Abstract
The amyloid hypothesis, which has been the predominant framework for research in Alzheimer's disease (AD), has been the source of considerable controversy. The amyloid hypothesis postulates that amyloid-β peptide (Aβ) is the causative agent in AD. It is strongly supported by data from rare autosomal dominant forms of AD. However, the evidence that Aβ causes or contributes to age-associated sporadic AD is more complex and less clear, prompting criticism of the hypothesis. We provide an overview of the major arguments for and against the amyloid hypothesis. We conclude that Aβ likely is the key initiator of a complex pathogenic cascade that causes AD. However, we argue that Aβ acts primarily as a trigger of other downstream processes, particularly tau aggregation, which mediate neurodegeneration. Aβ appears to be necessary, but not sufficient, to cause AD. Its major pathogenic effects may occur very early in the disease process.
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References
Hardy, J.A. & Higgins, G.A. Alzheimer's disease: the amyloid cascade hypothesis. Science 256, 184–185 (1992).
Bettens, K., Sleegers, K. & Van Broeckhoven, C. Genetic insights in Alzheimer's disease. Lancet Neurol. 12, 92–104 (2013).
Levy, E. et al. Mutation of the Alzheimer's disease amyloid gene in hereditary cerebral hemorrhage, Dutch type. Science 248, 1124–1126 (1990).
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).
Tsubuki, S., Takaki, Y. & Saido, T.C. Dutch, Flemish, Italian, and Arctic mutations of APP and resistance of Abeta to physiologically relevant proteolytic degradation. Lancet 361, 1957–1958 (2003).
Tomiyama, T. et al. A new amyloid beta variant favoring oligomerization in Alzheimer's-type dementia. Ann. Neurol. 63, 377–387 (2008).
Rovelet-Lecrux, A. et al. APP locus duplication causes autosomal dominant early-onset Alzheimer disease with cerebral amyloid angiopathy. Nat. Genet. 38, 24–26 (2006).
Sleegers, K. et al. APP duplication is sufficient to cause early onset Alzheimer's dementia with cerebral amyloid angiopathy. Brain 129, 2977–2983 (2006).
Cabrejo, L. et al. Phenotype associated with APP duplication in five families. Brain 129, 2966–2976 (2006).
Prasher, V.P. et al. Molecular mapping of Alzheimer-type dementia in Down's syndrome. Ann. Neurol. 43, 380–383 (1998).
Citron, M. et al. Mutation of the beta-amyloid precursor protein in familial Alzheimer's disease increases beta-protein production. Nature 360, 672–674 (1992).
Eckman, C.B. et al. A new pathogenic mutation in the APP gene (I716V) increases the relative proportion of A beta 42(43). Hum. Mol. Genet. 6, 2087–2089 (1997).
Chávez-Gutiérrez, L. et al. The mechanism of gamma-Secretase dysfunction in familial Alzheimer disease. EMBO J. 31, 2261–2274 (2012).
Shepherd, C., McCann, H. & Halliday, G.M. Variations in the neuropathology of familial Alzheimer's disease. Acta Neuropathol. 118, 37–52 (2009).
Bateman, R.J. et al. Clinical and biomarker changes in dominantly inherited Alzheimer's disease. N. Engl. J. Med. 367, 795–804 (2012).
Ryman, D.C. et al. Symptom onset in autosomal dominant Alzheimer disease: a systematic review and meta-analysis. Neurology 83, 253–260 (2014).
Corder, E.H. et al. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science 261, 921–923 (1993).
Chiang, G.C. et al. Hippocampal atrophy rates and CSF biomarkers in elderly APOE2 normal subjects. Neurology 75, 1976–1981 (2010).
Verghese, P.B., Castellano, J.M. & Holtzman, D.M. Apolipoprotein E in Alzheimer's disease and other neurological disorders. Lancet Neurol. 10, 241–252 (2011).
Castellano, J.M. et al. Human apoE isoforms differentially regulate brain amyloid-beta peptide clearance. Sci. Transl. Med. 3, 89ra57 (2011).
Fagan, A.M. et al. Human and murine ApoE markedly alters A beta metabolism before and after plaque formation in a mouse model of Alzheimer's disease. Neurobiol. Dis. 9, 305–318 (2002).
Hudry, E. et al. Gene transfer of human Apoe isoforms results in differential modulation of amyloid deposition and neurotoxicity in mouse brain. Sci. Transl. Med. 5, 212ra161 (2013).
Morris, J.C. et al. APOE predicts amyloid-beta but not tau Alzheimer pathology in cognitively normal aging. Ann. Neurol. 67, 122–131 (2010).
Vemuri, P. et al. Effect of apolipoprotein E on biomarkers of amyloid load and neuronal pathology in Alzheimer disease. Ann. Neurol. 67, 308–316 (2010).
Verghese, P.B. et al. ApoE influences amyloid-beta (Abeta) clearance despite minimal apoE/Abeta association in physiological conditions. Proc. Natl. Acad. Sci. USA 110, E1807–E1816 (2013).
Bales, K.R. et al. Lack of apolipoprotein E dramatically reduces amyloid beta-peptide deposition. Nat. Genet. 17, 263–264 (1997).
Bien-Ly, N., Gillespie, A.K., Walker, D., Yoon, S.Y. & Huang, Y. Reducing human apolipoprotein E levels attenuates age-dependent Abeta accumulation in mutant human amyloid precursor protein transgenic mice. J. Neurosci. 32, 4803–4811 (2012).
Kim, J. et al. Haploinsufficiency of human APOE reduces amyloid deposition in a mouse model of amyloid-beta amyloidosis. J. Neurosci. 31, 18007–18012 (2011).
Kim, J. et al. Anti-apoE immunotherapy inhibits amyloid accumulation in a transgenic mouse model of Abeta amyloidosis. J. Exp. Med. 209, 2149–2156 (2012).
Sunderland, T. et al. Cerebrospinal fluid beta-amyloid1–42 and tau in control subjects at risk for Alzheimer's disease: the effect of APOE epsilon4 allele. Biol. Psychiatry 56, 670–676 (2004).
Jonsson, T. et al. A mutation in APP protects against Alzheimer's disease and age-related cognitive decline. Nature 488, 96–99 (2012).
Braak, H. & Braak, E. Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol. 82, 239–259 (1991).
Serrano-Pozo, A., Frosch, M.P., Masliah, E. & Hyman, B.T. Neuropathological alterations in Alzheimer disease. Cold Spring Harb. Perspect. Med. 1, a006189 (2011).
Gómez-Isla, T. et al. Neuronal loss correlates with but exceeds neurofibrillary tangles in Alzheimer's disease. Ann. Neurol. 41, 17–24 (1997).
Arriagada, P.V., Marzloff, K. & Hyman, B.T. Distribution of Alzheimer-type pathologic changes in nondemented elderly individuals matches the pattern in Alzheimer's disease. Neurology 42, 1681–1688 (1992).
Arriagada, P.V., Growdon, J.H., Hedley-Whyte, E.T. & Hyman, B.T. Neurofibrillary tangles but not senile plaques parallel duration and severity of Alzheimer's disease. Neurology 42, 631–639 (1992).
Price, J.L., Davis, P.B., Morris, J.C. & White, D.L. The distribution of tangles, plaques and related immunohistochemical markers in healthy aging and Alzheimer's disease. Neurobiol. Aging 12, 295–312 (1991).
Braak, H. & Del Tredici, K. The pathological process underlying Alzheimer's disease in individuals under thirty. Acta Neuropathol. 121, 171–181 (2011).
Price, J.L. & Morris, J.C. Tangles and plaques in nondemented aging and “preclinical” Alzheimer's disease. Ann. Neurol. 45, 358–368 (1999).
Elobeid, A., Soininen, H. & Alafuzoff, I. Hyperphosphorylated tau in young and middle-aged subjects. Acta Neuropathol. 123, 97–104 (2012).
Knopman, D.S. et al. Neuropathology of cognitively normal elderly. J. Neuropathol. Exp. Neurol. 62, 1087–1095 (2003).
Petersen, R.C. et al. Neuropathologic features of amnestic mild cognitive impairment. Arch. Neurol. 63, 665–672 (2006).
Gómez-Isla, T. et al. Profound loss of layer II entorhinal cortex neurons occurs in very mild Alzheimer's disease. J. Neurosci. 16, 4491–4500 (1996).
West, M.J., Coleman, P.D., Flood, D.G. & Troncoso, J.C. Differences in the pattern of hippocampal neuronal loss in normal ageing and Alzheimer's disease. Lancet 344, 769–772 (1994).
Tiraboschi, P., Hansen, L.A., Thal, L.J. & Corey-Bloom, J. The importance of neuritic plaques and tangles to the development and evolution of AD. Neurology 62, 1984–1989 (2004).
Reed, L.A. et al. Autosomal dominant dementia with widespread neurofibrillary tangles. Ann. Neurol. 42, 564–572 (1997).
Lindquist, S.G. et al. Alzheimer disease-like clinical phenotype in a family with FTDP-17 caused by a MAPT R406W mutation. Eur. J. Neurol. 15, 377–385 (2008).
Kauwe, J.S. et al. Variation in MAPT is associated with cerebrospinal fluid tau levels in the presence of amyloid-beta deposition. Proc. Natl. Acad. Sci. USA 105, 8050–8054 (2008).
Ferreira, A., Lu, Q., Orecchio, L. & Kosik, K.S. Selective phosphorylation of adult tau isoforms in mature hippocampal neurons exposed to fibrillar A beta. Mol. Cell. Neurosci. 9, 220–234 (1997).
Zempel, H., Thies, E., Mandelkow, E. & Mandelkow, E.M. Abeta oligomers cause localized Ca(2+) elevation, missorting of endogenous Tau into dendrites, Tau phosphorylation, and destruction of microtubules and spines. J. Neurosci. 30, 11938–11950 (2010).
Rapoport, M., Dawson, H.N., Binder, L.I., Vitek, M.P. & Ferreira, A. Tau is essential to beta -amyloid-induced neurotoxicity. Proc. Natl. Acad. Sci. USA 99, 6364–6369 (2002).
Jin, M. et al. Soluble amyloid beta-protein dimers isolated from Alzheimer cortex directly induce Tau hyperphosphorylation and neuritic degeneration. Proc. Natl. Acad. Sci. USA 108, 5819–5824 (2011).
Choi, S.H. et al. A three-dimensional human neural cell culture model of Alzheimer's disease. Nature 515, 274–278 (2014).
Hurtado, D.E. et al. A{beta} accelerates the spatiotemporal progression of tau pathology and augments tau amyloidosis in an Alzheimer mouse model. Am. J. Pathol. 177, 1977–1988 (2010).
Lewis, J. et al. Enhanced neurofibrillary degeneration in transgenic mice expressing mutant tau and APP. Science 293, 1487–1491 (2001).
Götz, J., Chen, F., van Dorpe, J. & Nitsch, R.M. Formation of neurofibrillary tangles in P301l tau transgenic mice induced by Abeta 42 fibrils. Science 293, 1491–1495 (2001).
Roberson, E.D. et al. Reducing endogenous tau ameliorates amyloid beta-induced deficits in an Alzheimer's disease mouse model. Science 316, 750–754 (2007).
Roberson, E.D. et al. Amyloid-beta/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).
Lippa, C.F. et al. Lewy bodies contain altered alpha-synuclein in brains of many familial Alzheimer's disease patients with mutations in presenilin and amyloid precursor protein genes. Am. J. Pathol. 153, 1365–1370 (1998).
Hashimoto, M. & Masliah, E. Alpha-synuclein in Lewy body disease and Alzheimer's disease. Brain Pathol. 9, 707–720 (1999).
Masliah, E. et al. beta-amyloid peptides enhance alpha-synuclein accumulation and neuronal deficits in a transgenic mouse model linking Alzheimer's disease and Parkinson's disease. Proc. Natl. Acad. Sci. USA 98, 12245–12250 (2001).
Larson, M.E. et al. Soluble alpha-synuclein is a novel modulator of Alzheimer's disease pathophysiology. J. Neurosci. 32, 10253–10266 (2012).
Josephs, K.A. et al. TDP-43 is a key player in the clinical features associated with Alzheimer's disease. Acta Neuropathol. 127, 811–824 (2014).
Jack, C.R. Jr. et al. Tracking pathophysiological processes in Alzheimer's disease: an updated hypothetical model of dynamic biomarkers. Lancet Neurol. 12, 207–216 (2013).
Jack, C.R. Jr. et al. Evidence for ordering of Alzheimer disease biomarkers. Arch. Neurol. 68, 1526–1535 (2011).
Roe, C.M. et al. Amyloid imaging and CSF biomarkers in predicting cognitive impairment up to 7.5 years later. Neurology 80, 1784–1791 (2013).
Vos, S.J. et al. Preclinical Alzheimer's disease and its outcome: a longitudinal cohort study. Lancet Neurol. 12, 957–965 (2013).
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).
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. Longitudinal assessment of Abeta and cognition in aging and Alzheimer disease. Ann. Neurol. 69, 181–192 (2011).
Knopman, D.S. et al. Short-term clinical outcomes for stages of NIA-AA preclinical Alzheimer disease. Neurology 78, 1576–1582 (2012).
Tarawneh, R. et al. Visinin-like protein-1: diagnostic and prognostic biomarker in Alzheimer disease. Ann. Neurol. 70, 274–285 (2011).
Donohue, M.C. et al. The preclinical Alzheimer cognitive composite: measuring amyloid-related decline. JAMA Neurol. 71, 961–970 (2014).
Chételat, G. et al. Accelerated cortical atrophy in cognitively normal elderly with high beta-amyloid deposition. Neurology 78, 477–484 (2012).
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).
Walsh, D.M. et al. Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo. Nature 416, 535–539 (2002).
Mucke, L. & Selkoe, D.J. Neurotoxicity of amyloid beta-protein: synaptic and network dysfunction. Cold Spring Harb. Perspect. Med. 2, a006338 (2012).
Esparza, T.J. et al. Amyloid-beta oligomerization in Alzheimer dementia versus high-pathology controls. Ann. Neurol. 73, 104–119 (2013).
Tomic, J.L., Pensalfini, A., Head, E. & Glabe, C.G. Soluble fibrillar oligomer levels are elevated in Alzheimer's disease brain and correlate with cognitive dysfunction. Neurobiol. Dis. 35, 352–358 (2009).
McLean, C.A. et al. Soluble pool of Abeta amyloid as a determinant of severity of neurodegeneration in Alzheimer's disease. Ann. Neurol. 46, 860–866 (1999).
Lesné, S.E. et al. Brain amyloid-beta oligomers in ageing and Alzheimer's disease. Brain 136, 1383–1398 (2013).
Handoko, M. et al. Correlation of specific amyloid-beta oligomers with tau in cerebrospinal fluid from cognitively normal older adults. JAMA Neurol. 70, 594–599 (2013).
Zhang, Y. et al. A lifespan observation of a novel mouse model: in vivo evidence supports abeta oligomer hypothesis. PLoS ONE 9, e85885 (2014).
Tomiyama, T. et al. A mouse model of amyloid beta oligomers: their contribution to synaptic alteration, abnormal tau phosphorylation, glial activation, and neuronal loss in vivo. J. Neurosci. 30, 4845–4856 (2010).
Lesné, S. et al. A specific amyloid-beta protein assembly in the brain impairs memory. Nature 440, 352–357 (2006).
Ma, Q.L. et al. Beta-amyloid oligomers induce phosphorylation of tau and inactivation of insulin receptor substrate via c-Jun N-terminal kinase signaling: suppression by omega-3 fatty acids and curcumin. J. Neurosci. 29, 9078–9089 (2009).
Ittner, L.M. et al. Dendritic function of tau mediates amyloid-beta toxicity in Alzheimer's disease mouse models. Cell 142, 387–397 (2010).
Haass, C. & Mandelkow, E. Fyn-tau-amyloid: a toxic triad. Cell 142, 356–358 (2010).
Zhang, Z. et al. Cleavage of tau by asparagine endopeptidase mediates the neurofibrillary pathology in Alzheimer's disease. Nat. Med. 20, 1254–1262 (2014).
Martin, L. et al. Tau protein kinases: involvement in Alzheimer's disease. Ageing Res. Rev. 12, 289–309 (2013).
Meyer-Luehmann, M. et al. Exogenous induction of cerebral beta-amyloidogenesis is governed by agent and host. Science 313, 1781–1784 (2006).
Sanders, D.W. et al. Distinct tau prion strains propagate in cells and mice and define different tauopathies. Neuron 82, 1271–1288 (2014).
de Calignon, A. et al. Propagation of tau pathology in a model of early Alzheimer's disease. Neuron 73, 685–697 (2012).
Liu, L. et al. Trans-synaptic spread of tau pathology in vivo. PLoS ONE 7, e31302 (2012).
Guo, J.L. et al. Distinct alpha-synuclein strains differentially promote tau inclusions in neurons. Cell 154, 103–117 (2013).
Giasson, B.I. et al. Initiation and synergistic fibrillization of tau and alpha-synuclein. Science 300, 636–640 (2003).
Dasuri, K., Zhang, L. & Keller, J.N. Oxidative stress, neurodegeneration, and the balance of protein degradation and protein synthesis. Free Radic. Biol. Med. 62, 170–185 (2013).
De Strooper, B. Proteases and proteolysis in Alzheimer disease: a multifactorial view on the disease process. Physiol. Rev. 90, 465–494 (2010).
Nixon, R.A. & Yang, D.S. Autophagy failure in Alzheimer's disease–locating the primary defect. Neurobiol. Dis. 43, 38–45 (2011).
Taylor, R.C. & Dillin, A. Aging as an event of proteostasis collapse. Cold Spring Harb. Perspect. Biol. 3, a004440 (2011).
Lu, T. et al. REST and stress resistance in ageing and Alzheimer's disease. Nature 507, 448–454 (2014).
Praticò, D., Uryu, K., Leight, S., Trojanoswki, J.Q. & Lee, V.M. Increased lipid peroxidation precedes amyloid plaque formation in an animal model of Alzheimer amyloidosis. J. Neurosci. 21, 4183–4187 (2001).
Benzing, W.C. et al. Evidence for glial-mediated inflammation in aged APP(SW) transgenic mice. Neurobiol. Aging 20, 581–589 (1999).
Calkins, M.J., Manczak, M., Mao, P., Shirendeb, U. & Reddy, P.H. Impaired mitochondrial biogenesis, defective axonal transport of mitochondria, abnormal mitochondrial dynamics and synaptic degeneration in a mouse model of Alzheimer's disease. Hum. Mol. Genet. 20, 4515–4529 (2011).
Guix, F.X. et al. Modification of gamma-secretase by nitrosative stress links neuronal ageing to sporadic Alzheimer's disease. EMBO Mol. Med. 4, 660–673 (2012).
Wahlster, L. et al. Presenilin-1 adopts pathogenic conformation in normal aging and in sporadic Alzheimer's disease. Acta Neuropathol. 125, 187–199 (2013).
Kukreja, L., Kujoth, G.C., Prolla, T.A., Van Leuven, F. & Vassar, R. Increased mtDNA mutations with aging promotes amyloid accumulation and brain atrophy in the APP/Ld transgenic mouse model of Alzheimer's disease. Mol. Neurodegener. 9, 16 (2014).
Liu, Y. et al. IKKbeta deficiency in myeloid cells ameliorates Alzheimer's disease-related symptoms and pathology. J. Neurosci. 34, 12982–12999 (2014).
Durazzo, T.C., Mattsson, N. & Weiner, M.W. Smoking and increased Alzheimer's disease risk: a review of potential mechanisms. Alzheimers Dement. 10, S122–S145 (2014).
Moreno-Gonzalez, I., Estrada, L.D., Sanchez-Mejias, E. & Soto, C. Smoking exacerbates amyloid pathology in a mouse model of Alzheimer's disease. Nat. Commun. 4, 1495 (2013).
Ulrich, J.D. et al. Altered microglial response to Abeta plaques in APPPS1–21 mice heterozygous for TREM2. Mol. Neurodegener. 9, 20 (2014).
Cady, J. et al. TREM2 variant p.R47H as a risk factor for sporadic amyotrophic lateral sclerosis. JAMA Neurol. 71, 449–453 (2014).
Rayaprolu, S. et al. TREM2 in neurodegeneration: evidence for association of the p.R47H variant with frontotemporal dementia and Parkinson's disease. Mol. Neurodegener. 8, 19 (2013).
Melnikova, T. et al. Reversible pathologic and cognitive phenotypes in an inducible model of Alzheimer-amyloidosis. J. Neurosci. 33, 3765–3779 (2013).
Kim, J. et al. Normal cognition in transgenic BRI2-Abeta mice. Mol. Neurodegener. 8, 15 (2013).
Berger-Sweeney, J. et al. Impairments in learning and memory accompanied by neurodegeneration in mice transgenic for the carboxyl-terminus of the amyloid precursor protein. Brain Res. Mol. Brain Res. 66, 150–162 (1999).
Gao, Y. & Pimplikar, S.W. The gamma -secretase-cleaved C-terminal fragment of amyloid precursor protein mediates signaling to the nucleus. Proc. Natl. Acad. Sci. USA 98, 14979–14984 (2001).
Dodart, J.C. et al. Immunization reverses memory deficits without reducing brain Abeta burden in Alzheimer's disease model. Nat. Neurosci. 5, 452–457 (2002).
Zheng, H. & Koo, E.H. Biology and pathophysiology of the amyloid precursor protein. Mol. Neurodegener. 6, 27 (2011).
Bero, A.W. et al. Neuronal activity regulates the regional vulnerability to amyloid-beta deposition. Nat. Neurosci. 14, 750–756 (2011).
Kang, J.E. et al. Amyloid-beta dynamics are regulated by orexin and the sleep-wake cycle. Science 326, 1005–1007 (2009).
Xie, L. et al. Sleep drives metabolite clearance from the adult brain. Science 342, 373–377 (2013).
Siegel, S.J., Bieschke, J., Powers, E.T. & Kelly, J.W. The oxidative stress metabolite 4-hydroxynonenal promotes Alzheimer protofibril formation. Biochemistry 46, 1503–1510 (2007).
Head, E. et al. Oxidation of Abeta and plaque biogenesis in Alzheimer's disease and Down syndrome. Neurobiol. Dis. 8, 792–806 (2001).
Kress, B.T. et al. Impairment of paravascular clearance pathways in the aging brain. Ann. Neurol. 76, 845–861 (2014).
Zhao, W., Zhang, J., Davis, E.G. & Rebeck, G.W. Aging reduces glial uptake and promotes extracellular accumulation of Abeta from a lentiviral vector. Front. Aging Neurosci. 6, 210 (2014).
Mawuenyega, K.G. et al. Decreased clearance of CNS beta-amyloid in Alzheimer's disease. Science 330, 1774 (2010).
Hipp, M.S., Park, S.H. & Hartl, F.U. Proteostasis impairment in protein-misfolding and -aggregation diseases. Trends Cell Biol. 24, 506–514 (2014).
Holmes, C. et al. Long-term effects of Abeta42 immunization in Alzheimer's disease: follow-up of a randomised, placebo-controlled phase I trial. Lancet 372, 216–223 (2008).
Boche, D. et al. Reduction of aggregated Tau in neuronal processes but not in the cell bodies after Abeta42 immunisation in Alzheimer's disease. Acta Neuropathol. 120, 13–20 (2010).
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).
Vellas, B. et al. Long-term follow-up of patients immunized with AN1792: reduced functional decline in antibody responders. Curr. Alzheimer Res. 6, 144–151 (2009).
Mills, S.M. et al. Preclinical trials in autosomal dominant AD: implementation of the DIAN-TU trial. Rev. Neurol. (Paris) 169, 737–743 (2013).
Reiman, E.M. et al. Alzheimer's Prevention Initiative: a plan to accelerate the evaluation of presymptomatic treatments. J. Alzheimers Dis. 26 (suppl. 3), 321–329 (2011).
Acknowledgements
E.S.M. is supported by NINDS grant K08NS079405 and Alzheimer's Association grant NIRG-305476. D.M.H. is supported by NIH grants R01 NS090934, R01 AG047644, P01 NS074969, P01 NS080675, PO1-AG03991, R01 NS034467, P01-AG026276, and U01 AG032438 and from the Tau Consortium and Cure Alzheimer's Fund.
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D.M.H. is a co-founder of C2N Diagnostics, LLC, a member of the scientific advisory board of C2N Diagnostics, and a consultant for Genentech, AstraZeneca, Neurophage and Eli Lilly. Washington University receives grants for the laboratory of D.M.H. from C2N Diagnostics, Eli Lilly and Janssen.
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Musiek, E., Holtzman, D. Three dimensions of the amyloid hypothesis: time, space and 'wingmen'. Nat Neurosci 18, 800–806 (2015). https://doi.org/10.1038/nn.4018
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DOI: https://doi.org/10.1038/nn.4018
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