Skip to main content

Advertisement

Log in

Hat die Alzheimer-Forschung versagt?

Das Scheitern amyloidbasierter klinischer Studien

Did Alzheimer research fail entirely?

Failure of amyloid-based clinical studies

  • Leitthema
  • Published:
Der Nervenarzt Aims and scope Submit manuscript

Zusammenfassung

Zahlreiche auf der Amyloid-Hypothese basierende klinische Studien sind gescheitert. Heißt dies nun, dass die Mechanismen der Alzheimer-Erkrankung neu überdacht werden müssen und dass Amyloid nicht der Auslöser der Erkrankung ist? Gegen diese fatalistische Ansicht spricht die Genetik der familiären Alzheimer-Erkrankung. Mutationen in allen assoziierten Genen beeinflussen ohne Ausnahme die Amyloidaggregation und eine protektive Mutation reduziert die Amyloidbildung. Klinische Studien scheitern, weil Sekretaseinhibitoren die Prozessierung zahlreicher physiologisch wichtiger Substrate der Sekretasen verhindern und die Erkrankung lange vor den ersten Symptomen angelegt wird. Am Beispiel anderer prototypischer Amyloidosen wird eine erfolgreiche Behandlung mit Amyloidmedikamenten beschrieben und neue mikrogliale Zielmoleküle werden diskutiert.

Abstract

Numerous amyloid-based clinical studies have recently failed. Does this mean that the mechanisms of Alzheimer’s disease have to be reinvestigated and that amyloid is not the trigger of the disease? Strong genetic evidence from familial Alzheimer’s disease contradicts this fatalistic opinion. Mutations in all genes associated with familial Alzheimer’s disease affect amyloid metabolism and aggregation. Moreover, a protective mutation reduces amyloid production by 20–30% throughout the lifetime. Clinical studies rather failed because secretase inhibitors block cleavage of numerous other physiologically important substrates of secretases. Moreover, the disease is initiated decades before symptoms occur. Successful treatment attempts with anti-amyloid medication based on other prototype amyloidoses are described. Finally, new therapeutic target molecules expressed in microglia cells are discussed.

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

Access this article

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

Instant access to the full article PDF.

Abb. 1
Abb. 2

Literatur

  1. 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 (2012) Clinical and biomarker changes in dominantly inherited Alzheimer’s disease. N Engl J Med 367:795–804

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Berk JL, Suhr OB, Obici L, Sekijima Y, Zeldenrust SR, Yamashita T, Heneghan MA, Gorevic PD, Litchy WJ, Wiesman JF, Nordh E, Corato M, Lozza A, Cortese A, Robinson-Papp J, Colton T, Rybin DV, Bisbee AB, Ando Y, Ikeda S, Seldin DC, Merlini G, Skinner M, Kelly JW, Dyck PJ, Diflunisal Trial Consortium (2013) Repurposing diflunisal for familial amyloid polyneuropathy: A randomized clinical trial. JAMA 310:2658–2667

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Chartier-Harlin MC, Crawford F, Houlden H, Warren A, Hughes D, Fidani L, Goate A, Rossor M, Roques P, Hardy J et al (1991) Early-onset Alzheimer’s disease caused by mutations at codon 717 of the beta-amyloid precursor protein gene. Nature 353:844–846

    Article  CAS  PubMed  Google Scholar 

  4. Citron M, Westaway D, Xia W, Carlson G, Diehl T, Levesque G, Johnson-Wood K, Lee M, Seubert P, Davis A, Kholodenko D, Motter R, Sherrington R, Perry B, Yao H, Strome R, Lieberburg I, Rommens J, Kim S, Schenk D, Fraser P, St George Hyslop P, Selkoe DJ (1997) Mutant presenilins of Alzheimer’s disease increase production of 42-residue amyloid beta-protein in both transfected cells and transgenic mice. Nat Med 3:67–72

    Article  CAS  PubMed  Google Scholar 

  5. Coelho T, Inês M, Conceição I, Soares M, de Carvalho M, Costa J (2018) Natural history and survival in stage 1 Val30Met transthyretin familial amyloid polyneuropathy. Neurology 91:e1999–e2009

    Article  CAS  PubMed  Google Scholar 

  6. Coelho T, Maia LF, da Silva AM, Cruz MW, Planté-Bordeneuve V, Suhr OB, Conceição I, Schmidt HH, Trigo P, Kelly JW, Labaudinière R, Chan J, Packman J, Grogan DR (2013) Long-term effects of tafamidis for the treatment of transthyretin familial amyloid polyneuropathy. J Neurol 260:2802–2814

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Coelho T, Maia LF, da Silva AM, Cruz MW, Planté-Bordeneuve V, Lozeron P, Suhr OB, Campistol JM, Conceição IM, Schmidt HH, Trigo P, Kelly JW, Labaudiniere R, Chan J, Packman J, Wilson A, Grogan DR (2012) Tafamidis for transthyretin familial amyloid polyneuropathy: A randomized, controlled trial. Neurology 79:785–792

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Colonna M, Wang Y (2016) TREM2 variants: New keys to decipher Alzheimer disease pathogenesis. Nat Rev Neurosci 17:201–207

    Article  CAS  PubMed  Google Scholar 

  9. Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small GW, Roses AD, Haines JL, Pericak-Vance MA (1993) Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science 261:921–923

    Article  CAS  PubMed  Google Scholar 

  10. Crump CJ, Johnson DS, Li YM (2013) Development and mechanism of gamma-secretase modulators for Alzheimer’s disease. Biochemistry 52:3197–3216

    Article  CAS  PubMed  Google Scholar 

  11. Davidson YS, Robinson A, Prasher VP, Mann DMA (2018) The age of onset and evolution of Braak tangle stage and Thal amyloid pathology of Alzheimer’s disease in individuals with Down syndrome. Acta Neuropathol Commun 6:56

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Doran E, Keator D, Head E, Phelan MJ, Kim R, Totoiu M, Barrio JR, Small GW, Potkin SG, Lott IT (2017) Down syndrome, partial trisomy 21, and absence of alzheimer’s disease: The role of APP. J Alzheimers Dis 56:459–470

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Egan MF, Kost J, Voss T, Mukai Y, Aisen PS, Cummings JL, Tariot PN, Vellas B, van Dyck CH, Boada M, Zhang Y, Li W, Furtek C, Mahoney E, Harper Mozley L, Mo Y, Sur C, Michelson D (2019) Randomized trial of verubecestat for prodromal alzheimer’s disease. N Engl J Med 380:1408–1420

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Gertz MA, Dispenzieri A, Sher T (2015) Pathophysiology and treatment of cardiac amyloidosis. Nat Rev Cardiol 12:91–102

    Article  CAS  PubMed  Google Scholar 

  15. Golde TE, Estus S, Younkin LH, Selkoe DJ, Younkin SG (1992) Processing of the amyloid protein precursor to potentially amyloidogenic derivatives. Science 255:728–730

    Article  CAS  PubMed  Google Scholar 

  16. Götzl JK, Brendel M, Werner G, Parhizkar S, Sebastian Monasor L, Kleinberger G, Colombo AV, Deussing M, Wagner M, Winkelmann J, Diehl-Schmid J, Levin J, Fellerer K, Reifschneider A, Bultmann S, Bartenstein P, Rominger A, Tahirovic S, Smith ST, Madore C, Butovsky O, Capell A, Haass C (2019) Opposite microglial activation stages upon loss of PGRN or TREM2 result in reduced cerebral glucose metabolism. EMBO Mol Med 11. https://doi.org/10.15252/emmm.201809711

    Article  PubMed  PubMed Central  Google Scholar 

  17. Haass C (1997) Presenilins: Genes for life and death. Neuron 18:687–690

    Article  CAS  PubMed  Google Scholar 

  18. Haass C, Schlossmacher MG, Hung AY, Vigo-Pelfrey C, Mellon A, Ostaszewski BL, Lieberburg I, Koo EH, Schenk D, Teplow DB et al (1992) Amyloid beta-peptide is produced by cultured cells during normal metabolism. Nature 359:322–325

    Article  CAS  PubMed  Google Scholar 

  19. Haass C, Selkoe DJ (2007) Soluble protein oligomers in neurodegeneration: Lessons from the Alzheimer’s amyloid beta-peptide. Nat Rev Mol Cell Biol 8:101–112

    Article  CAS  PubMed  Google Scholar 

  20. Hardy J, Selkoe DJ (2002) The amyloid hypothesis of Alzheimer’s disease: Progress and problems on the road to therapeutics. Science 297:353–356

    Article  CAS  PubMed  Google Scholar 

  21. Hardy JA, Higgins GA (1992) Alzheimer’s disease: The amyloid cascade hypothesis. Science 256:184–185

    Article  CAS  PubMed  Google Scholar 

  22. Hemming ML, Elias JE, Gygi SP, Selkoe DJ (2008) Proteomic profiling of gamma-secretase substrates and mapping of substrate requirements. Plos Biol 6:e257

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Higashi S, Iseki E, Yamamoto R, Minegishi M, Hino H, Fujisawa K, Togo T, Katsuse O, Uchikado H, Furukawa Y, Kosaka K, Arai H (2007) Concurrence of TDP-43, tau and alpha-synuclein pathology in brains of Alzheimer’s disease and dementia with Lewy bodies. Brain Res 1184:284–294

    Article  CAS  PubMed  Google Scholar 

  24. 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 (2012) A mutation in APP protects against Alzheimer’s disease and age-related cognitive decline. Nature 488:96–99

    Article  CAS  PubMed  Google Scholar 

  25. Jucker M, Walker LC (2015) Neurodegeneration: Amyloid-beta pathology induced in humans. Nature 525:193–194

    Article  CAS  PubMed  Google Scholar 

  26. Kang J, Lemaire HG, Unterbeck A, Salbaum JM, Masters CL, Grzeschik KH, Multhaup G, Beyreuther K, MÜller-Hill B (1987) The precursor of Alzheimer’s disease amyloid A4 protein resembles a cell-surface receptor. Nature 325:733–736

    Article  CAS  PubMed  Google Scholar 

  27. Keren-Shaul H, Spinrad A, Weiner A, Matcovitch-Natan O, Dvir-Szternfeld R, Ulland TK, David E, Baruch K, Lara-Astaiso D, Toth B, Itzkovitz S, Colonna M, Schwartz M, Amit I (2017) A unique Microglia type associated with restricting development of alzheimer’s disease. Cell 169:1276–1290

    Article  CAS  PubMed  Google Scholar 

  28. Kim J, Basak JM, Holtzman DM (2009) The role of apolipoprotein E in Alzheimer’s disease. Neuron 63:287–303

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Kim J, Eltorai AE, Jiang H, Liao F, Verghese PB, Kim J, Stewart FR, Basak JM, Holtzman DM (2012) Anti-apoE immunotherapy inhibits amyloid accumulation in a transgenic mouse model of Abeta amyloidosis. J Exp Med 209:2149–2156

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Krasemann S, Madore C, Cialic R, Baufeld C, Calcagno N, El Fatimy R, Beckers L, O’Loughlin E, Xu Y, Fanek Z, Greco DJ, Smith ST, Tweet G, Humulock Z, Zrzavy T, Conde-Sanroman P, Gacias M, Weng Z, Chen H, Tjon E, Mazaheri F, Hartmann K, Madi A, Ulrich JD, Glatzel M, Worthmann A, Heeren J, Budnik B, Lemere C, Ikezu T, Heppner FL, Litvak V, Holtzman DM, Lassmann H, Weiner HL, Ochando J, Haass C, Butovsky O (2017) The TREM2-APOE pathway drives the transcriptional phenotype of dysfunctional microglia in neurodegenerative diseases. Immunity 47:566–581

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Kuhn PH, Koroniak K, Hogl S, Colombo A, Zeitschel U, Willem M, Volbracht C, Schepers U, Imhof A, Hoffmeister A, Haass C, Rossner S, Brase S, Lichtenthaler SF (2012) Secretome protein enrichment identifies physiological BACE1 protease substrates in neurons. EMBO J 31:3157–3168

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Mazaheri F, Snaidero N, Kleinberger G, Madore C, Daria A, Werner G, Krasemann S, Capell A, Trumbach D, Wurst W, Brunner B, Bultmann S, Tahirovic S, Kerschensteiner M, Misgeld T, Butovsky O, Haass C (2017) TREM2 deficiency impairs chemotaxis and microglial responses to neuronal injury. EMBO Rep 18:1186–1198

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. McDade E, Bateman RJ (2017) Stop Alzheimer’s before it starts. Nature 547:153–155

    Article  CAS  PubMed  Google Scholar 

  34. Meyer-Luehmann M, Coomaraswamy J, Bolmont T, Kaeser S, Schaefer C, Kilger E, Neuenschwander A, Abramowski D, Frey P, Jaton AL, Vigouret JM, Paganetti P, Walsh DM, Mathews PM, Ghiso J, Staufenbiel M, Walker LC, Jucker M (2006) Exogenous induction of cerebral beta-amyloidogenesis is governed by agent and host. Science 313:1781–1784

    Article  CAS  PubMed  Google Scholar 

  35. Parhizkar S, Arzberger T, Brendel M, Kleinberger G, Deussing M, Focke C, Nuscher B, Xiong M, Ghasemigharagoz A, Katzmarski N, Krasemann S, Lichtenthaler SF, Müller SA, Colombo A, Monasor LS, Tahirovic S, Herms J, Willem M, Pettkus N, Butovsky O, Bartenstein P, Edbauer D, Rominger A, Ertürk A, Grathwohl SA, Neher JJ, Holtzman DM, Meyer-Luehmann M, Haass C (2019) Loss of TREM2 function increases amyloid seeding but reduces plaque-associated ApoE. Nat Neurosci 22:191–204

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Preische O, Schultz SA, Apel A, Kuhle J, Kaeser SA, Barro C, Graber S, Kuder-Buletta E, LaFougere C, Laske C, Voglein J, Levin J, Masters CL, Martins R, Schofield PR, Rossor MN, Graff-Radford NR, Salloway S, Ghetti B, Ringman JM, Noble JM, Chhatwal J, Goate AM, Benzinger TLS, Morris JC, Bateman RJ, Wang G, Fagan AM, McDade EM, Gordon BA, Jucker M, Dominantly Inherited Alzheimer (2019) Serum neurofilament dynamics predicts neurodegeneration and clinical progression in presymptomatic Alzheimer’s disease. Nat Med 25:277–283

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Selkoe DJ, Hardy J (2016) The amyloid hypothesis of Alzheimer’s disease at 25 years. Embo Mol Med 8:595–608

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Sevigny J, Chiao P, Bussière T, Weinreb PH, Williams L, Maier M, Dunstan R, Salloway S, Chen T, Ling Y, O’Gorman J, Qian F, Arastu M, Li M, Chollate S, Brennan MS, Quintero-Monzon O, Scannevin RH, Arnold HM, Engber T, Rhodes K, Ferrero J, Hang Y, Mikulskis A, Grimm J, Hock C, Nitsch RM, Sandrock A (2016) The antibody aducanumab reduces Abeta plaques in Alzheimer’s disease. Nature 537:50–56

    Article  CAS  PubMed  Google Scholar 

  39. Wang Y, Ulland TK, Ulrich JD, Song W, Tzaferis JA, Hole JT, Yuan P, Mahan TE, Shi Y, Gilfillan S, Cella M, Grutzendler J, DeMattos RB, Cirrito JR, Holtzman DM, Colonna M (2016) TREM2-mediated early microglial response limits diffusion and toxicity of amyloid plaques. J Exp Med 213:667–675

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Wolfe MS, Xia W, Ostaszewski BL, Diehl TS, Kimberly WT, Selkoe DJ (1999) Two transmembrane aspartates in presenilin-1 required for presenilin endoproteolysis and gamma-secretase activity. Nature 398:513–517

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Christian Haass.

Ethics declarations

Interessenkonflikt

C. Haass kooperiert mit DENALI, hat 2018 an einem Advisory Board Meeting von Biogen teilgenommen, ist Berater bei ISAR-Bioscience und hat ein Sprecherhonorar von Novartis und Roche erhalten. J. Levin gibt an, keinen Interessenkonflikt zu haben.

Für diesen Beitrag wurden von den Autoren keine Studien an Menschen oder Tieren durchgeführt. Für die aufgeführten Studien gelten die jeweils dort angegebenen ethischen Richtlinien.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Haass, C., Levin, J. Hat die Alzheimer-Forschung versagt?. Nervenarzt 90, 884–890 (2019). https://doi.org/10.1007/s00115-019-0751-1

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00115-019-0751-1

Schlüsselwörter

Keywords

Navigation