Biomarkers in Alzheimer’s Disease—Perspectives for the Future


Biomarkers may assist in identifying subpopulations of AD patients responsive to specific therapies. Bapineuzumab, for example, appears to have more side effects and may have less efficacy in ApoE ε4 carriers.37


Biomarkers may help follow therapy, assist with dose selection, or help decide when to terminate or to reinitiate treatment after a hiatus. Biomarkers could help inform the choice of a combination of multiple agents in a rational polypharmacy regimen depending on which pathways, proteins, and responses were identified. Ongoing biomarker data may have a role in safety monitoring of long-term treatment.


Use of biomarkers in pre-clinical studies to help identify viable treatment alternatives and employment of biomarkers in clinical development programs to identify doses, follow side effects, and establish efficacy are becoming increasingly important and promise to accelerate the pace of AD treatment development. n


1. 2. 3.


Biomarkers Definitions Working Group, Biomarkers and surrogate endpoints: preferred definitions and conceptual framework, Clin Pharmacol Ther, 2001;69:89–95.


Cummings JL, Biomarkers in Alzheimer’s disease drug development, Alzheimer’s Disease and Dementia, 2010; in press.


DeCarli C, Frisoni GB, Clark CM, et al., Qualitative estimates of medial temporal atrophy as a predictor of progression from mild cognitive impairment to dementia, Arch Neurol, 2007;64:108–15.


4.


Jack CR Jr, Lowe VJ, Senjem ML, et al., 11C PiB and structural MRI provide complementary information in imaging of Alzheimer’s disease and amnestic mild cognitive impairment, Brain, 2008;131:665–80.


5. 6.


Ridha BH, Anderson VM, Barnes J, et al., Volumetric MRI and cognitive measures in Alzheimer disease: comparison of markers of progression, J Neurol, 2008;255:567–74.


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;43:458–69.


7.


Jack CR Jr, 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;132:1355–65.


8. 9.


Diamond EL, Miller S, Dickerson BC, et al., Relationship of fMRI activation to clinical trial memory measures in Alzheimer disease, Neurology, 2007;69:1331–41.


Silverman D, Small GW, Chang CY, et al., Positron emission tomography in evaluation of dementia: regional brain metabolism and long-term outcome, JAMA, 2001;286: 2120–27.


10. Fouquet M, Desgranges B, Landeau B, et al., Longitudinal brain metabolic changes from amnestic mild cognitive impairment to Alzheimer’s disease, Brain, 2009;132: 2058–67.


11. Landau SM, Harvey D, Madison CM, et al., Associations between cognitive, functional, and FDG-PET measures of decline in AD and MCI, Neurobiol Aging, 2009 (epub ahead of print).


12. Edison P, Archer HA, Hinz R, et al., Amyloid, hypometabolism, and cognition in Alzheimer disease: an [11C]PIB and [18F]FDG PET study, Neurology, 2007;68:501–8.


13. Foster NL, Heidebrink JL, Clark CM, et al., FDG-PET improves accuracy in distinguishing frontotemporal dementia and Alzheimer’s disease, Brain, 2007;130:2616–35.


14. Ikonomovic MD, Klunk WE, Abrahamson EE, et al., Post- mortem correlates of in vivo PiB-PET amyloid imaging in a


Jeffrey L Cummings, MD, is Director of the Cleveland Clinic Lou Ruvo Center for Brain Health in Las Vegas. This unique enterprise supports clinical trials across central nervous system diseases and provides education and training programs for academics and pharmaceutical personnel. His research and leadership contributions in the field of Alzheimer’s disease have been recognized through the receipt of awards from several leading Alzheimer’s associations. Professor Cummings is the


author of the Neuropsychiatric Inventory (NPI), which has become the reference standard for characterizing behavioral disturbances in dementia syndromes and for measuring the effect of antidementia therapies on neuropsychiatric symptoms in Alzheimer’s disease and other dementias. He is an experienced clinical trialist with expertise in clinical trial design and analysis, global trial implementation, and trial outcome measures. Professor Cummings is a member of the Alzheimer’s Disease Cooperative Study and of the oversight committee of the National Institute of Neurological Disorders and Stroke (NINDS) Neuroprotection in Parkinson’s Disease program.


typical case of Alzheimer’s disease, Brain, 2008;131:1630–45.


15. 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;50:1887–94.


16. Rowe CC, Ackerman U, Browne W, et al., Imaging of amyloid beta in Alzheimer’s disease with 18F-BAY94-9172, a novel PET tracer: proof of mechanism, Lancet Neurol, 2008;7: 129–35.


17. Klunk WE, Mathis CA, Price JC, et al., Two-year follow-up of amyloid deposition in patients with Alzheimer’s disease, Brain, 2006;129:2805–7.


18. Small GW, Kepe V, Ercoli LM, et al., PET of brain amyloid and tau in mild cognitive impairment, N Engl J Med, 2006;355: 2652–63.


19. 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;5:228–34.


20. Blennow K, Zetterberg H, Minthon L, et al., Longitudinal stability of CSF biomarkers in Alzheimer’s disease, Neurosci Lett, 2007;419:18–22.


21. 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;59:512–19.


22. Tapiola T, Alafuzoff I, Herukka SK, et al., Cerebrospinal fluid {beta}-amyloid 42 and tau proteins as biomarkers of Alzheimer-type pathologic changes in the brain, Arch Neurol, 2009;66:382–9.


23. Graff-Radford NR, Crook JE, Lucas J, et al., Association of low plasma Abeta42/Abeta40 ratios with increased imminent risk for mild cognitive impairment and Alzheimer disease, Arch Neurol, 2007;64:354–62.


24. Ray S, Britschgi M, Herbert C, et al., Classification and prediction of clinical Alzheimer’s diagnosis based on plasma signaling proteins, Nat Med, 2007;13:1359–62.


25. Cummings J, Doody M, Clark C, Disease-modifying therapies for Alzheimer disease, Neurology, 2007;69:1622–39.


26. Kivipelto M, Ngandu T, Laatikainen T, et al., Risk score for the prediction of dementia risk in 20 years among middle aged people: a longitudinal, population-based study, Lancet Neurol, 2006;5:735–41.


27. Cairns NJ, Ikonomovic MD, Benzinger T, et al., Absence of PIttsburgh Compound B Detection of CerebralAmyloid Beta in a Patient With Clinical, Cognitive, and Cerebrospinal FluidMarkers of Alzheimer Disease, Arch Neurol, 2009;66: 1557–62.


28. Bourgeat P, Chetelat G, Villemagne VL, et al., Beta-amyloid


burden in the temporal neocortex is related to hippocampal atrophy in elderly subjects without dementia, Neurology, 2010;74:121–7.


29. 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;66:1469–75.


30. 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;6:734–46.


31. Wagner JA. Strategic approach to fit-for-purpose biomarkers in drug development, Annu Rev Pharmacol Toxicol, 2008;48:631–51.


32. Cummings JL, Integrating ADNI results into Alzheimer’s disease drug development programs, Neurobiol Aging, 2010;31(8):1481–92.


33. Bateman RJ, Munsell LY, Morris JC, et al., Human amyloid- beta synthesis and clearance rates as measured in cerebrospinal fluid in vivo, Nat Med, 2006;12:856–61.


34. Bateman RJ, Siemers ER, Mawuenyega KG, et al., A gamma- secretase inhibitor decreases amyloid-beta production in the central nervous system, Ann Neurol, 2009;66:48–54.


35. Siemers ER, Quinn JF, Kaye J, et al., Effects of a gamma- secretase inhibitor in a randomized study of patients with Alzheimer disease, Neurology, 2006;66:602–4.


36. 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;9:363–72.


37. 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;73:2061–70.


38. Cummings JL, Optimizing phase II of drug development for disease-modifying compounds, Alzheimers Dement, 2008;4: S15–20.


39. Jack CR, Slomkowski M, Gracon S, et al., MRI as a biomarker of disease progression in a therapeutic trial of milameline for AD, Neurology, 2003;60:253–60.


40. Cummings JL. Defining and labeling disease-modifying treatments for Alzheimer’s disease, Alzheimers Dement, 2009;5:406–18.


41. Katz R. Biomarkers and surrogate markers: An FDA perspective, NeuroRx, 2004;1:189–95.


42. Cagnin A, Brooks DJ, Kennedy AM, et al., In vivo measurement of activated microglia in dementia, Lancet, 2001;358:461– 7.


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