The amyloid cascade hypothesis for Alzheimer's disease: an appraisal for the development of therapeutics (original) (raw)

• 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).
  Article CAS PubMed Google Scholar
• 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).
  Article Google Scholar
• Bateman, R. J. et al. A γ-secretase inhibitor decreases amyloid-β production in the central nervous system. Ann. Neurol. 66, 48–54 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• 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).
  Article CAS PubMed Google Scholar
• Wakabayashi, T. & De Strooper, B. Presenilins: members of the γ-secretase quartets, but part-time soloists too. Physiology (Bethesda) 23, 194–204 (2008).
  CAS Google Scholar
• Holtzman, D. M., Morris, J. C. & Goate, A. M. Alzheimer's disease: the challenge of the second century. Sci. Transl. Med. 3, 77sr1 (2011).
  PubMed PubMed Central Google Scholar
• 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).
  Article CAS PubMed PubMed Central Google Scholar
• Burns, A. & Ilife, S. Dementia. BMJ 338, 405–409 (2009).
  Google Scholar
• Wimo, A. & Prince, M. World Alzheimer Report 2010: The Global Economic Impact of Dementia. Alzheimer's Disease International [online], (2011).
  Google Scholar
• Alzheimer, A. About a peculiar disease of the cerebral cortex. [in German] Centralblatt für Nervenheilkunde Psychiatrie 30, 177–179 (1907).
  Google Scholar
• 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). This seminal paper identified that a mutation in the APP gene causes autosomal dominant AD, thereby providing important support for the amyloid cascade hypothesis.
  Article CAS PubMed Google Scholar
• Hussain, I. et al. Identification of a novel aspartic protease (Asp 2) as β-secretase. Mol. Cell Neurosci. 14, 419–427 (1999).
  Article CAS PubMed Google Scholar
• 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).
  Article CAS PubMed PubMed Central Google Scholar
• Sinha, S. et al. Purification and cloning of amyloid precursor protein β-secretase from human brain. Nature 402, 537–540 (1999).
  Article CAS PubMed Google Scholar
• Vassar, R. et al. β-secretase cleavage of Alzheimer's amyloid precursor protein by the transmembrane aspartic protease BACE. Science 286, 735–741 (1999).
  Article CAS PubMed Google Scholar
• Yan, R. et al. Membrane-anchored aspartyl protease with Alzheimer's disease β-secretase activity. Nature 402, 533–537 (1999). References 12, 13, 14 and 16 identified the BACE enzyme, which is the enzyme responsible for initiating amyloid-β generation.
  Article CAS PubMed Google Scholar
• De Strooper, B. et al. Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein. Nature 391, 387–390 (1998). This work demonstrated that PSEN1 is an essential component of the γ-secretase complex, and required for γ-secretase activity.
  Article CAS PubMed Google Scholar
• Wolfe, M. S. et al. Two transmembrane aspartates in presenilin-1 required for presenilin endoproteolysis and γ-secretase activity. Nature 398, 513–517 (1999). This was the first paper to suggest that the aspartate residues in transmembrane domains 6 and 7 of PSEN participate in the catalytic function of γ-secretase.
  Article CAS PubMed Google Scholar
• Hardy, J. A. & Higgins, G. A. Alzheimer's disease: the amyloid cascade hypothesis. Science 256, 184–185 (1992). This paper is acknowledged as being the first, complete articulation of the amyloid cascade hypothesis.
  Article CAS PubMed Google Scholar
• 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).
  Article CAS PubMed Google Scholar
• Selkoe, D. J. The molecular pathology of Alzheimer's disease. Neuron 6, 487–498 (1991).
  Article CAS PubMed Google Scholar
• Hardy, J. & Allsop, D. Amyloid deposition as the central event in the aetiology of Alzheimer's disease. Trends Pharmacol. Sci. 12, 383–388 (1991).
  Article CAS PubMed Google Scholar
• Sherrington, R. et al. Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease. Nature 375, 754–760 (1995). This work identified the PSEN1 gene by linkage analysis.
  Article CAS PubMed Google Scholar
• Levy-Lahad, E. et al. Candidate gene for the chromosome 1 familial Alzheimer's disease locus. Science 269, 973–977 (1995).
  Article CAS PubMed Google Scholar
• 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).
  Article CAS PubMed Google Scholar
• 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). This paper identified APOE4 as a major risk gene for AD.
  Article CAS PubMed Google Scholar
• 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).
  Article CAS PubMed PubMed Central Google Scholar
• 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).
  Article CAS PubMed PubMed Central Google Scholar
• 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).
  Article CAS PubMed Google Scholar
• 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). This paper demonstrates the crucial role of APOE in amyloid-β deposition, providing a link between the major genetic risk factor for AD and the amyloid cascade hypothesis.
  Article CAS PubMed PubMed Central Google Scholar
• Kim, J., Basak, J. M. & Holtzman, D. M. The role of apolipoprotein E in Alzheimer's disease. Neuron 63, 287–303 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• 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).
  Article CAS PubMed Google Scholar
• 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).
  Article CAS PubMed Google Scholar
• 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).
  Article CAS PubMed Google Scholar
• 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). This paper identified mutations in the tau gene that cause frontotemporal dementia, showing that tau pathology alone is sufficient to cause progressive neurodegeneration.
  Article CAS PubMed Google Scholar
• 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).
  Article CAS PubMed PubMed Central Google Scholar
• 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).
  Article CAS PubMed Google Scholar
• Welander, H. et al. Aβ43 is more frequent than Aβ40 in amyloid plaque cores from Alzheimer disease brains. J. Neurochem. 110, 697–706 (2009).
  Article CAS PubMed Google Scholar
• 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).
  Article CAS PubMed Google Scholar
• 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).
  Article PubMed Google Scholar
• 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).
  Article CAS PubMed Google Scholar
• Naslund, J. et al. Correlation between elevated levels of amyloid β-peptide in the brain and cognitive decline. JAMA 283, 1571–1577 (2000).
  Article CAS PubMed Google Scholar
• Delacourte, A. et al. Nonoverlapping but synergetic tau and APP pathologies in sporadic Alzheimer's disease. Neurology 59, 398–407 (2002).
  Article CAS PubMed Google Scholar
• 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). This paper describes the SILK technology.
  Article CAS PubMed Google Scholar
• 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). This was a systematic analysis of amyloid-β catabolic pathways in vivo , which revealed the role of neprilysin in amyloid-β clearance.
  Article CAS PubMed Google Scholar
• Vekrellis, K. et al. Neurons regulate extracellular levels of amyloid β-protein via proteolysis by insulin-degrading enzyme. J. Neurosci. 20, 1657–1665 (2000). This paper identified insulin degrading enzyme in vitro as one of the enzymes involved in amyloid-β clearance.
  Article CAS PubMed PubMed Central Google Scholar
• Wang, D.-S., Dickson, D. W. & Malter, J. S. β-Amyloid degradation and Alzheimer's disease. J. Biomed. Biotechnol. 2006, 1–12 (2006).
  Article CAS Google Scholar
• 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).
  Article CAS PubMed Google Scholar
• 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).
  Article CAS PubMed PubMed Central Google Scholar
• 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).
  Article CAS PubMed PubMed Central Google Scholar
• 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).
  Article CAS PubMed Google Scholar
• Esler, W. P. et al. Alzheimer's disease amyloid propagation by a template-dependent dock-lock mechanism. Biochemistry 39, 6288–6295 (2000).
  Article CAS PubMed Google Scholar
• 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).
  Article CAS PubMed PubMed Central Google Scholar
• Yan, P. et al. Characterizing the appearance and growth of amyloid plaques in APP/PS1 mice. J. Neurosci. 29, 10706–10714 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• 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).
  Article CAS PubMed PubMed Central Google Scholar
• 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).
  Article CAS PubMed PubMed Central Google Scholar
• Jack, C. R. Jr et al. Hypothetical model of dynamic biomarkers of the Alzheimer's pathological cascade. Lancet Neurol. 9, 119–128 (2010). This is a very influential paper that describes the temporal nature of key AD biomarkers.
  Article CAS PubMed PubMed Central Google Scholar
• 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).
  Article CAS PubMed Google Scholar
• Jankowsky, J. L. et al. Persistent amyloidosis following suppression of Aβ production in a transgenic model of Alzheimer disease. PLoS Med. 2, e355 (2005).
  Article CAS PubMed PubMed Central Google Scholar
• 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).
  Article CAS PubMed Google Scholar
• 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). This was a key paper describing the peripheral sink hypothesis that underpins the development of solanezumab.
  Article CAS PubMed Google Scholar
• 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).
  Article CAS PubMed PubMed Central Google Scholar
• Schenk, D. et al. Immunization with amyloid-β attenuates Alzheimer-disease-like pathology in the PDAPP mouse. Nature 400, 173–177 (1999). A key paper demonstrating that the immunization of PDAPP mice with Aβ42 raises antibodies that facilitate the clearance of parenchymal plaques. This work finally led to the development of bapineuzumab and other amyloid-β-specific antibodies.
  Article CAS PubMed Google Scholar
• 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).
  Article CAS PubMed Google Scholar
• 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).
  Article CAS PubMed Google Scholar
• Price, J. L. et al. Neuropathology of non-demented aging: presumptive evidence for preclinical Alzheimer disease. Neurobiol. Aging 30, 1026–1036 (2009).
  Article PubMed PubMed Central Google Scholar
• Shaw, L. M. et al. Cerebrospinal fluid biomarker signature in Alzheimer's disease neuroimaging initiative subjects. Ann. Neurol. 65, 403–413 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• De Meyer, G. et al. Diagnosis-independent Alzheimer disease biomarker signature in cognitively normal elderly people. Arch. Neurol. 67, 949–956 (2010).
  Article PubMed PubMed Central Google Scholar
• 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).
  Article CAS PubMed PubMed Central Google Scholar
• 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).
  Article CAS PubMed Google Scholar
• 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).
  Article CAS PubMed Google Scholar
• 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).
  Article CAS PubMed Google Scholar
• De Strooper, B. Proteases and proteolysis in Alzheimer disease: a multifactorial view on the disease process. Physiol. Rev. 90, 465–494 (2010).
  Article CAS PubMed Google Scholar
• 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). This was the first evidence that the different γ-secretase complexes differentially contribute to Notch signalling and amyloid-β generation.
  Article CAS PubMed PubMed Central Google Scholar
• 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).
  Article CAS PubMed PubMed Central Google Scholar
• 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).
  Article CAS PubMed Google Scholar
• 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).
  Article CAS PubMed PubMed Central Google Scholar
• Bentahir, M. et al. Presenilin clinical mutations can affect γ-secretase activity by different mechanisms. J. Neurochem. 96, 732–742 (2006). This paper shows that amyloid-β peptide ratios are more important than absolute levels of amyloid-β in understanding the pathogenicity of FAD-linked PSEN mutations.
  Article CAS PubMed Google Scholar
• 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).
  Article CAS PubMed PubMed Central Google Scholar
• 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).
  Article CAS PubMed PubMed Central Google Scholar
• 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).
  Article CAS PubMed Google Scholar
• 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).
  Article CAS PubMed PubMed Central Google Scholar
• Saito, T. et al. Potent amyloidogenicity and pathogenicity of Aβ43. Nature Neurosci. 14, 1023–1032 (2011).
  Article CAS PubMed Google Scholar
• 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).
  Article CAS PubMed PubMed Central Google Scholar
• 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).
  Article PubMed Google Scholar
• 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).
  Article CAS PubMed PubMed Central Google Scholar
• Kim, J. et al. Aβ40 inhibits amyloid deposition in vivo. J. Neurosci. 27, 627–633 (2007).
  Article CAS PubMed PubMed Central Google Scholar
• Meyer-Luehmann, M. et al. Exogenous induction of cerebral β- amyloidogenesis is governed by agent and host. Science 313, 1781–1784 (2006).
  Article CAS PubMed Google Scholar
• Braak, H. & Braak, E. Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol. 82, 239–259 (1991). This is a landmark paper that describes the temporal and brain-regional evolution of AD pathology.
  Article CAS PubMed Google Scholar
• Gomez-Isla, T. et al. Neuronal loss correlates with but exceeds neurofibrillary tangles in Alzheimer's disease. Ann. Neurol. 41, 17–24 (1997).
  Article CAS PubMed Google Scholar
• Savva, G. M. et al. Age, neuropathology, and dementia. N. Engl. J. Med. 360, 2302–2309 (2009).
  Article CAS PubMed Google Scholar
• 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).
  Article PubMed Google Scholar
• Clavaguera, F. et al. Transmission and spreading of tauopathy in transgenic mouse brain. Nature Cell Biol. 11, 909–913 (2009).
  Article CAS PubMed Google Scholar
• Olzscha, H. et al. Amyloid-like aggregates sequester numerous metastable proteins with essential cellular functions. Cell 144, 67–78 (2011).
  Article CAS PubMed Google Scholar
• Thies, W. & Bleiler, L. 2011 Alzheimer's disease facts and figures. Alzheimers Dement. 7, 208–244 (2011).
  Article Google Scholar
• Reisberg, B. Dementia: a systematic approach to identifying reversible causes. Geriatrics 41, 30–46 (1986).
  CAS PubMed Google Scholar
• Helzner, E. P. et al. Survival in Alzheimer disease: a multiethnic, population-based study of incident cases. Neurology 71, 1489–1495 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Larson, E. B. et al. Survival after initial diagnosis of Alzheimer disease. Ann. Intern. Med. 140, 501–509 (2004).
  Article PubMed Google Scholar
• 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).
  Article PubMed Google Scholar
• Holmes, C. Genotype and phenotype in Alzheimer's disease. Br. J. Psychiatry 180, 131–134 (2002).
  Article PubMed Google Scholar
• 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).
  Article CAS PubMed Google Scholar
• Holmes, C. & Lovestone, S. The clinical phenotype of familial and sporadic late onset Alzheimer's disease. Int. J. Geriatr. Psychiatry 17, 146–149 (2002).
  Article PubMed Google Scholar
• 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).
  Article CAS PubMed Google Scholar
• 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).
  Article CAS PubMed Google Scholar
• 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).
  Article PubMed Google Scholar
• Meyer, M. R. et al. APOE genotype predicts when — not whether — one is predisposed to develop Alzheimer disease. Nature Genet. 19, 321–322 (1998).
  Article CAS PubMed Google Scholar
• Craft, S. et al. Accelerated decline in apolipoprotein E-epsilon4 homozygotes with Alzheimer's disease. Neurology 51, 149–153 (1998).
  Article CAS PubMed Google Scholar
• Dal Forno, G. et al. APOE genotype and survival in men and women with Alzheimer's disease. Neurology 58, 1045–1050 (2002).
  Article CAS PubMed Google Scholar
• 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).
  Article PubMed Google Scholar
• Pastor, P. et al. Apolipoprotein Eɛ4 modifies Alzheimer's disease onset in an E280A PS1 kindred. Ann. Neurol. 54, 163–169 (2003).
  Article CAS PubMed Google Scholar
• Morris, J. C. et al. APOE predicts amyloid-β but not tau Alzheimer pathology in cognitively normal aging. Ann. Neurol. 67, 122–131 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• 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).
  Article CAS PubMed Google Scholar
• 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).
  Article CAS PubMed PubMed Central Google Scholar
• Lesne, S. et al. A specific amyloid-β protein assembly in the brain impairs memory. Nature. 440, 352–357 (2006).
  Article CAS PubMed Google Scholar
• 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).
  Article CAS PubMed Google Scholar
• Hepler, R. W. et al. Solution state characterization of amyloid β-derived diffusible ligands. Biochemistry 45, 15157–15167 (2006). This detailed analysis describes the methodological problems associated with the biochemical characterization of amyloid-β.
  Article CAS PubMed Google Scholar
• 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).
  Article CAS PubMed PubMed Central Google Scholar
• 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).
  Article CAS PubMed Google Scholar
• Wang, B. et al. γ-secretase gene mutations in familial acne inversa. Science 330, 1065 (2010).
  Article CAS PubMed Google Scholar
• Pink, A. E. et al. PSENEN and NCSTN mutations in familial hidradenitis suppurativa (acne inversa). J. Invest. Dermatol. 131, 1568–1570 (2011).
  Article CAS PubMed Google Scholar
• Blennow, K. et al. Immunotherapy with bapineuzumab lowers CSF tau protein levels in patients with Alzheimer's disease. Alzheimers Dement. 6, S134–S135 (2010).
  Article Google Scholar
• 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).
  Article CAS PubMed Google Scholar
• 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).
  Article CAS PubMed Google Scholar
• Mangialasche, F., Solomon, A., Winblad, B., Mecocci, P. & Kivipelto, M. Alzheimer's disease: clinical trials and drug development. Lancet Neurol. 9, 702–716 (2010).
  Article CAS PubMed Google Scholar
• Braak, H. & Braak, E. Staging of Alzheimer-related cortical destruction. Int. Psychogeriatr. 9 (Suppl. 1), 257–261 (1997). This paper classifies the development of AD pathology into 'Braak stages'.
  Article PubMed Google Scholar
• Jalbert, J. J., Daiello, L. A. & Lapane, K. L. Dementia of the Alzheimer type. Epidemiol. Rev. 30, 15–34 (2008).
  Article PubMed Google Scholar
• Rosen, W. G., Mohs, R. C. & Davis, K. L. A new rating scale for Alzheimer's disease. Am. J. Psychiatry 141, 1356–1364 (1984). This description of the cognition rating scales is used in clinical trials testing AD therapeutics.
  Article CAS PubMed Google Scholar
• Schneider, L. S. & Sano, M. Current Alzheimer's disease clinical trials: methods and placebo outcomes. Alzheimers Dement. 5, 388–397 (2009).
  Article PubMed PubMed Central Google Scholar
• Mohs, R. C. The clinical syndrome of Alzheimer's disease: aspects particularly relevant to clinical trials. Genes Brain Behav. 4, 129–133 (2005).
  Article CAS PubMed Google Scholar
• Morris, J. C. The Clinical Dementia Rating (CDR): current version and scoring rules. Neurology 43, 2412–2414 (1993).
  Article CAS PubMed Google Scholar
• 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).
  Article Google Scholar
• 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).
  Article CAS PubMed Google Scholar
• 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).
  Article Google Scholar
• Hampel, H. et al. Biomarkers for Alzheimer's disease: academic, industry and regulatory perspectives. Nature Rev. Drug Discov. 9, 560–574 (2010).
  Article CAS Google Scholar
• Leber, P. Slowing the progression of Alzheimer disease: methodologic issues. Alzheimer Dis. Assoc. Disord. 11 (Suppl. 5), 10–21 (1997).
  Google Scholar
• 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).
  Article CAS PubMed Google Scholar
• 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).
  Article CAS PubMed PubMed Central Google Scholar
• 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).
  Article PubMed Google Scholar
• 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).
  Article PubMed PubMed Central Google Scholar
• 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).
  Article PubMed PubMed Central Google Scholar
• Khachaturian, Z. S. et al. Developing a global strategy to prevent Alzheimer's disease: Leon Thal Symposium 2010. Alzheimers Dement. 7, 127–132 (2011).
  Article PubMed Google Scholar
• 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).
  Article PubMed Google Scholar
• Games, D. et al. Alzheimer-type neuropathology in transgenic mice overexpressing V717F β-amyloid precursor protein. Nature 373, 523–527 (1995). This description of the first transgenic mouse model reliably demonstrated the amyloid plaque pathology of AD.
  Article CAS PubMed Google Scholar
• Glabe, C. G. Common mechanisms of amyloid oligomer pathogenesis in degenerative disease. Neurobiol. Aging 27, 570–575 (2006).
  Article CAS PubMed Google Scholar
• 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).
  Article CAS PubMed Google Scholar
• 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).
  Article CAS PubMed PubMed Central Google Scholar
• 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).
  Article CAS Google Scholar
• 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). This was the first study linking PSEN mutations to abnormal APP processing.
  Article CAS PubMed Google Scholar
• van Broeckhoven, C. & Kumar-Singh, S. Genetics and pathology of α-secretase site Aβ PP mutations in the understanding of Alzheimer's disease. J. Alzheimers Dis. 9, 389–398 (2006).
  Article CAS PubMed Google Scholar
• Zhang-Nunes, S. X. et al. The cerebral β- amyloid angiopathies: hereditary and sporadic. Brain Pathol. 16, 30–39 (2006).
  Article CAS PubMed PubMed Central Google Scholar