Abstract
Alzheimer's disease (AD) is a biologically complex neurodegenerative dementia. Nearly 20 years ago, with the combination of observations from biochemistry, neuropathology and genetics, a compelling hypothesis known as the amyloid cascade hypothesis was formulated. The core of this hypothesis is that it is pathological accumulations of amyloid-β, a peptide fragment of a membrane protein called amyloid precursor protein, that act as the root cause of AD and initiate its pathogenesis. Yet, with the passage of time, growing amounts of data have accumulated that are inconsistent with the basically linear structure of this hypothesis. And while there is fear in the field over the consequences of rejecting it outright, clinging to an inaccurate disease model is the option we should fear most. This Perspective explores the proposition that we are over-reliant on amyloid to define and diagnose AD and that the time has come to face our fears and reject the amyloid cascade hypothesis.
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References
Querfurth, H.W. & LaFerla, F.M. Alzheimer's disease. N. Engl. J. Med. 362, 329–344 (2010).
Hebert, L.E., Weuve, J., Scherr, P.A. & Evans, D.A. Alzheimer disease in the United States (2010–2050) estimated using the 2010 census. Neurology 80, 1778–1783 (2013).
Alzheimer's Association . 2013 Alzheimer's disease facts and figures. Alzheimers Dement. 9, 208–245 (2013).
Hyman, B.T., Van Hoesen, G.W., Damasio, A.R. & Barnes, C.L. Alzheimer's disease: cell-specific pathology isolates the hippocampal formation. Science 225, 1168–1170 (1984).
Zweig, R.M. et al. Neuropathology of aminergic nuclei in Alzheimer's disease. Prog. Clin. Biol. Res. 317, 353–365 (1989).
Zweig, R.M. et al. The neuropathology of aminergic nuclei in Alzheimer's disease. Ann. Neurol. 24, 233–242 (1988).
Whitehouse, P.J. et al. Alzheimer's disease and senile dementia: loss of neurons in the basal forebrain. Science 215, 1237–1239 (1982).
Braak, H. & Del Tredici, K. The pathological process underlying Alzheimer's disease in individuals under thirty. Acta Neuropathol. 121, 171–181 (2011).
Hamos, J.E., DeGennaro, L.J. & Drachman, D.A. Synaptic loss in Alzheimer's disease and other dementias. Neurology 39, 355–361 (1989).
DeKosky, S.T. & Scheff, S.W. Synapse loss in frontal cortex biopsies in Alzheimer's disease: correlation with cognitive severity. Ann. Neurol. 27, 457–464 (1990).
Terry, R.D. et al. Physical basis of cognitive alterations in Alzheimer's disease: synapse loss is the major correlate of cognitive impairment. Ann. Neurol. 30, 572–580 (1991).
Masliah, E., Mallory, M., Hansen, L., DeTeresa, R. & Terry, R.D. Quantitative synaptic alterations in the human neocortex during normal aging. Neurology 43, 192–197 (1993).
Selkoe, D.J. Alzheimer's disease is a synaptic failure. Science 298, 789–791 (2002).
Arendt, T. Synaptic degeneration in Alzheimer's disease. Acta Neuropathol. 118, 167–179 (2009).
Schellenberg, G.D. & Montine, T.J. The genetics and neuropathology of Alzheimer's disease. Acta Neuropathol. 124, 305–323 (2012).
Tanzi, R.E. The genetics of Alzheimer disease. Cold Spring Harb. Perspect. Med. 2, a006296 (2012).
Hardy, J. et al. Pathways to Alzheimer's disease. J. Intern. Med. 275, 296–303 (2014).
Spires-Jones, T.L. & Hyman, B.T. The intersection of amyloid beta and tau at synapses in Alzheimer's disease. Neuron 82, 756–771 (2014).
Palop, J.J. & Mucke, L. Amyloid-beta-induced neuronal dysfunction in Alzheimer's disease: from synapses toward neural networks. Nat. Neurosci. 13, 812–818 (2010).
Bertram, L., Lill, C.M. & Tanzi, R.E. The genetics of Alzheimer disease: back to the future. Neuron 68, 270–281 (2010).
Jonsson, T. et al. A mutation in APP protects against Alzheimer's disease and age-related cognitive decline. Nature 488, 96–99 (2012).
Strittmatter, W.J. et al. Apolipoprotein E: high-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease. Proc. Natl. Acad. Sci. USA 90, 1977–1981 (1993).
McKhann, G.M. et al. The diagnosis of dementia due to Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement. 7, 263–269 (2011).
Hardy, J.A. & Higgins, G.A. Alzheimer's disease: the amyloid cascade hypothesis. Science 256, 184–185 (1992).
Selkoe, D.J. Toward a comprehensive theory for Alzheimer's disease. Hypothesis: Alzheimer's disease is caused by the cerebral accumulation and cytotoxicity of amyloid beta-protein. Ann. NY Acad. Sci. 924, 17–25 (2000).
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).
Citron, M. Strategies for disease modification in Alzheimer's disease. Nat. Rev. Neurosci. 5, 677–685 (2004).
Lemere, C.A. & Masliah, E. Can Alzheimer disease be prevented by amyloid-beta immunotherapy? Nat. Rev. Neurol. 6, 108–119 (2010).
Nelson, P.T., Braak, H. & Markesbery, W.R. Neuropathology and cognitive impairment in Alzheimer disease: a complex but coherent relationship. J. Neuropathol. Exp. Neurol. 68, 1–14 (2009).
Mathis, C.A. et al. A lipophilic thioflavin-T derivative for positron emission tomography (PET) imaging of amyloid in brain. Bioorg. Med. Chem. Lett. 12, 295–298 (2002).
Zhang, W., Kung, M.P., Oya, S., Hou, C. & Kung, H.F. 18F-labeled styrylpyridines as PET agents for amyloid plaque imaging. Nucl. Med. Biol. 34, 89–97 (2007).
Villemagne, V.L. et al. Longitudinal assessment of Aβ and cognition in aging and Alzheimer disease. Ann. Neurol. 69, 181–192 (2011).
Klunk, W. et al. Amyloid imaging with PET in Alzheimer's disease, mild cognitive impairment, and clinically unimpaired subjects. in PET in the Evaluation of Alzheimer's Disease and Related Disorders (ed. Silverman, D.) 119–147 (Springer Science + Business Media LLC, 2009).
Chen, X. et al. Pittsburgh compound B retention and progression of cognitive status–a meta-analysis. Eur. J. Neurol. 21, 1060–1067 (2014).
Villemagne, V.L. et al. Amyloid beta deposition, neurodegeneration, and cognitive decline in sporadic Alzheimer's disease: a prospective cohort study. Lancet Neurol. 12, 357–367 (2013).
LaFerla, F.M. & Green, K.N. Animal models of Alzheimer disease. Cold Spring Harb. Perspect. Med. 2, a006320 (2012).
Webster, S.J., Bachstetter, A.D., Nelson, P.T., Schmitt, F.A. & Van Eldik, L.J. Using mice to model Alzheimer's dementia: an overview of the clinical disease and the preclinical behavioral changes in 10 mouse models. Front. Genet. 5, 88 (2014).
Hochgräfe, K., Sydow, A. & Mandelkow, E.M. Regulatable transgenic mouse models of Alzheimer disease: onset, reversibility and spreading of Tau pathology. FEBS J. 280, 4371–4381 (2013).
Kitazawa, M., Medeiros, R. & Laferla, F.M. Transgenic mouse models of Alzheimer disease: developing a better model as a tool for therapeutic interventions. Curr. Pharm. Des. 18, 1131–1147 (2012).
Hock, B.J. Jr. & Lamb, B.T. Transgenic mouse models of Alzheimer's disease. Trends Genet. 17, S7–S12 (2001).
Götz, J. & Ittner, L.M. Animal models of Alzheimer's disease and frontotemporal dementia. Nat. Rev. Neurosci. 9, 532–544 (2008).
Kim, J. et al. Normal cognition in transgenic BRI2-Aβ mice. Mol. Neurodegener. 8, 15 (2013).
Whalen, B.M., Selkoe, D.J. & Hartley, D.M. Small non-fibrillar assemblies of amyloid beta-protein bearing the Arctic mutation induce rapid neuritic degeneration. Neurobiol. Dis. 20, 254–266 (2005).
Varvel, N.H. et al. Aβ oligomers induce neuronal cell cycle events in Alzheimer's disease. J. Neurosci. 28, 10786–10793 (2008).
Shankar, G.M. et al. Amyloid-beta protein dimers isolated directly from Alzheimer's brains impair synaptic plasticity and memory. Nat. Med. 14, 837–842 (2008).
Cramer, P.E. et al. ApoE-directed therapeutics rapidly clear beta-amyloid and reverse deficits in AD mouse models. Science 335, 1503–1506 (2012).
Schenk, D. et al. Immunization with amyloid-beta attenuates Alzheimer-disease-like pathology in the PDAPP mouse. Nature 400, 173–177 (1999).
Dodart, J.C. et al. Immunization reverses memory deficits without reducing brain Aβ burden in Alzheimer's disease model. Nat. Neurosci. 5, 452–457 (2002).
Kotilinek, L.A. et al. Reversible memory loss in a mouse transgenic model of Alzheimer's disease. J. Neurosci. 22, 6331–6335 (2002).
Janus, C. et al. A beta peptide immunization reduces behavioural impairment and plaques in a model of Alzheimer's disease. Nature 408, 979–982 (2000).
Orgogozo, J.M. et al. Subacute meningoencephalitis in a subset of patients with AD after Aβ42 immunization. Neurology 61, 46–54 (2003).
Serrano-Pozo, A. et al. Beneficial effect of human anti-amyloid-beta active immunization on neurite morphology and tau pathology. Brain 133, 1312–1327 (2010).
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).
Doody, R.S. et al. Phase 3 trials of solanezumab for mild-to-moderate Alzheimer's disease. N. Engl. J. Med. 370, 311–321 (2014).
Salloway, S. et al. Two phase 3 trials of bapineuzumab in mild-to-moderate Alzheimer's disease. N. Engl. J. Med. 370, 322–333 (2014).
Vellas, B. et al. Designing drug trials for Alzheimer's disease: what we have learned from the release of the phase III antibody trials: a report from the EU/US/CTAD Task Force. Alzheimers Dement. 9, 438–444 (2013).
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).
Herrup, K. Reimagining Alzheimer's disease–an age-based hypothesis. J. Neurosci. 30, 16755–16762 (2010).
Herrup, K. Current conceptual view of Alzheimer's disease. in Alzheimer's Disease × Modernizing Concept, Biological Diagnosis and Therapy Vol. 28 (eds. Carrillo, M.C. & Hampel, H.) 30–48 (Karger, 2012).
Nixon, R.A. & Yang, D.S. Autophagy failure in Alzheimer's disease-locating the primary defect. Neurobiol. Dis. 43, 38–45 (2011).
Nixon, R.A. & Cataldo, A.M. Lysosomal system pathways: genes to neurodegeneration in Alzheimer's disease. J. Alzheimers Dis. 9, 277–289 (2006).
Bezprozvanny, I. & Mattson, M.P. Neuronal calcium mishandling and the pathogenesis of Alzheimer's disease. Trends Neurosci. 31, 454–463 (2008).
Demuro, A., Parker, I. & Stutzmann, G.E. Calcium signaling and amyloid toxicity in Alzheimer disease. J. Biol. Chem. 285, 12463–12468 (2010).
Green, K.N. & LaFerla, F.M. Linking calcium to Aβ and Alzheimer's disease. Neuron 59, 190–194 (2008).
Khachaturian, Z.S. Hypothesis on the regulation of cytosol calcium concentration and the aging brain. Neurobiol. Aging 8, 345–346 (1987).
Supnet, C. & Bezprozvanny, I. The dysregulation of intracellular calcium in Alzheimer disease. Cell Calcium 47, 183–189 (2010).
Szydlowska, K. & Tymianski, M. Calcium, ischemia and excitotoxicity. Cell Calcium 47, 122–129 (2010).
Yu, J.T., Chang, R.C. & Tan, L. Calcium dysregulation in Alzheimer's disease: from mechanisms to therapeutic opportunities. Prog. Neurobiol. 89, 240–255 (2009).
Arendt, T., Bruckner, M.K., Mosch, B. & Losche, A. Selective cell death of hyperploid neurons in Alzheimer's disease. Am. J. Pathol. 177, 15–20 (2010).
Boeras, D.I. et al. Alzheimer's presenilin 1 causes chromosome missegregation and aneuploidy. Neurobiol. Aging 29, 319–328 (2008).
Busser, J., Geldmacher, D.S. & Herrup, K. Ectopic cell cycle proteins predict the sites of neuronal cell death in Alzheimer's disease brain. J. Neurosci. 18, 2801–2807 (1998).
Herrup, K. & Yang, Y. Cell cycle regulation in the postmitotic neuron: oxymoron or new biology? Nat. Rev. Neurosci. 8, 368–378 (2007).
Kruman, I.I. et al. Cell cycle activation linked to neuronal cell death initiated by DNA damage. Neuron 41, 549–561 (2004).
McShea, A., Harris, P.L., Webster, K.R., Wahl, A.F. & Smith, M.A. Abnormal expression of the cell cycle regulators P16 and CDK4 in Alzheimer's disease. Am. J. Pathol. 150, 1933–1939 (1997).
Nagy, Z., Esiri, M.M., Cato, A.M. & Smith, A.D. Cell cycle markers in the hippocampus in Alzheimer's disease. Acta Neuropathol. 94, 6–15 (1997).
Vincent, I., Rosado, M. & Davies, P. Mitotic mechanisms in Alzheimer's disease? J. Cell Biol. 132, 413–425 (1996).
Yang, Y., Geldmacher, D.S. & Herrup, K. DNA replication precedes neuronal cell death in Alzheimer's disease. J. Neurosci. 21, 2661–2668 (2001).
Yang, Y., Mufson, E.J. & Herrup, K. Neuronal cell death is preceded by cell cycle events at all stages of Alzheimer's disease. J. Neurosci. 23, 2557–2563 (2003).
Mosher, K.I. & Wyss-Coray, T. Microglial dysfunction in brain aging and Alzheimer's disease. Biochem. Pharmacol. 88, 594–604 (2014).
Cameron, B. & Landreth, G.E. Inflammation, microglia, and Alzheimer's disease. Neurobiol. Dis. 37, 503–509 (2010).
Heneka, M.T. & O′Banion, M.K. Inflammatory processes in Alzheimer's disease. J. Neuroimmunol. 184, 69–91 (2007).
McGeer, P.L., Schulzer, M. & McGeer, E.G. Arthritis and anti-inflammatory agents as possible protective factors for Alzheimer's disease: a review of 17 epidemiologic studies. Neurology 47, 425–432 (1996).
Krstic, D. & Knuesel, I. Deciphering the mechanism underlying late-onset Alzheimer disease. Nat. Rev. Neurol. 9, 25–34 (2013).
Zhu, X. et al. Mitochondrial abnormalities and oxidative imbalance in Alzheimer disease. J. Alzheimers Dis. 9, 147–153 (2006).
Mouton-Liger, F. et al. Oxidative stress increases BACE1 protein levels through activation of the PKR-eIF2α pathway. Biochim. Biophys. Acta 1822, 885–896 (2012).
Bucholtz, N. & Demuth, I. DNA-repair in mild cognitive impairment and Alzheimer's disease. DNA Repair (Amst.) 12, 811–816 (2013).
Canugovi, C., Misiak, M., Ferrarelli, L.K., Croteau, D.L. & Bohr, V.A. The role of DNA repair in brain related disease pathology. DNA Repair (Amst.) 12, 578–587 (2013).
Coppedè, F. & Migliore, L. DNA damage and repair in Alzheimer's disease. Curr. Alzheimer Res. 6, 36–47 (2009).
Cotman, C.W. & Su, J.H. Mechanisms of neuronal death in Alzheimer's disease. Brain Pathol. 6, 493–506 (1996).
Herrup, K., Li, J. & Chen, J. The role of ATM and DNA damage in neurons: upstream and downstream connections. DNA Repair (Amst.) 12, 600–604 (2013).
Iourov, I.Y., Vorsanova, S.G., Liehr, T. & Yurov, Y.B. Aneuploidy in the normal, Alzheimer's disease and ataxia-telangiectasia brain: differential expression and pathological meaning. Neurobiol. Dis. 34, 212–220 (2009).
Lovell, M.A. & Markesbery, W.R. Oxidative DNA damage in mild cognitive impairment and late-stage Alzheimer's disease. Nucleic Acids Res. 35, 7497–7504 (2007).
Weissman, L., de Souza-Pinto, N.C., Mattson, M.P. & Bohr, V.A. DNA base excision repair activities in mouse models of Alzheimer's disease. Neurobiol. Aging 30, 2080–2081 (2009).
Swerdlow, R.H., Burns, J.M. & Khan, S.M. The Alzheimer's disease mitochondrial cascade hypothesis: progress and perspectives. Biochim. Biophys. Acta 1842, 1219–1231 (2014).
Swerdlow, R.H. & Khan, S.M.A. “Mitochondrial cascade hypothesis” for sporadic Alzheimer's disease. Med. Hypotheses 63, 8–20 (2004).
Yao, J. et al. Mitochondrial bioenergetic deficit precedes Alzheimer's pathology in female mouse model of Alzheimer's disease. Proc. Natl. Acad. Sci. USA 106, 14670–14675 (2009).
Hunter, S., Arendt, T. & Brayne, C. The senescence hypothesis of disease progression in Alzheimer disease: an integrated matrix of disease pathways for FAD and SAD. Mol. Neurobiol. 48, 556–570 (2013).
Ferreira, S.T., Clarke, J.R., Bomfim, T.R. & De Felice, F.G. Inflammation, defective insulin signaling, and neuronal dysfunction in Alzheimer's disease. Alzheimers Dement. 10, S76–S83 (2014).
Cholerton, B., Baker, L.D. & Craft, S. Insulin, cognition, and dementia. Eur. J. Pharmacol. 719, 170–179 (2013).
Wang, R. et al. Metabolic stress modulates Alzheimer's beta-secretase gene transcription via SIRT1-PPARγ-PGC-1 in neurons. Cell Metab. 17, 685–694 (2013).
Acknowledgements
The author thanks his many friends and colleagues whose spirited discussions over the years have helped sharpen the arguments raised here. Special thanks to S. Herculano-Houzel for her critical and insightful reading of an early draft of the work. Support for the writing came from The Hong Kong University of Science and Technology, the National Key Basic Research Program of China (2013CB530900), the Research Grants Council, Hong Kong Special Administrative Region (GRF660813) and the BrightFocus Foundation (A2012101).
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Herrup, K. The case for rejecting the amyloid cascade hypothesis. Nat Neurosci 18, 794–799 (2015). https://doi.org/10.1038/nn.4017
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DOI: https://doi.org/10.1038/nn.4017
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