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The Ethics of Biomarker-Based Preclinical Diagnosis of Alzheimer’s Disease

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Book cover Biomarkers for Preclinical Alzheimer’s Disease

Part of the book series: Neuromethods ((NM,volume 137))

Abstract

In older adults who are developing Alzheimer-typical pathology but do not experience any symptoms—a condition termed “preclinical” Alzheimer’s disease—the individual prognostic value of current biomarkers is low. Only a minority of those who have positive findings on biomarkers in the cerebrospinal fluid or upon brain imaging experience cognitive decline within 3–5 years. On the other hand, the majority of people who have negative biomarker results remain cognitively intact. This may be expected in research settings where alternative causes of cognitive impairment are infrequent. The main reasons for the poor predictive performance of biomarkers in asymptomatic individuals are the dynamic nature of the assessments with abnormality evolving over time and the large interindividual variability of the threshold for clinical manifestation. We do not recommend biomarker assessment and disclosure of biomarker results to asymptomatic individuals outside of research protocols or clinical trials at this point in time. More needs to be learned about the interplay between biomarkers, risk factors, and protective factors. Also, studies are required with extended follow-up intervals on less selected participant groups to determine the long-term predictive potential of biomarkers in presymptomatic Alzheimer’s disease.

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References

  1. Vos SJB, Xiong C, Visser PJ et al (2013) Preclinical Alzheimer’s disease and its outcome: a longitudinal cohort study. Lancet Neurol 12:957–965

    Article  PubMed  PubMed Central  Google Scholar 

  2. Dubois B, Hampel H, Feldman HH et al (2016) Preclinical Alzheimer’s disease: definition, natural history, and diagnostic criteria. Alzheimers Dement 12:292–323

    Article  PubMed  Google Scholar 

  3. Petersen RC (2011) Mild cognitive impairment. N Engl J Med 364:2227–2234

    Article  CAS  PubMed  Google Scholar 

  4. Ritchie K, Carrière I, Berr C et al (2016) The clinical picture of Alzheimer’s disease in the decade before diagnosis: clinical and biomarker trajectories. J Clin Psychiatry 77:e305–e311

    Article  PubMed  Google Scholar 

  5. Roberts JS, Dunn LB, Rabinovici GD (2013) Amyloid imaging, risk disclosure and Alzheimer’s disease: ethical and practical issues. Neurodegener Dis Manag 3:219–229

    Article  PubMed  PubMed Central  Google Scholar 

  6. Witte MM, Foster NL, Fleisher AS et al (2015) Clinical use of amyloid-positron emission tomography neuroimaging: practical and bioethical considerations. Alzheimers Dement 1:358–367

    Google Scholar 

  7. Jack CR, Albert M, Knopman DS et al (2011) Introduction to revised criteria for the diagnosis of Alzheimer’s disease: national institute on aging and the Alzheimer association workgroups. Alzheimers Dement 7:257–262

    Article  PubMed  PubMed Central  Google Scholar 

  8. Arlt S (2013) Non-Alzheimer’s disease–related memory impairment and dementia. Dialogues Clin Neurosci 15:465–473

    PubMed  PubMed Central  Google Scholar 

  9. Villemagne VL, Burnham S, Bourgeat P et al (2013) Amyloid beta deposition, and cognitive decline in sporadic Alzheimer’s disease: a prospective cohort study. Lancet Neurol 12:357–367

    Article  CAS  PubMed  Google Scholar 

  10. Han SD, Gruhl J, Beckett L et al (2012) Beta amyloid, tau, neuroimaging, and cognition: sequence modeling of biomarkers for Alzheimer’s disease. Brain Imaging Behav 6:610–620

    Article  PubMed  PubMed Central  Google Scholar 

  11. Jack CR, Knopman DS, Jagust WJ et al (2013) Tracking pathophysiological processes in Alzheimer’s disease: an updated hypothetical model of dynamic biomarkers. Lancet Neurol 12:207–216

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Sutphen CL, Jasielec MS, Shah AR et al (2015) Longitudinal cerebrospinal fluid biomarker changes in preclinical Alzheimer disease during middle age. JAMA Neurol 72:1029–1042

    Article  PubMed  PubMed Central  Google Scholar 

  13. Wirth M, Villeneuve S, Haase CM et al (2013) Association between Alzheimer disease biomarkers, neurodegeneration, and cognition in cognitively normal older people. JAMA Neurol 70:1512–1519

    PubMed  PubMed Central  Google Scholar 

  14. Knopman DS, Jack CR, Lundt ES et al (2015) Role of beta-amyloidosis and neurodegeneration in subsequent changes in mild cognitive impairment. JAMA Neurol 72:1475–1483

    Article  PubMed  PubMed Central  Google Scholar 

  15. Alexopoulos P, Werle L, Roesler J et al (2016) Conflicting cerebrospinal fluid biomarkers and progression to dementia due to Alzheimer’s disease. Alzheimers Res Ther 8:51

    Article  PubMed  PubMed Central  Google Scholar 

  16. Porteri C, Frisoni GB (2014) Biomarker-based diagnosis of mild cognitive impairment due to Alzheimer’s disease: how and what to tell. A kickstart to an ethical discussion. Front Aging Neurosci 6:41

    Article  PubMed  PubMed Central  Google Scholar 

  17. Landau SM, Lu M, Joshi AD et al (2013) Comparing PET imaging and CSF measurements of A beta. Ann Neurol 74:826–836

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Toledo JB, Weiner MW, Wolk DA et al (2014) Neuronal injury biomarkers and prognosis in ADNI subjects with normal cognition. Acta Neuropathol Commun 2:26

    Article  PubMed  PubMed Central  Google Scholar 

  19. Leuzy A, Carter SF, Chiotis K et al (2015) Concordance and diagnostic accuracy of 11C PIB PET and cerebrospinal fluid biomarkers in a sample of patients with mild cognitive impairment and Alzheimer’s disease. J Alzheimers Dis 45:1077–1088

    CAS  PubMed  Google Scholar 

  20. Leuzy A, Chiotis K, Hasselbalch SG et al (2016) Pittsburgh compound B imaging and cerebrospinal fluid amyloid-beta in a multicentre European memory clinic study. Brain 139:2540–2553

    Article  PubMed  PubMed Central  Google Scholar 

  21. Vos SJB, Gordon BA, Su Y et al (2016) NIAA-AA staging of preclinical Alzheimer disease: discordance and concordance of CSF and imaging biomarkers. Neurobiol Aging 44:1–8

    Article  PubMed  PubMed Central  Google Scholar 

  22. Valenzuela MJ (2008) Brain reserve and the prevention of dementia. Curr Opin Psychiatry 21:296–302

    Article  PubMed  Google Scholar 

  23. Murray AD, Staff RT, McNeil CJ et al (2011) The balance between cognitive reserve and brain imaging biomarkers of cerebrovascular and Alzheimer’s diseases. Brain 134:3687–3696

    Article  PubMed  Google Scholar 

  24. Almeida RP, Schultz SA, Austin BP et al (2015) Cognitive reserve modifies age-related alterations in CSF biomarkers of Alzheimer’s disease. JAMA Neurol 72:699–706

    Article  PubMed  PubMed Central  Google Scholar 

  25. Doraiswamy PM, Sperling RA, Johnson K et al (2014) Florbetapir F 18 amyloid PET and 36-month cognitive decline: a prospective multicenter study. Mol Psychiatry 19:1044–1051

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. McKhann GM, Knopman DS, Chertkow H et al (2011) The diagnosis of dementia due to Alzheimer’s disease: recommendations from the national institute on aging and the Alzheimer’s association workgroup. Alzheimers Dement 7(3):263–269

    Article  PubMed  PubMed Central  Google Scholar 

  27. Janelidze S, Zetterberg H, Mattsson N et al (2016) CSF Abeta 42/Abeta 40 and Abeta42/−abeta38 ratios: better diagnostic markers of Alzheimer’s disease. Ann Clin Transl Neurol 3:154–165

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Counts SE, Ikonomovic MD, Mercao N et al (2017) Biomarkers for the early detection and progression of Alzheimer’s disease. Neurotherapeutics 14:35–53

    Article  CAS  PubMed  Google Scholar 

  29. Chételat G, La Joie R, Villain N et al (2013) Amyloid imaging in cognitively normal individuals, at-risk populations and preclinical Alzheimer’s disease. NeuroImage Clin 2:356–365

    Article  PubMed  PubMed Central  Google Scholar 

  30. Soldan A, Pettigrew C, Cai Q et al (2016) Hypothetical preclinical Alzheimer disease groups and longitudinal cognitive change. JAMA Neurol 73:698–705

    Article  PubMed  PubMed Central  Google Scholar 

  31. Goldman JS (2012) New approaches to genetic counseling and testing for Alzheimer’s disease and frontotemporal degeneration. Curr Neurol Neurosci Rep 12:502–510

    Article  PubMed  PubMed Central  Google Scholar 

  32. Hauser PS, Ryan RO (2013) Impact of apolipoprotein E on Alzheimer’s disease. Curr Alzheimer Res 10:809–817

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Randall C, Mosconi L, de Leon M et al (2014) Cerebrospinal fluid biomarkers of Alzheimer’s disease in cognitively healthy elderly. Front Biosci 18:1150–1173

    Google Scholar 

  34. Fleisher AS, Chen K, Liu X et al (2013) Apolipoprotein E e4 effects on florbetapir positron emission tomography in healthy aging and Alzheimer disease. Neurobiol Aging 34:1–12

    Article  CAS  PubMed  Google Scholar 

  35. Steenland K, Zhao L, Goldstein F et al (2014) Biomarkers for predicting cognitive decline in those with normal cognition. J Alzheimers Dis 40:587–594

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Johnson KA, Minoshima S, Bohnen NI et al (2013) Appropriate use criteria for amyloid PET: a report of the amyloid imaging task force, the society of nuclear medicine and molecular imaging, and the Alzheimer’s association. Alzheimers Dement 9:e-1–e-15

    Article  Google Scholar 

  37. Morris JC, Roe CM, Grant EA et al (2009) PIB imaging predicts progression from cognitively normal to symptomatic Alzheimer’s disease. Arch Neurol 66:1469–1475

    Article  PubMed  PubMed Central  Google Scholar 

  38. Villemagne VL, Pike KE, Chételat G et al (2011) Longitudinal assessment of Abeta and cognition in aging and Alzheimer disease. Ann Neurol 69:181–192

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Harkins K, Sankar P, Sperling R et al (2015) Development of a process to disclose amyloid imaging results to cognitively normal older adult research participants. Alzheimers Res Ther 7:26

    Article  PubMed  PubMed Central  Google Scholar 

  40. Rabinovici GD, Karlawish J, Knopman D et al (2016) Testing and disclosure related to amyloid imaging and Alzheimer’s disease: common questions and fact sheet summary. Alzheimers Dement 12:510–515

    Article  PubMed  Google Scholar 

  41. Rowe CC, Bourgeat P, Ellis KA et al (2013) Predicting Alzheimer disease with beta-amyloid imaging: results from the Australian imaging, biomarkers, and lifestyle study of ageing. Ann Neurol 74:905–913

    Article  CAS  PubMed  Google Scholar 

  42. Howe E (2013) Clinical implications of the new diagnostic guidelines for dementia. Innov Clin Neurosci 10:32–38

    PubMed  PubMed Central  Google Scholar 

  43. Baum ML (2016) Patient requests for off-label bioprediction of dementia. Camb Q Healthc Ethics 25:686–690

    Article  PubMed  Google Scholar 

  44. Gordon M (2013) Identification of potential or preclinical cognitive impairment and the implications of sophisticated screening with biomarkers and cognitive testing: does it really matter? Biomed Res Int 2013:976130

    Article  PubMed  PubMed Central  Google Scholar 

  45. Karlawish J (2011) Addressing the ethical, policy, and social challenges of preclinical Alzheimer disease. Neurology 77:1487–1493

    Article  PubMed  PubMed Central  Google Scholar 

  46. Kim SYH, Karlawish J, Berkman BE (2015) Ethics of genetic and biomarker test disclosures in neurodegenerative disease prevention trials. Neurology 84:1488–1494

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Schicktanz S, Schweda M, Ballenger JF et al (2014) Before it is too late: professional responsibilities in late-onset Alzheimer’s research and pre-symptomatic prediction. Front Hum Neurosci 8:921

    Article  PubMed  PubMed Central  Google Scholar 

  48. Caselli RJ, Langbaum J, Marchant GE et al (2014) Public perceptions of presymptomatic testing for Alzheimer’s disease. Mayo Clin Proc 89:1389–1396

    Article  PubMed  PubMed Central  Google Scholar 

  49. Villemagne VL, Fodero-Tavoletti MT, Masters CL et al (2015) Tau imaging: early progress and future directions. Lancet Neurol 14:114–124

    Article  PubMed  Google Scholar 

  50. Tanzi RE (2012) The genetics of Alzheimer disease. Cold Spring Harb Perspect Med 2:a006296

    Article  PubMed  PubMed Central  Google Scholar 

  51. Bemelmans SASA, Tromp K, Bunnik EM et al (2016) Psychological, behavioral and social effects of disclosing Alzheimer’s disease biomarkers to research participants: a systematic review. Alzheimers Res Ther 8:46

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Lim YY, Maruff P, Getter C et al (2016) Disclosure of positron emission tomography amyloid imaging results: a preliminary study of safety and tolerability. Alzheimers Dement 12:454–458

    Article  PubMed  Google Scholar 

  53. Paulsen JS, Nance M, Kim JI et al (2013) A review of quality of life after predictive testing for and earlier identification of neurodegenerative diseases. Prog Neurobiol 110:2–28

    Article  PubMed  Google Scholar 

  54. Hooper M, Grill JD, Rodriguez-Agudelo Y et al (2013) The impact of the availability of prevention studies on the desire to undergo predictive testing in persons at-risk for autosomal dominant Alzheimer’s disease. Contemp Clin Trials 36:256–262

    Article  PubMed  Google Scholar 

  55. Steinbart EJ, Smith CO, Poorkay P et al (2001) Impact of DNA testing for early-onset familial Alzheimer disease and frontotemporal dementia. Arch Neurol 58:1828–1831

    Article  CAS  PubMed  Google Scholar 

  56. Cassidy MR, Roberts JS, Bird TD et al (2008) Comparing test-specific distress of susceptibility versus deterministic genetic testing for Alzheimer’s disease. Alzheimers Dement 4:406–413

    Article  PubMed  PubMed Central  Google Scholar 

  57. Goldman JS, Rademakers R, Huey ED et al (2011) An algorithm for genetic testing of frontotemporal lobar degeneration. Neurology 76:476–483

    Article  Google Scholar 

  58. Molinuevo JL, Cami J, Carné S et al (2016) Ethical challenges in preclinical Alzheimer’s disease observational studies and trials: results of the Barcelona summit. Alzheimers Dement 12:614–622

    Article  PubMed  PubMed Central  Google Scholar 

  59. Soldan A, Pettigrew C, Li S et al (2013) Relationship of cognitive reserve and CSF biomarkers to emergence of clinical symptoms in preclinical Alzheimer’s disease. Neurobiol Aging 34:2827–2834

    Article  CAS  PubMed  Google Scholar 

  60. Donovan NJ, Hsu DC, Dagley AS et al (2015) Depressive symptoms and biomarkers of Alzheimer’s disease in cognitively normal older adults. J Alzheimers Dis 46:63–73

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Garrett MD, Valle R (2016) A methodological critique of the national institute of aging and Alzheimer’s association guidelines for Alzheimer’s disease, dementia, and mild cognitive impairments. Dementia 15:239–254

    Article  PubMed  Google Scholar 

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Author information

Authors and Affiliations

  1. Department of Psychiatry and Psychotherapy, Klinikum rechts der Isar, Technische Universität München, Munich, Germany

    Alexander F. Kurz

  2. Academic Unit for Psychiatry of Old Age, Department of Psychiatry, The University of Melbourne and NorthWestern Mental Health, Mental Health, Melbourne, Australia

    Nicola T. Lautenschlager

Authors
  1. Alexander F. Kurz
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  2. Nicola T. Lautenschlager
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Correspondence to Alexander F. Kurz .

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Editors and Affiliations

  1. Department of Psychiatry and Psychotherapy, Ludwig-Maximilians-Universität München, Munich, Germany

    Robert Perneczky

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Kurz, A.F., Lautenschlager, N.T. (2018). The Ethics of Biomarker-Based Preclinical Diagnosis of Alzheimer’s Disease. In: Perneczky, R. (eds) Biomarkers for Preclinical Alzheimer’s Disease. Neuromethods, vol 137. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-7674-4_17

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  • DOI: https://doi.org/10.1007/978-1-4939-7674-4_17

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  • Publisher Name: Humana Press, New York, NY

  • Print ISBN: 978-1-4939-7673-7

  • Online ISBN: 978-1-4939-7674-4

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