The amyloid cascade hypothesis for Alzheimer's disease: An appraisal for the development of therapeutics

Nature Reviews Drug Discovery

Volumn 10, Issue 9, 2011, Pages 698-712

  Karran, Eric ^a   Mercken, Marc ^a   Strooper, Bart De ^b  

^a JANSSEN RESEARCH AND DEVELOPMENT   (Belgium)

^b UNIVERSITY OF LEUVEN   (Belgium)

Author keywords

[No Author keywords available]

Indexed keywords

AMYLOID BETA PROTEIN; AMYLOID BETA PROTEIN[1-40]; AMYLOID BETA PROTEIN[1-42]; AMYLOID PRECURSOR PROTEIN; APOLIPOPROTEIN E2; APOLIPOPROTEIN E3; APOLIPOPROTEIN E4; BAPINEUZUMAB; BETA SECRETASE; DONEPEZIL; DOXYCYCLINE; GALANTAMINE; GAMMA SECRETASE INHIBITOR; MEMANTINE; N2 [2 (3,5 DIFLUOROPHENYL) 2 HYDROXYACETYL] N1 (6,7 DIHYDRO 5 METHYL 6 OXO 5H DIBENZ[B,D]AZEPIN 7 YL)ALANINAMIDE; PLACEBO; PRESENILIN 1; PRESENILIN 2; RIVASTIGMINE; SOLANEZUMAB; TAU PROTEIN;

ALZHEIMER DISEASE; AMINO ACID SUBSTITUTION; AMYLOID PLAQUE; BLOOD BRAIN BARRIER; BRAIN ATROPHY; CEREBROSPINAL FLUID; DEMENTIA; DISEASE COURSE; DISEASE DURATION; ENZYME INHIBITION; FAMILIAL DISEASE; GENETIC ASSOCIATION; HEALTH CARE COST; HEALTH CARE SYSTEM; HUMAN; INTERSTITIAL FLUID; NEUROFIBRILLARY TANGLE; NEUROTRANSMISSION; NONHUMAN; ONSET AGE; PRIORITY JOURNAL; PROTEIN AGGREGATION; PROTEIN CLEAVAGE; REVIEW; RISK FACTOR;

AGE OF ONSET; ALZHEIMER DISEASE; AMYLOID BETA-PEPTIDES; ANIMALS; BRAIN CHEMISTRY; CLINICAL TRIALS, PHASE II AS TOPIC; CLINICAL TRIALS, PHASE III AS TOPIC; DISEASE PROGRESSION; HUMANS; PLAQUE, AMYLOID; RESEARCH DESIGN; TREATMENT FAILURE;

EID: 80052266213     PISSN: 14741776     EISSN: 14741784     Source Type: Journal    
DOI: 10.1038/nrd3505     Document Type: Review

References (150)

1. Golde, T. E., Petrucelli, L. & Lewis, J. Targeting Aβ and tau in Alzheimer's disease, an early interim report. Exp. Neurol. 223, 252-266 (2010).
2. Ness, D. K. et al. Reduced β-amyloid burden, increased C-99 concentrations and evaluation of neuropathology in the brains of PDAPP mice given LY450139 dihydrate daily by gavage for 5 months. Neurobiol. Aging 25, S238-S239 (2004).
3. Bateman, R. J. et al. A γ-secretase inhibitor decreases amyloid-β production in the central nervous system. Ann. Neurol. 66, 48-54 (2009).
4. Lanz, T. A. et al. Concentration-dependent modulation of amyloid-β in vivo and in vitro using the γ-secretase inhibitor, LY-450139. J. Pharmacol. Exp. Ther. 319, 924-933 (2006).
5. Wakabayashi, T. & De Strooper, B. Presenilins: members of the γ-secretase quartets, but part-time soloists too. Physiology (Bethesda) 23, 194-204 (2008).
6. Holtzman, D. M., Morris, J. C. & Goate, A. M. Alzheimer's disease: the challenge of the second century. Sci. Transl. Med. 3, 77sr1 (2011).
7. Golde, T. E., Schneider, L. S. & Koo, E. H. Anti-Aβ therapeutics in Alzheimer's disease: the need for a paradigm shift. Neuron 69, 203-213 (2011).
8. Burns, A. & Ilife, S. Dementia. BMJ 338, 405-409 (2009).
9. Wimo, A. & Prince, M. World Alzheimer Report 2010: The Global Economic Impact of Dementia. Alzheimer's Disease International [online], http://www.alz.co.uk/research/files/WorldAlzheimerReport2010.pdf (2011).
10. Alzheimer, A. About a peculiar disease of the cerebral cortex. [in German] Centralblatt für Nervenheilkunde Psychiatrie 30, 177-179 (1907).
11. Goate, A. et al. Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease. Nature 349, 704-706 (1991). (Pubitemid 21912142)
12. Hussain, I. et al. Identification of a novel aspartic protease (Asp 2) as β-secretase. Mol. Cell Neurosci. 14, 419-427 (1999). (Pubitemid 30026585)
13. Lin, X. et al. Human aspartic protease memapsin 2 cleaves the β-secretase site of β-amyloid precursor protein. Proc. Natl Acad. Sci. USA 97, 1456-1460 (2000). (Pubitemid 30118462)
14. Sinha, S. et al. Purification and cloning of amyloid precursor protein β-secretase from human brain. Nature 402, 537-540 (1999).
15. Vassar, R. et al. β-secretase cleavage of Alzheimer's amyloid precursor protein by the transmembrane aspartic protease BACE. Science 286, 735-741 (1999).
16. Yan, R. et al. Membrane-anchored aspartyl protease with Alzheimer's disease β-secretase activity. Nature 402, 533-537 (1999).
17. De Strooper, B. et al. Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein. Nature 391, 387-390 (1998). (Pubitemid 28093512)
18. Wolfe, M. S. et al. Two transmembrane aspartates in presenilin-1 required for presenilin endoproteolysis and γ-secretase activity. Nature 398, 513-517 (1999).
19. Hardy, J. A. & Higgins, G. A. Alzheimer's disease: the amyloid cascade hypothesis. Science 256, 184-185 (1992).
20. Hardy, J. & Selkoe, D. J. The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science 297, 353-356 (2002). (Pubitemid 34790756)
21. Selkoe, D. J. The molecular pathology of Alzheimer's disease. Neuron 6, 487-498 (1991).
22. Hardy, J. & Allsop, D. Amyloid deposition as the central event in the aetiology of Alzheimer's disease. Trends Pharmacol. Sci. 12, 383-388 (1991).
23. Sherrington, R. et al. Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease. Nature 375, 754-760 (1995).
24. Levy-Lahad, E. et al. Candidate gene for the chromosome 1 familial Alzheimer's disease locus. Science 269, 973-977 (1995).
25. Rogaev, E. I. et al. Familial Alzheimer's disease in kindreds with missense mutations in a gene on chromosome 1 related to the Alzheimer's disease type 3 gene. Nature 376, 775-778 (1995).
26. Corder, E. H. et al. Gene dosage of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science 261, 921-923 (1993). (Pubitemid 23275809)
27. Strittmatter, W. J. et al. Apolipoprotein E: high avidity binding to β-amyloid and increased frequency of type 4 allele in late onset familial Alzheimer disease. Proc. Natl Acad. Sci. USA 90, 1977-1981 (1993). (Pubitemid 23069980)
28. Nickerson, D. A. et al. Sequence diversity and large-scale typing of SNPs in the human apolipoprotein E gene. Genome Res. 10, 1532-1545 (2000).
29. Farrer, L. A. et al. Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. A meta-analysis. JAMA 278, 1349-1356 (1997). (Pubitemid 27449696)
30. Holtzman, D. M. et al. Apolipoprotein E isoform-dependent amyloid deposition and neuritic degeneration in a mouse model of Alzheimer's disease. Proc. Natl Acad. Sci. USA 97, 2892-2897 (2000). (Pubitemid 30159268)
31. Kim, J., Basak, J. M. & Holtzman, D. M. The role of apolipoprotein E in Alzheimer's disease. Neuron 63, 287-303 (2009).
32. Harold, D. et al. Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease. Nature Genet. 41, 1088-1093 (2009).
33. Lambert, J. C. et al. Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer's disease. Nature Genet. 41, 1094-1099 (2009).
34. Hollingworth, P. et al. Common variants at ABCA7, MS4Ai6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer's disease. Nature Genet. 43, 429-435 (2011).
35. Hutton, M. et al. Association of missense and 5′-splice-site mutations in tau with the inherited dementia FTDP-17. Nature 393, 702-705 (1998).
36. Roberson, E. D. et al. Amyloid-β/Fyn-induced synaptic, network, and cognitive impairments depend on tau levels in multiple mouse models of Alzheimer's disease. J. Neurosci. 31, 700-711 (2011).
37. Roberson, E. D. et al. Reducing endogenous tau ameliorates amyloid β-induced deficits in an Alzheimer's disease mouse model. Science 316, 750-754 (2007). (Pubitemid 46717684)
38. Welander, H. et al. Aβ43 is more frequent than Aβ40 in amyloid plaque cores from Alzheimer disease brains. J. Neurochem. 110, 697-706 (2009).
39. Arnold, S. E., Hyman, B. T., Flory, J., Damasio, A. R. & Van Hoesen, G. W. The topographical and neuro-anatomical distribution of neurofibrillary tangles and neuritic plaques in the cerebral cortex of patients with Alzheimer's disease. Cereb. Cortex 1, 103-116 (1991).
40. Azevedo, F. A. et al. Equal numbers of neuronal and nonneuronal cells make the human brain an isometrically scaled-up primate brain. J. Comp. Neurol. 513, 532-541 (2009).
41. Gravina, S. A. et al. Amyloid β protein (Aβ) in Alzheimer's disease brain. Biochemical and immunocytochemical analysis with antibodies specific for forms ending at Aβ40 or Aβ42(43). J. Biol. Chem. 270, 7013-7016 (1995).
42. Naslund, J. et al. Correlation between elevated levels of amyloid β-peptide in the brain and cognitive decline. JAMA 283, 1571-1577 (2000). (Pubitemid 30161512)
43. Delacourte, A. et al. Nonoverlapping but synergetic tau and APP pathologies in sporadic Alzheimer's disease. Neurology 59, 398-407 (2002). (Pubitemid 34857933)
44. Bateman, R. J. et al. Human amyloid-β synthesis and clearance rates as measured in cerebrospinal fluid in vivo. Nature Med. 12, 856-861 (2006). (Pubitemid 44050079)
45. Iwata, N. et al. Identification of the major Aβ1-42-degrading catabolic pathway in brain parenchyma: suppression leads to biochemical and pathological deposition. Nature Med. 6, 143-150 (2000). (Pubitemid 30082357)
46. Vekrellis, K. et al. Neurons regulate extracellular levels of amyloid β-protein via proteolysis by insulin-degrading enzyme. J. Neurosci. 20, 1657-1665 (2000). (Pubitemid 30220363)
47. Wang, D.-S., Dickson, D. W. & Malter, J. S. β-Amyloid degradation and Alzheimer's disease. J. Biomed. Biotechnol. 2006, 1-12 (2006).
48. Tseng, B. P. et al. Deposition of monomeric, not oligomeric, Aβ mediates growth of Alzheimer's disease amyloid plaques in human brain preparations. Biochemistry 38, 10424-10431 (1999).
49. Shibata, M. et al. Clearance of Alzheimer's amyloid-β1-40 peptide from brain by LDL receptor-related protein-1 at the blood-brain barrier. J. Clin. Invest. 106, 1489-1499 (2000). (Pubitemid 32038587)
50. Cirrito, J. R. et al. In vivo assessment of brain interstitial fluid with microdialysis reveals plaque-associated changes in amyloid-β metabolism and half-life. J. Neurosci. 23, 8844-8853 (2003). (Pubitemid 37210896)
51. Redzic, Z. B., Preston, J. E., Duncan, J. A., Chodobski, A. & Szmydynger-Chodobska, J. The choroid plexus-cerebrospinal fluid system: from development to aging. Curr. Top. Dev. Biol. 71, 1-52 (2005). (Pubitemid 43588887)
52. Esler, W. P. et al. Alzheimer's disease amyloid propagation by a template-dependent dock-lock mechanism. Biochemistry 39, 6288-6295 (2000). (Pubitemid 30347132)
53. Maggio, J. E. et al. Reversible in vitro growth of Alzheimer disease β-amyloid plaques by deposition of labeled amyloid peptide. Proc. Natl Acad. Sci. USA 89, 5462-5466 (1992).
54. Yan, P. et al. Characterizing the appearance and growth of amyloid plaques in APP/PS1 mice. J. Neurosci. 29, 10706-10714 (2009).
55. Garcia-Alloza, M. et al. Existing plaques and neuritic abnormalities in APP: PS1 mice are not affected by administration of the γ-secretase inhibitor LY-411575. Mol. Neurodegener. 4, 19 (2009).
56. Hefendehl, J. K. et al. Long-term in vivo imaging of β-amyloid plaque appearance and growth in a mouse model of cerebral β-amyloidosis. J. Neurosci. 31, 624-629 (2011).
57. Jack, C. R. Jr et al. Hypothetical model of dynamic biomarkers of the Alzheimer's pathological cascade. Lancet Neurol. 9, 119-128 (2010).
58. Abramowski, D. et al., Dynamics of Aβ turnover and deposition in different β-amyloid precursor protein transgenic mouse models following γ-secretase inhibition. J. Pharmacol. Exp. Ther. 327, 411-424 (2008).
59. Jankowsky, J. L. et al. Persistent amyloidosis following suppression of Aβ production in a transgenic model of Alzheimer disease. PLoS Med. 2, e355 (2005).
60. McConlogue, L. et al. Partial reduction of BACE1 has dramatic effects on Alzheimer plaque and synaptic pathology in APP transgenic mice. J. Biol. Chem. 282, 26326-26334 (2007). (Pubitemid 47443774)
61. DeMattos, R. B., Bales, K. R., Cummins, D. J., Paul, S. M. & Holtzman, D. M. Brain to plasma amyloid-β efflux: a measure of brain amyloid burden in a mouse model of Alzheimer's disease. Science 295, 2264-2267 (2002). (Pubitemid 34258840)
62. DeMattos, R. B. et al. Peripheral anti-Aβ antibody alters CNS and plasma Aβ clearance and decreases brain Aβ burden in a mouse model of Alzheimer's disease. Proc. Natl Acad. Sci. USA 98, 8850-8855 (2001).
63. Schenk, D. et al. Immunization with amyloid-β attenuates Alzheimer-disease-like pathology in the PDAPP mouse. Nature 400, 173-177 (1999). (Pubitemid 29327547)
64. Bard, F. et al. Peripherally administered antibodies against amyloid β-peptide enter the central nervous system and reduce pathology in a mouse model of Alzheimer disease. Nature Med. 6, 916-919 (2000). (Pubitemid 30644751)
65. Fagan, A. M. et al. Inverse relation between in vivo amyloid imaging load and cerebrospinal fluid Aβ42 in humans. Ann. Neurol. 59, 512-519 (2006). (Pubitemid 43358072)
66. Price, J. L. et al. Neuropathology of non-demented aging: presumptive evidence for preclinical Alzheimer disease. Neurobiol. Aging 30, 1026-1036 (2009).
67. Shaw, L. M. et al. Cerebrospinal fluid biomarker signature in Alzheimer's disease neuroimaging initiative subjects. Ann. Neurol. 65, 403-413 (2009).
68. De Meyer, G. et al. Diagnosis-independent Alzheimer disease biomarker signature in cognitively normal elderly people. Arch. Neurol. 67, 949-956 (2010).
69. Fagan, A. M. et al. Cerebrospinal fluid tau and ptau181 increase with cortical amyloid deposition in cognitively normal individuals: implications for future clinical trials of Alzheimer's disease. EMBO Mol. Med. 1, 371-380 (2009).
70. Saido, T. C., Yamao-Harigaya, W., Iwatsubo, T. & Kawashima, S. Amino-and carboxyl-terminal heterogeneity of β-amyloid peptides deposited in human brain. Neurosci. Lett. 215, 173-176 (1996). (Pubitemid 26323454)
71. Saido, T. C. et al. Dominant and differential deposition of distinct β-amyloid peptide species, AβN3(pE), in senile plaques. Neuron 14, 457-466 (1995).
72. Nicoll, J. A. et al. Neuropathology of human Alzheimer disease after immunization with amyloid-β peptide: a case report. Nature Med. 9, 448-452 (2003).
73. De Strooper, B. Proteases and proteolysis in Alzheimer disease: a multifactorial view on the disease process. Physiol. Rev. 90, 465-494 (2010).
74. Serneels, L. et al. Differential contribution of the three Aph1 genes to γ-secretase activity in vivo. Proc. Natl Acad. Sci. USA 102, 1719-1724 (2005). (Pubitemid 40209234)
75. Herreman, A. et al. Presenilin 2 deficiency causes a mild pulmonary phenotype and no changes in amyloid precursor protein processing but enhances the embryonic lethal phenotype of presenilin 1 deficiency. Proc. Natl Acad. Sci. USA 96, 11872-11877 (1999). (Pubitemid 29502825)
76. Baumeister, R. et al. Human presenilin-1, but not familial Alzheimer's disease (FAD) mutants, facilitate Caenorhabditis elegans Notch signalling independently of proteolytic processing. Genes Funct. 1, 149-159 (1997).
77. Song, W. et al. Proteolytic release and nuclear translocation of Notch-1 are induced by presenilin-1 and impaired by pathogenic presenilin-1 mutations. Proc. Natl Acad. Sci. USA 96, 6959-6963 (1999). (Pubitemid 29274992)
78. Bentahir, M. et al. Presenilin clinical mutations can affect γ-secretase activity by different mechanisms. J. Neurochem. 96, 732-742 (2006).
79. De Strooper, B. Loss-of-function presenilin mutations in Alzheimer disease. Talking point on the role of presenilin mutations in Alzheimer disease. EMBO Rep. 8, 141-146 (2007). (Pubitemid 46420841)
80. Wolfe, M. S. When loss is gain: reduced presenilin proteolytic function leads to increased Aβ42/Aβ40. Talking point on the role of presenilin mutations in Alzheimer disease. EMBO Rep. 8, 136-140 (2007). (Pubitemid 46420840)
81. Yagishita, S., Morishima-Kawashima, M., Tanimura, Y., Ishiura, S. & Ihara, Y. DAPT-induced intracellular accumulations of longer amyloid β-proteins: further implications for the mechanism of intramembrane cleavage by γ-secretase. Biochemistry 45, 3952-3960 (2006).
82. Takami, M. et al. γ-Secretase: successive tripeptide and tetrapeptide release from the transmembrane domain of β-carboxyl terminal fragment. J. Neurosci. 29, 13042-13052 (2009).
83. Saito, T. et al. Potent amyloidogenicity and pathogenicity of Aβ43. Nature Neurosci. 14, 1023-1032 (2011).
84. Portelius, E. et al. Distinct cerebrospinal fluid amyloid β peptide signatures in sporadic and PSEN1 A431E-associated familial Alzheimer's disease. Mol. Neurodegener. 5, 2 (2010).
85. Snider, B. J. et al. Novel presenilin 1 mutation (S170F) causing Alzheimer disease with Lewy bodies in the third decade of life. Arch. Neurol. 62, 1821-1830 (2005). (Pubitemid 41785075)
86. Hellstrom-Lindahl, E., Viitanen, M. & Marutle, A. Comparison of Aβ levels in the brain of familial and sporadic Alzheimer's disease. Neurochem. Int. 55, 243-252 (2009).
87. Kim, J. et al. Aβ40 inhibits amyloid deposition in vivo. J. Neurosci. 27, 627-633 (2007). (Pubitemid 46143766)
88. Meyer-Luehmann, M. et al. Exogenous induction of cerebral β-amyloidogenesis is governed by agent and host. Science 313, 1781-1784 (2006). (Pubitemid 44454153)
89. Braak, H. & Braak, E. Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol. 82, 239-259 (1991).
90. Gomez-Isla, T. et al. Neuronal loss correlates with but exceeds neurofibrillary tangles in Alzheimer's disease. Ann. Neurol. 41, 17-24 (1997). (Pubitemid 27057088)
91. Savva, G. M. et al. Age, neuropathology, and dementia. N. Engl. J. Med. 360, 2302-2309 (2009).
92. Rowe, C. C. et al. Amyloid imaging results from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study of aging. Neurobiol. Aging 31, 1275-1283 (2010).
93. Clavaguera, F. et al. Transmission and spreading of tauopathy in transgenic mouse brain. Nature Cell Biol. 11, 909-913 (2009).
94. Olzscha, H. et al. Amyloid-like aggregates sequester numerous metastable proteins with essential cellular functions. Cell 144, 67-78 (2011).
95. Thies, W. & Bleiler, L. 2011 Alzheimer's disease facts and figures. Alzheimers Dement. 7, 208-244 (2011).
96. Reisberg, B. Dementia: a systematic approach to identifying reversible causes. Geriatrics 41, 30-46 (1986). (Pubitemid 16014042)
97. Helzner, E. P. et al. Survival in Alzheimer disease: a multiethnic, population-based study of incident cases. Neurology 71, 1489-1495 (2008).
98. Larson, E. B. et al. Survival after initial diagnosis of Alzheimer disease. Ann. Intern. Med. 140, 501-509 (2004).
99. Ganguli, M., Dodge, H. H., Shen, C., Pandav, R. S. & DeKosky, S. T. Alzheimer disease and mortality: a 15-year epidemiological study. Arch. Neurol. 62, 779-784 (2005). (Pubitemid 40656094)
100. Holmes, C. Genotype and phenotype in Alzheimer's disease. Br. J. Psychiatry 180, 131-134 (2002). (Pubitemid 34142783)
101. Swearer, J. M., O'Donnell, B. F., Ingram, S. M. & Drachman, D. A. Rate of progression in familial Alzheimer's disease. J. Geriatr. Psychiatry Neurol. 9, 22-25 (1996). (Pubitemid 26090772)
102. Holmes, C. & Lovestone, S. The clinical phenotype of familial and sporadic late onset Alzheimer's disease. Int. J. Geriatr. Psychiatry 17, 146-149 (2002). (Pubitemid 34130305)
103. Kumar-Singh, S. et al. Mean age-of-onset of familial alzheimer disease caused by presenilin mutations correlates with both increased Aβ42 and decreased Aβ40. Hum. Mutat. 27, 686-695 (2006).
104. Acosta-Baena, N. et al. Pre-dementia clinical stages in presenilin 1 E280A familial early-onset Alzheimer's disease: a retrospective cohort study. Lancet Neurol. 10, 213-220 (2011).
105. Godbolt, A. K. et al. The natural history of Alzheimer disease: a longitudinal presymptomatic and symptomatic study of a familial cohort. Arch. Neurol. 61, 1743-1748 (2004). (Pubitemid 39463432)
106. Meyer, M. R. et al. APOE genotype predicts when-not whether-one is predisposed to develop Alzheimer disease. Nature Genet. 19, 321-322 (1998). (Pubitemid 28357900)
107. Craft, S. et al. Accelerated decline in apolipoprotein E-epsilon4 homozygotes with Alzheimer's disease. Neurology 51, 149-153 (1998). (Pubitemid 28345375)
108. Dal Forno, G. et al. APOE genotype and survival in men and women with Alzheimer's disease. Neurology 58, 1045-1050 (2002). (Pubitemid 34298543)
109. Allan, C. L. & Ebmeier, K. P. The influence of APOE4 on clinical progression of dementia: a meta-analysis. Int. J. Geriatr. Psychiatry 26, 520-526 (2011).
110. Pastor, P. et al. Apolipoprotein Eε4 modifies Alzheimer's disease onset in an E280A PS1 kindred. Ann. Neurol. 54, 163-169 (2003). (Pubitemid 36909615)
111. Morris, J. C. et al. APOE predicts amyloid-β but not tau Alzheimer pathology in cognitively normal aging. Ann. Neurol. 67, 122-131 (2010).
112. Hardy, J. Expression of normal sequence pathogenic proteins for neurodegenerative disease contributes to disease risk: 'permissive templating' as a general mechanism underlying neurodegeneration. Biochem. Soc. Trans. 33, 578-581 (2005). (Pubitemid 41160813)
113. Lambert, M. P. et al. Diffusible, nonfibrillar ligands derived from Aβ1-42 are potent central nervous system neurotoxins. Proc. Natl Acad. Sci. USA 95, 6448-6453 (1998).
114. Lesne, S. et al. A specific amyloid-β protein assembly in the brain impairs memory. Nature. 440, 352-357 (2006).
115. Shankar, G. M. et al. Amyloid-β protein dimers isolated directly from Alzheimer's brains impair synaptic plasticity and memory. Nature Med. 14, 837-842 (2008).
116. Hepler, R. W. et al. Solution state characterization of amyloid β-derived diffusible ligands. Biochemistry 45, 15157-15167 (2006). (Pubitemid 46032442)
117. Jones, L. et al. Genetic evidence implicates the immune system and cholesterol metabolism in the aetiology of Alzheimer's disease. PLoS ONE 5, e13950 (2010).
118. Shen, J. & Kelleher, R. J. The presenilin hypothesis of Alzheimer's disease: evidence for a loss-of-function pathogenic mechanism. Proc. Natl Acad. Sci. USA 104, 403-409 (2007). (Pubitemid 46123039)
119. Wang, B. et al. γ-secretase gene mutations in familial acne inversa. Science 330, 1065 (2010).
120. Pink, A. E. et al. PSENEN and NCSTN mutations in familial hidradenitis suppurativa (acne inversa). J. Invest. Dermatol. 131, 1568-1570 (2011).
121. Blennow, K. et al. Immunotherapy with bapineuzumab lowers CSF tau protein levels in patients with Alzheimer's disease. Alzheimers Dement. 6, S134-S135 (2010).
122. Rinne, J. O. et al. 11C-PiB PET assessment of change in fibrillar amyloid-β load in patients with Alzheimer's disease treated with bapineuzumab: a phase 2, double-blind, placebo-controlled, ascending-dose study. Lancet Neurol. 9, 363-372 (2010).
123. Holmes, C. et al. Long-term effects of Aβ42 immunisation in Alzheimer's disease: follow-up of a randomised, placebo-controlled phase I trial. Lancet 372, 216-223 (2008). (Pubitemid 351978111)
124. Mangialasche, F., Solomon, A., Winblad, B., Mecocci, P. & Kivipelto, M. Alzheimer's disease: clinical trials and drug development. Lancet Neurol. 9, 702-716 (2010).
125. Braak, H. & Braak, E. Staging of Alzheimer-related cortical destruction. Int. Psychogeriatr. 9 (Suppl. 1), 257-261 (1997).
126. Jalbert, J. J., Daiello, L. A. & Lapane, K. L. Dementia of the Alzheimer type. Epidemiol. Rev. 30, 15-34 (2008).
127. Rosen, W. G., Mohs, R. C. & Davis, K. L. A new rating scale for Alzheimer's disease. Am. J. Psychiatry 141, 1356-1364 (1984).
128. Schneider, L. S. & Sano, M. Current Alzheimer's disease clinical trials: methods and placebo outcomes. Alzheimers Dement. 5, 388-397 (2009).
129. Mohs, R. C. The clinical syndrome of Alzheimer's disease: aspects particularly relevant to clinical trials. Genes Brain Behav. 4, 129-133 (2005). (Pubitemid 40559139)
130. Morris, J. C. The Clinical Dementia Rating (CDR): current version and scoring rules. Neurology 43, 2412-2414 (1993). (Pubitemid 23346995)
131. Galasko, D. et al. An inventory to assess activities of daily living for clinical trials in Alzheimer's disease. The Alzheimer's Disease Cooperative Study. Alzheimer Dis. Assoc. Disord. 11 (Suppl. 2), 33-39 (1997).
132. Gelinas, I., Gauthier, L., McIntyre, M. & Gauthier, S. Development of a functional measure for persons with Alzheimer's disease: the disability assessment for dementia. Am. J. Occup. Ther. 53, 471-481 (1999).
133. Schneider, L. S. et al. Validity and reliability of the Alzheimer's disease cooperative study-clinical global impression of change. The Alzheimer's Disease Cooperative Study. Alzheimer Dis. Assoc. Disord. 11 (Suppl. 2), 22-32 (1997).
134. Hampel, H. et al. Biomarkers for Alzheimer's disease: academic, industry and regulatory perspectives. Nature Rev. Drug Discov. 9, 560-574 (2010).
135. Leber, P. Slowing the progression of Alzheimer disease: methodologic issues. Alzheimer Dis. Assoc. Disord. 11 (Suppl. 5), 10-21 (1997).
136. Mohs, R. C., Kawas, C. & Carrillo, M. C. Optimal design of clinical trials for drugs designed to slow the course of Alzheimer's disease. Alzheimers Dement. 2, 131-139 (2006). (Pubitemid 43843103)
137. Moghekar, A. et al. Large quantities of Aβ peptide are constitutively released during amyloid precursor protein metabolism in vivo and in vitro. J. Biol. Chem. 286, 15989-15997 (2011).
138. Silverberg, G. D., Mayo, M., Saul, T., Rubenstein, E. & McGuire, D. Alzheimer's disease, normal-pressure hydrocephalus, and senescent changes in CSF circulatory physiology: a hypothesis. Lancet Neurol. 2, 506-511 (2003). (Pubitemid 36876108)
139. Jack, C. R. Jr et al. Introduction to the recommendations from the National Institute on Aging and the Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement. 7, 257-262 (2011).
140. Sperling, R. A. et al. Toward defining the preclinical stages of Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement. 7, 280-292 (2011).
141. Khachaturian, Z. S. et al. Developing a global strategy to prevent Alzheimer's disease: Leon Thal Symposium 2010. Alzheimers Dement. 7, 127-132 (2011).
142. Thorvaldsson, V. et al. Onset and rate of cognitive change before dementia diagnosis: findings from two Swedish population-based longitudinal studies. J. Int. Neuropsychol. Soc. 17, 154-162 (2011).
143. Games, D. et al. Alzheimer-type neuropathology in transgenic mice overexpressing V717F β-amyloid precursor protein. Nature 373, 523-527 (1995).
144. Glabe, C. G. Common mechanisms of amyloid oligomer pathogenesis in degenerative disease. Neurobiol. Aging 27, 570-575 (2006). (Pubitemid 43290525)
145. Walsh, D. M. et al. Naturally secreted oligomers of amyloid β protein potently inhibit hippocampal long-term potentiation in vivo. Nature 416, 535-539 (2002). (Pubitemid 34288854)
146. Kuperstein, I. et al. Neurotoxicity of Alzheimer's disease Aβ peptides is induced by small changes in the Aβ42 to Aβ40 ratio. EMBO J. 29, 3408-3420 (2010).
147. Bernstein, S. L. et al. Amyloid-β protein oligomerization and the importance of tetramers and dodecamers in the aetiology of Alzheimer's disease. Nature Chem. 1, 326-331 (2009).
148. Scheuner, D. et al. Secreted amyloid β-protein similar to that in the senile plaques of Alzheimer's disease is increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer's disease. Nature Med. 2, 864-870 (1996). (Pubitemid 26296755)
149. van Broeckhoven, C. & Kumar-Singh, S. Genetics and pathology of α-secretase site AβPP mutations in the understanding of Alzheimer's disease. J. Alzheimers Dis. 9, 389-398 (2006). (Pubitemid 44253333)
150. Zhang-Nunes, S. X. et al. The cerebral β-amyloid angiopathies: hereditary and sporadic. Brain Pathol. 16, 30-39 (2006).