Immunological Aspects and Anti-Amyloid Strategy for Alzheimer’s Dementia

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Alzheimer’s dementia (AD) is the most common form of dementia among the elderly, accounting for at least two-thirds of all dementia cases. It represents a costly burden, since its global prevalence is estimated at 24 million cases. Amyloid beta or Aβ plaques and neurofibrillary tangles define AD pathologically but do not fully explain it, because dementia may also be caused by inflammation resulting in neuronal, axonal synaptic loss and dysfunction. An important component of AD pathophysiology are amyloid plaques surrounded by activated microglia, cytokines, and complement components, suggesting inflammation. In the diagnosis of AD, cerebrospinal fluid markers, especially in vivo amyloid measurements, contribute to an accurate assessment of AD pathology and differential diagnosis. Aβ levels are a very good marker for the presence of amyloid deposits in the brain, while total tau and phosphorylated tau are useful for the detection of neurodegeneration. The implementation of anti-amyloid therapy and other disease-modifying interventions may have immense clinical impact if initiated at an early or presymptomatic stage of AD, before significant brain damage occurs. This paper briefly reviews the abovementioned topics and provides recommendations for future studies.

1. Jonsson T, Atwal JK, Steinberg S, Snaedal J, Jonsson PV, Bjornsson S, Stefansson H, Sulem P, Gudbjartsson D, Maloney J, Hoyte K, Gustafson A, Liu Y, Lu Y, Bhangale T, Graham RR, Huttenlocher J, Bjornsdottir G, Andreassen OA, Jonsson EG, Palotie A, Behrens TW, Magnusson OT, Kong A, Thorsteinsdottir U, Watts RJ, Stefansson K. A mutation in APP protects against Alzheimer’s disease and age-related cognitive decline. Nature 2012;488:96-9. doi: 10.1038/ nature11283

2. Hampel H, Buerger K, Zinkowski R, Teipel SJ, Goernitz A, Andreasen N, Sjoegren M, DeBernardis J, Kerkman D, Ishiguro K, Ohno H, Vanmechelen E, Vanderstichele H, McCulloch C, Moller HJ, Davies P, Blennow K. Measurement of phosphorylated tau epitopes in the differential diagnosis of Alzheimer disease: a comparative cerebrospinal fl uid study. Arch Gen Psychiatry 2004;61:95-102. PMID: 4706948

3. Reitz C, Brayne C, Mayeux R. Epidemiology of Alzheimer disease. Nat Rev Neurol 2011;7:137-52. doi: 10.1038/ nrneurol.2011.2

4. Mirra SS, Heyman A, McKeel D, Sumi SM, Crain BJ, Brownlee LM, Vogel FS, Hughes JP, van Belle G, Berg L. The Consortium to Establish a Registry for Alzheimer’s Disease (CERAD). Part II. Standardization of the neuropathologic assessment of Alzheimer’s disease. Neurology 1991;41:479-86. doi: 10.1212/WNL.41.4.479

5. Schellenberg GD, Montine TJ. The genetics and neuropathology of Alzheimer’s disease. Acta Neuropathol 2012;124:305-23. doi: 10.1007/s00401-012-0996-2

6. Holtzman DM. CSF biomarkers for Alzheimer’s disease: current utility and potential future use. Neurobiol Aging 2 0 11 ; 3 2 ( S u p p l 1 ) : S 4 - 9 . d o i : 1 0 . 1 0 1 6 / j . neurobiolaging.2011.09.003

7. Hardy J, Selkoe DJ. The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science 2002;297:353-6.

8. Strittmatter WJ, Roses AD. Apolipoprotein E and Alzheimer disease. Annu Rev Neurosci 1996;19:53-77. doi: 10.1146/

9. Benveniste EN, Nguyen VT, O’Keefe GM. Immunological aspects of microglia: relevance to Alzheimer’s disease. Neurochem Int 2001;39:381-91. PMID: 11578773

10. McGeer EG, McGeer PL. Brain infl ammation in Alzheimer disease and the therapeutic implications. Curr Pharm Des 1999;5:821-36. PMID: 10526088

11. Bateman RJ, Munsell LY, Morris JC, Swarm R, Yarasheski KE, Holtzman DM. Human amyloid-beta synthesis and clearance rates as measured in cerebrospinal fl uid in vivo. Nature Med 2006;12:856-61. doi: 10.1038/nm1438

12. Sunderland T, Linker G, Mirza N, Putnam KT, Friedman DL, Kimmel LH, Bergeson J, Manetti GJ, Zimmermann M, Tang B, Bartko JJ, Cohen RM. Decreased beta-amyloid1-42 and increased tau levels in cerebrospinal fl uid of patients with Alzheimer disease. JAMA 2003;289:2094-103. doi: 10.1001/ jama.289.16.2094

13. Fagan AM, Mintun MA, Mach RH, Lee SY, Dence CS, Shah AR, LaRossa GN, Spinner ML, Klunk WE, Mathis CA, DeKosky ST, Morris JC, Holtzman DM. Inverse relation between in vivo amyloid imaging load and cerebrospinal fl uid Abeta42 in humans. Ann Neurol 2006;59:512-9. PMID: 16372280

14. Fagan AM, Roe CM, Xiong C, Mintun MA, Morris JC, Holtzman DM. Cerebrospinal fl uid tau/beta-amyloid(42) ratio as a prediction of cognitive decline in nondemented older adults. Arch Neurol 2007;64:343-9. doi: 10.1001/ archneur.64.3.noc60123

15. Fagan AM, Mintun MA, Shah AR, Aldea P, Roe CM, Mach RH, Marcus D, Morris JC, Holtzman DM. Cerebrospinal fluid tau and ptau(181) increase with cortical amyloid deposition in cognitively normal individuals: implications for future clinical trials of Alzheimer’s disease. EMBO Mol Med 2009;1:371-80. doi: 10.1002/emmm.200900048

16. Rowe CC, Ng S, Ackermann U, Gong SJ, Pike K, Savage G, Cowie TF, Dickinson KL, Maruff P, Darby D, Smith C, Woodward M, Merory J, Tochon-Danguy H, O’Keefe G, Klunk WE, Mathis CA, Price JC, Masters CL, Villemagne VL. Imaging beta-amyloid burden in aging and dementia.\ Neurology 2007;68:1718-25. doi: 10.1212/01. wnl.0000261919.22630.ea

17. Cairns NJ, Ikonomovic MD, Benzinger T, Storandt M, Fagan AM, Shah AR, Reinwald LT, Carter D, Felton A, Holtzman DM, Mintun MA, Klunk WE, Morris JC. Absence of Pittsburgh compound B detection of cerebral amyloid beta in a patient with clinical, cognitive, and cerebrospinal fl uid markers of Alzheimer disease: a case report. Arch Neurol 2009;66:1557-62. doi: 10.1001/archneurol.2009.279.

18. Blennow K, Nellgard B. Amyloid beta 1-42 and tau in cerebrospinal fluid after severe traumatic brain injury. Neurology 2004;62:159; author reply 159-60. PMID: 14718730

19. Hesse C, Rosengren L, Andreasen N, Davidsson P, Vanderstichele H, Vanmechelen E, Blennow K. Transient increase in total tau but not phospho-tau in human cerebrospinal fluid after acute stroke. Neurosci Lett 2001;297:187-90. doi: 10.1016/s0304-3940(00)01697-9

20. Arai H, Ishiguro K, Ohno H, Moriyama M, Itoh N, Okamura N, Matsui T, Morikawa Y, Horikawa E, Kohno H, Sasaki H, Imahori K. CSF phosphorylated tau protein and mild cognitive impairment: a prospective study. Exp Neurol 2000;166:201-3. PMID: 11031097

21. Buerger K, Zinkowski R, Teipel SJ, Tapiola T, Arai H, Blennow K, Andreasen N, Hofmann-Kiefer K, DeBernardis J, Kerkman D, McCulloch C, Kohnken R, Padberg F, Pirttila T, Schapiro MB, Rapoport SI, Moller HJ, Davies P, Hampel H. Differential diagnosis of Alzheimer disease with cerebrospinal fl uid levels of tau protein phosphorylated at threonine 231. Arch Neurol 2002;59:1267-72. doi: 10.1001/ archneur.59.8.1267

22. Heneka MT, Kummer MP, Stutz A, Delekate A, Schwartz S, Vieira-Saecker A, Griep A, Axt D, Remus A, Tzeng TC, Gelpi E, Halle A, Korte M, Latz E, Golenbock DT. NLRP3 is activated in Alzheimer’s disease and contributes to pathology in APP/PS1 mice. Nature 2013;493:674-8. doi: 10.1038/ nature11729

23. Nicoll JA, Wilkinson D, Holmes C, Steart P, Markham H, Weller RO. Neuropathology of human Alzheimer disease after immunization with amyloid-beta peptide: a case report. Nature Med 2003;9:448-52. doi: 10.1038/nm840

24. Weinstein D. Failures halt Phase III trials of Alzheimer’s drug [displayed 22 September 2013] Available at drug/article/253659/

25. Alzheimer Research Forum. DIAN Trial Picks Gantenerumab, Solanezumab, Maybe BACE Inhibitor [displayed 22 September 2013]. Available at

26. 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;9:119-28. doi: 10.1016/S1474-4422(09)70299-6

27. 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, Schofi eld PR, Sperling RA, Salloway S, Morris JC; Dominantly Inherited Alzheimer Network. Clinical and biomarker changes in dominantly inherited Alzheimer’s disease. New Engl J Med 2012;367:795-804. doi: 10.1056/NEJMoa1202753

28. Alzheimer’s Disease Education and Referral Center. Dominantly Inherited Alzheimer Network Trial: An Opportunity to Prevent Dementia (DIAN TU) [displayed 22 September 2013]. Available at trial-opportunity-prevent-dementia

29. Jack CR Jr, Knopman DS, Jagust WJ, Petersen RC, Weiner MW, Aisen PS, Shaw LM, Vemuri P, Wiste HJ, Weigand SD, Lesnick TG, Pankratz VS, Donohue MC, Trojanowski JQ. Tracking pathophysiological processes in Alzheimer’s disease: an updated hypothetical model of dynamic biomarkers. Lancet Neurol 2013;12:207-16. doi: 10.1016/ S1474-4422(12)70291-0

30. Panza F, Frisardi V, Solfrizzi V, Imbimbo BP, Logroscino G, Santamato A, Greco A, Seripa D, Pilotto A. Immunotherapy for Alzheimer’s disease: from anti-beta-amyloid to tau-based immunization strategies. Immunotherapy 2012;4:213-38. doi: 10.2217/imt.11.170

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