly and amnestic MCI. Neurology 2005 Oct 25; 65(8): 1227–31

    Article  PubMed  Google Scholar 

  112. Dubois B, Feldman HH, Jacova C, et al. Revising the definition of Alzheimer's disease: a new lexicon. Lancet Neurol 2010 Nov; 9(11): 1118–27

    Article  PubMed  Google Scholar 

  113. McKhann GM, Knopman DS, Chertkow H, et al. The diagnosis of dementia due to Alzheimer's disease: recommendations from the National Institute on Aging and the Alzheimer's Association Workgroup. Alzheimers Dement 2011 May; 7(3): 263–9

    Article  PubMed  Google Scholar 

  114. Hashimoto M, Kazui H, Matsumoto K, et al. Does donepezil treatment slow the progression of hippocampal atrophy in patients with Alzheimer's disease? Am J Psychiatry 2005 Apr; 162(4): 676–82

    Article  PubMed  Google Scholar 

  115. Wang L, Harms MP, Staggs JM, et al. Donepezil treatment and changes in hippocampal structure in very mild Alzheimer disease. Arch Neurol 2010 Jan; 67(1): 99–106

    Article  PubMed  Google Scholar 

  116. Tateno M, Kobayashi S, Utsumi K, et al. Quantitative analysis of the effects of donepezil on regional cerebral blood flow in Alzheimer's disease by using an automated program, 3DSRT. Neuroradiology 2008 Aug; 50(8): 723–7

    Article  PubMed  Google Scholar 

  117. Cummings JL, Doody R, Clark C. Disease-modifying therapies for Alzheimer disease: challenges to early intervention. Neurology 2007 Oct 16; 69(16): 1622–34

    Article  PubMed  Google Scholar 

  118. Aisen PS. Amyloid-based therapeutics: findings translated into novel treatments. CNS Spectrums 2008 Oct; 13(10 Suppl. 16): 36–8

    PubMed  Google Scholar 

  119. Cummings JL. Defining and labeling disease-modifying treatments for Alzheimer's disease. Alzheimers Dement 2009 Sep; 5(5): 406–18

    Article  PubMed  Google Scholar 

  120. Lyketsos CG, Szekely CA, Mielke MM, et al. Developing new treatments for Alzheimer's disease: the who, what, when, and how of biomarker-guided therapies. Int Psychogeriatr 2008 Oct; 20(5): 871–89

    Article  PubMed  Google Scholar 

  121. Rinne JO, Brooks DJ, Rossor MN, et al. 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 Apr; 9(4): 363–72

    Article  PubMed  CAS  Google Scholar 

  122. Salloway S, Sperling R, Gilman S, et al. A phase 2 multiple ascending dose trial of bapineuzumab in mild to moderate Alzheimer disease. Neurology 2009 Dec 15; 73(24): 2061–70

    Article  PubMed  CAS  Google Scholar 

  123. Lannfelt L, Blennow K, Zetterberg H, et al. 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 Sep; 7(9): 779–86

    Article  PubMed  CAS  Google Scholar 

  124. Zhou B, Teramukai S, Yoshimura K, et al. Validity of cerebrospinal fluid biomarkers as endpoints in early-phase clinical trials for Alzheimer's disease. J Alzheimers Dis 2009; 18(1): 89–102

    PubMed  CAS  Google Scholar 

  125. Blennow K. Biomarkers in Alzheimer's disease drug development. Nature Med 2010 Nov; 16(11): 1218–22

    Article  PubMed  CAS  Google Scholar 

  126. Fox NC, Black RS, Gilman S, et al. Effects of Abeta immunization (AN1792) on MRI measures of cerebral volume in Alzheimer disease. Neurology 2005 May 10; 64(9): 1563–72

    Article  PubMed  CAS  Google Scholar 

  127. Vellas B, Black R, Thal LJ, et al. Long-term follow-up of patients immunized with AN1792: reduced functional decline in antibody responders. Current Alzheimer Res 2009 Apr; 6(2): 144–51

    Article  CAS  Google Scholar 

  128. Raschetti R, Albanese E, Vanacore N, et al. Cholinesterase inhibitors in mild cognitive impairment: a systematic review of randomised trials. PLoS Med 2007Nov27;4(11):e338

    Article  PubMed  CAS  Google Scholar 

  129. Visser PJ, Scheltens P, Verhey FR. Do MCI criteria in drug trials accurately identify subjects with predementia Alzheimer's disease? J Neurol Neurosurg Psychiatry 2005 Oct; 76(10): 1348–54

    Article  PubMed  CAS  Google Scholar 

  130. Aisen PS, Andrieu S, Sampaio C, et al. Report of the task force on designing clinical trials in early (predementia) AD. Neurology 2011 Jan 18; 76(3): 280–6

    Article  PubMed  CAS  Google Scholar 

  131. Shaw LM, Vanderstichele H, Knapik-Czajka M, et al. Qualification of the analytical and clinical performance of CSF biomarker analyses in ADNI. Acta Neuropathologica 2011 May; 121(5): 597–609

    Article  PubMed  CAS  Google Scholar 

  132. Bateman RJ, Aisen PS, De Strooper B, et al. Autosomal-dominant Alzheimer's disease: a review and proposal for the prevention of Alzheimer's disease. Alzheimers Res Ther 2011 Jan 6; 3(1): 1

    Article  PubMed  Google Scholar 

  133. Laske C, Leyhe T, Stransky E, et al. Identification of a blood-based biomarker panel for classification of Alzheimer's disease. Int J Neuropsychopharmacol 2011 Oct; 14(9): 1147–55

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

Dr. Wu was supported by the National Nature Science Foundation of China (grant no. 30700241), the Beijing Scientific and Technological New Star Program (grant no. 2007B069), and a Clinical Fellowship from Pfizer Canada. Drs. Rosa-Neto and Gauthier were supported by the Canadian Institutes of Health Research (CIHR). Dr. Rosa-Neto is a principal investigator in a Sanofi-Aventis sponsored clinical trial (trial no. DRI10734; ClinicalTrials.gov ID: NCT01266525).

Author information

Authors and Affiliations

  1. McGill Centre for Studies in Aging (MCSA), McGill University, 6825, Boul. LaSalle Blvd, Montreal, QC, H4H 1R3, Canada

    Liyong Wu, Pedro Rosa-Neto &  Serge Gauthier

  2. Translational Neuroimaging Laboratory, Douglas Research Institute, McGill University, Montreal, QC, Canada

    Liyong Wu & Pedro Rosa-Neto

  3. Department of Neurology, Xuan Wu Hospital, Capital Medical University, Beijing, China

    Liyong Wu

  4. McConnell Brain Imaging Centre, Montreal Neurological Institute, Montreal, QC, Canada

    Pedro Rosa-Neto

Authors
  1. Liyong Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Pedro Rosa-Neto
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Serge Gauthier
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Serge Gauthier.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wu, L., Rosa-Neto, P. & Gauthier, S. Use of Biomarkers in Clinical Trials of Alzheimer Disease. Mol Diag Ther 15, 313–325 (2011). https://doi.org/10.1007/BF03256467

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF03256467

Keywords

Search

Navigation