he amyloid hypothesis of Alzheimer's disease: past and present, hopes and disappointments

In 1887, S.A. Belyakov, a physician of the Imperial Medical and Surgical Academy, first described amyloid deposits in the brain of patients with dementia. Later, in 1906, A. Alzheimer revealed amyloid plaques and tau tangles in a patient with clinical signs of dementia. Over the following 100 years, the development of the concept of the amyloid origin of Alzheimer's disease (AD) confirmed numerous relationships between the brain accumulation of APs and cognitive decline. And if at the beginning of the amyloid era many researchers considered that the disease was caused by amyloid beta (Aβ) protein overproduction, in recent years they have increasingly pointed to a defect in the mechanisms of Aβ clearance, especially after the discovery of the lymphatic system of the brain. The role of disturbed homeostasis of redox-active metals, primarily iron and copper, in the development of the disease is also considered.

The amyloid hypothesis of AD has served as the basis for several areas in the design of drugs, such as secretase inhibitors, immunomodulatory drugs for active and passive immunization. However, only one drug (Akatinol memantine, an inhibitor of NMDA receptors and glutamatergic excitotoxicity) for the treatment of AD has been introduced into clinical practice over the past 20 years. Of interest are the data obtained in new studies of Akatinol memantine, which suggest that the latter is able to some extent affect the main pathophysiological processes underlying the development of cognitive impairment in Alzheimer-type pathology. 

1. Belyakov SA. On pathological and anatomical changes of the central nervous system in senile dementia. Dis. doct. med. sci. Saint-Petersburg; 1887. 72 p.

2. Odinak MM, Litvinenko IV, Emelin AYu, et al. Pathomorphological changes in dementia: the priority of domestic researchers. Zhurnal nevrologii i psikhiatrii im. S.S. Korsakova. 2016;116(6):28-34. (In Russ.).

3. Alzheimer A. Uber eine eigenartige Erkrankung der Hirnrinde. Allgemeine Zeitschrift fur Psychiatrie und phychishGerichtliche Medizin. 1907;64:146-8.

4. Glenner GG, Wong CW. Alzheimer's disease: Initial report of the purification and characterization of a novel cerebrovascular amyloid protein. Biochem Biophys Res Commun. 1984 May 16;120(3):885-90.

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

6. Huber G, Bailly Y, Martin JR, et al. Synaptic betaamyloid precursor proteins increase with learning capacity in rats. Neuroscience. 1997 Sep;80(2):313-20.

7. Nalivaeva NN, Turner AJ. The amyloid precursor protein: A biochemical enigma in brain development, function and disease. FEBS Lett. 2013 Jun 27;587(13):2046-54. doi: 10.1016/j.febslet.2013.05.010. Epub 2013 May 16.

8. Goozee K, Chatterjee P, James I, et al. Elevated plasma ferritin in elderly individuals with high neocortical amyloid-β load. Mol Psychiatry. 2018 Aug;23(8):1807-1812. doi: 10.1038/mp.2017.146. Epub 2017 Jul 11.

9. Altamura S, Muckenthaler MU. Iron toxicity in diseases of aging: Alzheimer's disease, Parkinson's disease and atherosclerosis. J Alzheimers Dis. 2009;16(4):879-95. doi: 10.3233/JAD-2009-1010.

10. Ayton S, Fazlollahi A, Bourgeat P. Cerebral quantitative susceptibility mapping predicts amyloid-β-related cognitive decline. Brain. 2017 Aug 1;140(8):2112-2119. doi: 10.1093/brain/awx137.

11. Guillemot J, Canuel R, Essalmani, et al. Implication of the proprotein convertases in iron homeostasis: proprotein convertase 7 sheds human transferrin receptor 1 and furin activates hepcidin. Hepatology. 2013 Jun;57(6):2514-24. doi: 10.1002/hep.26297. Epub 2013 May 15.

12. Ayton S, Faux NG, Bush AI. Ferritin levels in the cerebrospinal fluid predict Alzheimer's disease outcomes and are regulated by APOE. Nat Commun. 2015 May 19;6:6760. doi: 10.1038/ncomms7760.

13. Diouf I, Fazlollahi A, Bush AI, Ayton S. Cerebrospinal fluid ferritin levels predict brain hypometabolism in people with underlying βamyloid pathology. Alzheimer's disease Neuroimaging Initiative. Neurobiol Dis. 2019 Apr;124:335-339. doi: 10.1016/j.nbd.2018.12. 010. Epub 2018 Dec 14.

14. Cline EN, Bicca MA, Viola KL, Klein WL. The amyloid-oligomer hypothesis: Beginning of the third decade. J Alzheimers Dis. 2018;64(s1): S567-S610. doi: 10.3233/JAD-179941.

15. Kuruva CS, Reddy PH. Amyloid beta modulators and neuroprotection in Alzheimer's disease: A critical appraisal. Drug Discov Today. 2017 Feb;22(2):223-233. doi: 10.1016/j.drudis.2016.10.010. Epub 2016 Oct 27.

16. Emelin A.Yu, Lobzin VYu, Vorob'ev SV. Kognitivnye narusheniya: rukovodstvo dlya vrachei [Cognitive disorders: a guide for doctors]. Moscow; 2019. 416 p.

17. Hellstrom-Lindahl E, Ravid R, Nordberg A. Age-dependent decline of neprilysin in Alzheimer's disease and normal brain: Inverse correlation with A beta levels. Neurobiol Aging. 2008 Feb;29(2):210-21. Epub 2006 Nov 13.

18. Hanger DP, Anderton BH, Noble W. Tau phosphorilation: the therapeutic challenge for neurodegenerative disease. Trends Mol Med. 2009 Mar;15(3):112-9. doi: 10.1016/j.molmed.2009. 01.003. Epub 2009 Feb 24.

19. Braak H, Braak E. Neuropathological staging of Alzheimer-related changes. Acta Neuropathol. 1991;82(4):239-59.

20. De Lacoste M, White CL3rd. The role of cortical connectivity in Alzheimer's disease pathogenesis: a review and model system. Neurobiol Aging. 1993 Jan-Feb;14(1):1-16.

21. Boncristiano S, Calhoun ME, Howard V, et al. Neocortical synaptic bouton number is maintained despite robust amyloid deposition in APP23 transgenic mice. Neurobiol Aging. 2005 May;26(5):607-13.

22. Spires TL, Meyer-Luehmann M, Stern EA, et al. Dendritic spine abnormalities in amyloid precursor protein transgenic mice demonstrated by gene transfer and intravital multiphoton microscopy. J Neurosci. 2005 Aug 3;25(31): 7278-87.

23. Kukar T, Prescott S, Eriksen JL, et al. Chronic administration of R-flurbiprofen attenuates learning impairments in transgenic amyloid precursor protein mice. BMC Neurosci. 2007 Jul 24;8:54.

24. Li-Blatter X, Beck A, Seelig A. P-glycoprotein-ATPase modulation: the molecular mechanisms. Biophys J. 2012 Mar 21;102(6):1383-93. doi: 10.1016/j.bpj.2012.02.018. Epub 2012 Mar 20.

25. Xia X, Qian S, Soriano S, et al. Loss of presenilin 1 is associated with enhanced betacatenin signaling and skin tumorigenesis. Proc Natl Acad Sci U S A. 2001 Sep 11;98(19):10863-8. Epub 2001 Aug 21.

26. Doody RS, Raman R, Farlow M, et al. A phase 3 trial of semagacestat for treatment of Alzheimer's disease. N Engl J Med. 2013 Jul 25;369(4):341-50. doi: 10.1056/NEJMoa1210951.

27. Haapasalo A, Kovacs DM. The many substrates of presenilin/_-secretase. J Alzheimers Dis. 2011;25(1):3-28. doi: 10.3233/JAD-2011-101065.

28. Salloway S, Sperling R, Fox NC, et al. Two phase 3 trials of bapineuzumab in mild-tomoderateAlzheimer's disease. N Engl J Med. 2014 Jan 23;370(4):322-33. doi: 10.1056/NEJMoa1304839.

29. Doody RS, Thomas RG, Farlow M, et al. Phase 3 trials of solanezumab for mild-to-moderate Alzheimer's disease. N Engl J Med. 2014 Jan 23;370(4):311-21. doi: 10.1056/NEJMoa 1312889.

30. Morris GP, Clark IA, Vissel B. Inconsistencies and Controversies Surrounding the Amyloid Hypothesis of Alzheimer's Disease. Acta Neuropathol Commun. 2014 Sep 18;2:135. doi: 10.1186/s40478-014-0135-5.

31. Kametani F, Hasegawa M. Reconsideration of Amyloid Hypothesis and Tau Hypothesis in Alzheimer's Disease. Front Neurosci. 2018 Jan 30;12:25. doi: 10.3389/fnins.2018.00025. eCollection 2018.

32. Armstrong RA, Nochlin D, Sumi M, Alvord EC. Neuropathological changes in the visual cortex in Alzheimer's disease. Neurosci Res Commun. 1990;6(3):163-71.

33. Paroni G, Bisceglia P, Seripa D. Understanding the Amyloid Hypothesis in Alzheimer's Disease. J Alzheimers Dis. 2019;68(2):493-510. doi: 10.3233/JAD-180802.

34. Lacor PN, Buniel MC, Furlow PW, et al. Aβ Oligomer-Induced Aberrations in Synapse Composition, Shape, and Density Provide a Molecular Basis for Loss of Connectivity in Alzheimer's Disease. J Neurosci. 2007 Jan 24; 27(4):796-807.

35. Carroll BJ. Ageing, stress and the brain. Endocrine Facets of Ageing. Novartis Foundation Symposium 2002;242:26-36.

36. Armstrong RA. A critical analysis of the 'amyloid cascade hypothesis'. Folia Neuropathol 2014;52(3):211-225.

37. Litvinenko IV, Emelin AYu, Lobzin VYu, Kolmakova KA. Neuroimaging techniques for diagnosing Alzheimer’s disease and cerebrovascular diseases with cognitive impairment. Nevrologiya, neiropsikhiatriya, psikhosomatika = Neurology, Neuropsychiatry, Psychosomatics. 2019;11(3S):18-25. (In Russ.). doi: 10.14412/2074-2711-2019-3S-18-25

38. Huang YM, Shen J, Zhao HL. Major Clinical Trials Failed the Amyloid Hypothesis of Alzheimer's Disease. J Am Geriatr Soc. 2019 Apr; 67(4):841-844.

39. Matsunaga S, Kishi T, Iwata N. Memantine monotherapy for Alzheimer's disease: a systematic review and meta-analysis. PLoS One. 2015 Apr 10;10(4):e0123289.

40. Schmidt R, Ropele S, Pendl B, et al. Longitudinal multimodal imaging in mild to moderate Alzheimer disease: a pilot study with memantine. Folia Neuropathol. 2014;52(3): 211-25. doi:10.1136/jnnp.2007.141648.