Alzheimer's disease is a progressive loss of memory and cognition, for which there is no cure. Although genetic studies initially suggested a primary role for amyloid-in Alzheimer's disease, treatment strategies targeted at reducing amyloid-have failed to reverse cognitive symptoms. These clinical findings suggest that cognitive decline is the result of a complex pathophysiology and that targeting amyloid-alone may not be sufficient to treat Alzheimer's disease. Instead, a broad outlook on neural-circuit-damaging processes may yield insights into new therapeutic strategies for curing memory loss in the disease.
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Hurd, M. D., Martorell, P., Delavande, A., Mullen, K. J. & Langa, K. M. Monetary costs of dementia in the United States. N. Engl. J. Med. 368, 1326–1334 (2013).
Hyman, B. T. et al. National Institute on Aging—Alzheimer's Association guidelines for the neuropathologic assessment of Alzheimer's disease. Alzheimers Dement. 8, 1–13 (2012).
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). One of the first demonstrations that mutations in the gene APP correlate with familial AD, suggesting a prominent role for amyloid-β processing in the aetiology of AD.
Schellenberg, G. et al. Genetic linkage evidence for a familial Alzheimer's disease locus on chromosome 14. Science 258, 668–671 (1992).
Levy-Lahad, E. et al. Candidate gene for the chromosome 1 familial Alzheimer's disease locus. Science 269, 973–977 (1995).
Hardy, J. & Higgins, G. Alzheimer's disease: the amyloid cascade hypothesis. Science 256, 184–185 (1992). First article to synthesize the available data to formally propose that amyloid-β leads to varied neuronal disruption and cognitive impairment in AD.
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).
Lambert, J. C. et al. Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer's disease. Nature Genet. 45, 1452–1458 (2013). By aggregating data, this paper confirmed previous genetic risk factors associated with late-onset AD and also identified new loci that might increase susceptibility to the disease.
De Strooper, B. & Karran, E. The cellular phase of Alzheimer's disease. Cell 164, 603–615 (2016).
Palop, J. J. & Mucke, L. Amyloid-β-induced neuronal dysfunction in Alzheimer's disease: from synapses toward neural networks. Nature Neurosci. 13, 812–818 (2010).
Reitz, C. & Mayeux, R. Alzheimer disease: epidemiology, diagnostic criteria, risk factors and biomarkers. Biochem. Pharmacol. 88, 640–651 (2014).
Hardy, J. The Alzheimer family of diseases: many etiologies, one pathogenesis? Proc. Natl Acad. Sci. USA 94, 2095–2097 (1997).
Rovelet-Lecrux, A. et al. APP locus duplication causes autosomal dominant early-onset Alzheimer disease with cerebral amyloid angiopathy. Nature Genet. 38, 24–26 (2006).
Glenner, G. G. & Wong, C. W. Alzheimer's disease and Down's syndrome: sharing of a unique cerebrovascular amyloid fibril protein. Biochem. Biophys. Res. Commun. 122, 1131–1135 (1984).
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).
Jonsson, T. et al. A mutation in APP protects against Alzheimer's disease and age-related cognitive decline. Nature 488, 96–99 (2012).
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).
Morris, J. C. et al. APOE predicts amyloid-beta but not tau Alzheimer pathology in cognitively normal aging. Ann. Neurol. 67, 122–131 (2010).
Verghese, P. B. et al. ApoE influences amyloid-β (Aβ) clearance despite minimal apoE/Aβ association in physiological conditions. Proc. Natl Acad. Sci. USA 110, E1807–E1816 (2013).
Kayed, R. & Lasagna-Reeves, C. Molecular mechanisms of amyloid oligomers toxicity. J. Alzheimers Dis. 33, S67–S78 (2013).
Yankner, B. A., Duffy, L. K. & Kirschner, D. A. Neurotrophic and neurotoxic effects of amyloid beta protein: reversal by tachykinin neuropeptides. Science 250, 279–282 (1990).
Jack, C. R. et al. Serial PIB and MRI in normal, mild cognitive impairment and Alzheimer's disease: implications for sequence of pathological events in Alzheimer's disease. Brain 132, 1355–1365 (2009). Showed how certain events unfold in people with AD and contributed to an understanding of the temporal disconnection between amyloid-β deposition and cognitive impairment.
Shankar, G. M. et al. Natural oligomers of the Alzheimer amyloid-β protein induce reversible synapse loss by modulating an NMDA-type glutamate receptor-dependent signaling pathway. J. Neurosci. 27, 2866–2875 (2007).
Šišková, Z. et al. Dendritic structural degeneration is functionally linked to cellular hyperexcitability in a mouse model of Alzheimer's disease. Neuron 84, 1023–1033 (2014).
Palop, J. J. et al. Aberrant excitatory neuronal activity and compensatory remodeling of inhibitory hippocampal circuits in mouse models of Alzheimer's disease. Neuron 55, 697–711 (2007). Demonstrated that amyloid-β and AD-like features could induce hyperactivity in regions of the brain, challenging the idea that neurodegeneration leads to reduced neuronal activity and highlighting the complexity of changes seen in AD.
Cirrito, J. R. et al. Synaptic activity regulates interstitial fluid amyloid-β levels in vivo. Neuron 48, 913–922 (2005). First to indicate a considerable physiological role for amyloid-β in the brain, suggesting it could have important functions that influence AD phenotypes.
Wei, W. et al. Amyloid beta from axons and dendrites reduces local spine number and plasticity. Nature Neurosci. 13, 190–196 (2010).
Wu, J. et al. Arc/Arg3.1 regulates an endosomal pathway essential for activity-dependent β-amyloid generation. Cell 147, 615–628 (2011).
Das, U. et al. Activity-induced convergence of APP and BACE-1 in acidic microdomains via an endocytosis-dependent pathway. Neuron 79, 447–460 (2013).
Dougherty, J. J., Wu, J. & Nichols, R. A. β-Amyloid regulation of presynaptic nicotinic receptors in rat hippocampus and neocortex. J. Neurosci. 23, 6740–6747 (2003).
Abramov, E. et al. Amyloid-β as a positive endogenous regulator of release probability at hippocampal synapses. Nature Neurosci. 12, 1567–1576 (2009).
Snyder, E. M. et al. Regulation of NMDA receptor trafficking by amyloid-β. Nature Neurosci. 8, 1051–1058 (2005).
Roselli, F. et al. Soluble β-amyloid1–40 induces NMDA-dependent degradation of postsynaptic density-95 at glutamatergic synapses. J. Neurosci. 25, 11061–11070 (2005).
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).
Li, S. et al. Soluble oligomers of amyloid β protein facilitate hippocampal long-term depression by disrupting neuronal glutamate uptake. Neuron 62, 788–801 (2009).
Hsieh, H. et al. AMPAR removal underlies Aβ-induced synaptic depression and dendritic spine loss. Neuron 52, 831–843 (2006).
Verret, L. et al. Inhibitory interneuron deficit links altered network activity and cognitive dysfunction in Alzheimer model. Cell 149, 708–721 (2012).
Vossel, K. A. et al. Seizures and epileptiform activity in the early stages of Alzheimer disease. JAMA Neurol. 70, 1158–1166 (2013). Provided an early demonstration of neuronal hyperactivity in people with AD and confirmed findings made originally in rodent models of AD, suggesting that such models can recapitulate facets of AD accurately, despite limitations.
Volicer, L., Smith, S. & Volicer, B. J. Effect of seizures on progression of dementia of the Alzheimer type. Dementia 6, 258–263 (1995).
Bakker, A., Albert, M. S., Krauss, G., Speck, C. L. & Gallagher, M. Response of the medial temporal lobe network in amnestic mild cognitive impairment to therapeutic intervention assessed by fMRI and memory task performance. Neuroimage Clin. 7, 688–698 (2015).
Sanchez, P. E. et al. Levetiracetam suppresses neuronal network dysfunction and reverses synaptic and cognitive deficits in an Alzheimer's disease model. Proc. Natl Acad. Sci. USA 109, E2895–E2903 (2012).
Busche, M. A. et al. Rescue of long-range circuit dysfunction in Alzheimer's disease models. Nature Neurosci. 18, 1623–1630 (2015).
Thal, D. R., Rüb, U., Orantes, M. & Braak, H. Phases of Aβ-deposition in the human brain and its relevance for the development of AD. Neurology 58, 1791–1800 (2002).
Klunk, W. E. et al. Imaging brain amyloid in Alzheimer's disease with Pittsburgh compound-B. Ann. Neurol. 55, 306–319 (2004). This important paper was the first to describe the PET imaging of amyloids in people with AD.
Wong, D. F. et al. In vivo imaging of amyloid deposition in Alzheimer disease using the radioligand 18F-AV-45 (florbetapir F 18). J. Nucl. Med. 51, 913–920 (2010).
Jack, C. R. et al. Brain beta-amyloid measures and magnetic resonance imaging atrophy both predict time-to-progression from mild cognitive impairment to Alzheimer's disease. Brain 133, 3336–3348 (2010).
Forsberg, A. et al. PET imaging of amyloid deposition in patients with mild cognitive impairment. Neurobiol. Aging 29, 1456–1465 (2008).
Albert, M. S. et al. The diagnosis of mild cognitive impairment 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, 270–279 (2011).
Greicius, M. D., Srivastava, G., Reiss, A. L. & Menon, V. Default-mode network activity distinguishes Alzheimer's disease from healthy aging: evidence from functional MRI. Proc. Natl Acad. Sci. USA 101, 4637–4642 (2004).
Buckner, R. L. Molecular, structural, and functional characterization of Alzheimer's disease: evidence for a relationship between default activity, amyloid, and memory. J. Neurosci. 25, 7709–7717 (2005).
Sperling, R. A., LaViolette, P. & O'Keefe, K. Amyloid deposition is associated with impaired default network function in older persons without dementia. Neuron 63, 178–188 (2009).
Mormino, E. C. et al. Synergistic effect of β-amyloid and neurodegeneration on cognitive decline in clinically normal individuals. JAMA Neurol. 71, 1379–1385 (2014).
Villemagne, V. L. et al. Longitudinal assessment of Aβ and cognition in aging and Alzheimer disease. Ann. Neurol. 69, 181–192 (2011).
Damoiseaux, J. S., Prater, K. E., Miller, B. L. & Greicius, M. D. Functional connectivity tracks clinical deterioration in Alzheimer's disease. Neurobiol. Aging 33, 828.e19–828.e30 (2012).
Harris, J. A. et al. Transsynaptic progression of amyloid-β-induced neuronal dysfunction within the entorhinal–hippocampal network. Neuron 68, 428–441 (2010).
Jucker, M. & Walker, L. C. Self-propagation of pathogenic protein aggregates in neurodegenerative diseases. Nature 501, 45–51 (2013).
Fleisher, A. S. et al. Phase 2 safety trial targeting amyloid β production with a γ-secretase inhibitor in Alzheimer disease. Arch. Neurol. 65, 1031–1038 (2008).
May, P. C. et al. The Potent BACE1 inhibitor LY2886721 elicits robust central Aβ pharmacodynamic responses in mice, dogs, and humans. J. Neurosci. 35, 1199–1210 (2015).
De Strooper, B. Lessons from a failed γ-secretase Alzheimer trial. Cell 159, 721–726 (2014).
Vassar, R. BACE1 inhibitor drugs in clinical trials for Alzheimer's disease. Alzheimers Res. Ther. 6, 89 (2014).
Doody, R. S. et al. A phase 3 trial of semagacestat for treatment of Alzheimer's disease. N. Engl. J. Med. 369, 341–350 (2013).
Orgogozo, J. M. et al. Subacute meningoencephalitis in a subset of patients with AD after Aβ42 immunization. Neurology 61, 46–54 (2003).
Farlow, M. R. et al. Long-term treatment with active Aβ immunotherapy with CAD106 in mild Alzheimer's disease. Alzheimers Res. Ther. 7, 23 (2015).
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).
Siemers, E. R. et al. Phase 3 solanezumab trials: secondary outcomes in mild Alzheimer's disease patients. Alzheimers Dement. 12, 110–120 (2016).
J. Sevigny et al. The antibody aducanumab reduces Aβ plaques in Alzheimer's disease. Nature 537, 50–56 (2016).
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).
van der Kant, R. & Goldstein, L. S. B. Cellular functions of the amyloid precursor protein from development to dementia. Dev. Cell 32, 502–515 (2015).
Duggan, S. P. & McCarthy, J. V. Beyond γ-secretase activity: the multifunctional nature of presenilins in cell signalling pathways. Cell. Signal. 28, 1–11 (2016).
Müller, U. et al. Behavioral and anatomical deficits in mice homozygous for a modified β-amyloid precursor protein gene. Cell 79, 755–765 (1994).
Dawson, G. R. et al. Age-related cognitive deficits, impaired long-term potentiation and reduction in synaptic marker density in mice lacking the β-amyloid precursor protein. Neuroscience 90, 1–13 (1999).
Xia, D. et al. Presenilin-1 knockin mice reveal loss-of-function mechanism for familial Alzheimer's disease. Neuron 85, 967–981 (2015).
Nelson, O. et al. Familial Alzheimer disease-linked mutations specifically disrupt Ca2+ leak function of presenilin 1. J. Clin. Invest. 117, 1230–1239 (2007).
Fabelo, N. et al. Altered lipid composition in cortical lipid rafts occurs at early stages of sporadic Alzheimer's disease and facilitates APP/BACE1 interactions. Neurobiol. Aging 35, 1801–1812 (2014).
Sakae, N. et al. ABCA7 deficiency accelerates amyloid-β generation and Alzheimer's neuronal pathology. J. Neurosci. 36, 3848–3859 (2016).
Miller, S. E. et al. CALM regulates clathrin-coated vesicle size and maturation by directly sensing and driving membrane curvature. Dev. Cell 33, 163–175 (2015).
Hong, S. et al. Complement and microglia mediate early synapse loss in Alzheimer mouse models. Science 352, 712–716 (2016).
De Jager, P. L. et al. Alzheimer's disease: early alterations in brain DNA methylation at ANK1, BIN1, RHBDF2 and other loci. Nature Neurosci. 17, 1156–1163 (2014).
Yu, L. et al. Association of brain DNA methylation in SORL1, ABCA7, HLA-DRB5, SLC24A4, and BIN1 with pathological diagnosis of Alzheimer disease. JAMA Neurol. 72, 15–24 (2015).
Gjoneska, E. et al. Conserved epigenomic signals in mice and humans reveal immune basis of Alzheimer's disease. Nature 518, 365–369 (2015).
Gräff, J. et al. An epigenetic blockade of cognitive functions in the neurodegenerating brain. Nature 483, 222–226 (2012).
Lu, T. et al. REST and stress resistance in ageing and Alzheimer's disease. Nature 507, 448–454 (2014).
Jo, D.-G. et al. Evidence that γ-secretase mediates oxidative stress-induced β-secretase expression in Alzheimer's disease. Neurobiol. Aging 31, 917–925 (2010).
Mecocci, P., MacGarvey, U. & Beal, M. F. Oxidative damage to mitochondrial DNA is increased in Alzheimer's disease. Ann. Neurol. 36, 747–751 (1994).
Frost, B., Hemberg, M., Lewis, J. & Feany, M. B. Tau promotes neurodegeneration through global chromatin relaxation. Nature Neurosci. 17, 357–366 (2014).
Kim, D. et al. Deregulation of HDAC1 by p25/Cdk5 in neurotoxicity. Neuron 60, 803–817 (2008).
Anderson, A. J., Stoltzner, S., Lai, F., Su, J. & Nixon, R. A. Morphological and biochemical assessment of DNA damage and apoptosis in Down syndrome and Alzheimer disease, and effect of postmortem tissue archival on TUNEL. Neurobiol. Aging 21, 511–524 (2000).
Suberbielle, E. et al. Physiologic brain activity causes DNA double-strand breaks in neurons, with exacerbation by amyloid-β. Nature Neurosci. 16, 613–621 (2013).
Lu, T. et al. Gene regulation and DNA damage in the ageing human brain. Nature 429, 883–891 (2004).
Madabhushi, R. et al. Activity-induced DNA breaks govern the expression of neuronal early-response genes. Cell 161, 1592–1605 (2015).
LaFerla, F. M. Calcium dyshomeostasis and intracellular signalling in Alzheimer's disease. Nature Rev. Neurosci. 3, 862–872 (2002).
Seo, J. et al. Activity-dependent p25 generation regulates synaptic plasticity and Aβ-induced cognitive impairment. Cell 157, 486–498 (2014).
Lindwall, G. & Cole, R. D. Phosphorylation affects the ability of tau protein to promote microtubule assembly. J. Biol. Chem. 259, 5301–5305 (1984).
Bramblett, G. T. et al. Abnormal tau phosphorylation at Ser396 in Alzheimer's disease recapitulates development and contributes to reduced microtubule binding. Neuron 10, 1089–1099 (1993).
Sontag, E., Nunbhakdi-Craig, V., Lee, G., Bloom, G. S. & Mumby, M. C. Regulation of the phosphorylation state and microtubule-binding activity of tau by protein phosphatase 2A. Neuron 17, 1201–1207 (1996).
Vogelsberg-Ragaglia, V., Schuck, T., Trojanowski, J. Q. & Lee, V. M. PP2A mRNA expression is quantitatively decreased in Alzheimer's disease hippocampus. Exp. Neurol. 168, 402–412 (2001).
Cruz, J. C., Tseng, H. C., Goldman, J. A., Shih, H. & Tsai, L. H. Aberrant Cdk5 activation by p25 triggers pathological events leading to neurodegeneration and neurofibrillary tangles. Neuron 40, 471–483 (2003).
Yamada, K. et al. Neuronal activity regulates extracellular tau in vivo. J. Exp. Med. 211, 387–393 (2014).
Pooler, A. M., Phillips, E. C., Lau, D. H. W., Noble, W. & Hanger, D. P. Physiological release of endogenous tau is stimulated by neuronal activity. EMBO Rep. 14, 389–394 (2013).
Wu, J. W. et al. Neuronal activity enhances tau propagation and tau pathology in vivo. Nature Neurosci. 19, 1085–1092 (2016).
Cohen, T. J. et al. The acetylation of tau inhibits its function and promotes pathological tau aggregation. Nature Commun. 2, 252 (2011).
Moreau, K. et al. PICALM modulates autophagy activity and tau accumulation. Nature Commun. 5, 4998 (2014).
Kononenko, N. L. & Haucke, V. Molecular mechanisms of presynaptic membrane retrieval and synaptic vesicle reformation. Neuron 85, 484–496 (2015).
Treusch, S. et al. Functional links between Aβ toxicity, endocytic trafficking, and Alzheimer's disease risk factors in yeast. Science 334, 1241–1245 (2011).
Crotti, A. & Ransohoff, R. M. Microglial physiology and pathophysiology: insights from genome-wide transcriptional profiling. Immunity 44, 505–515 (2016).
Wang, Y. et al. TREM2 lipid sensing sustains the microglial response in an Alzheimer's disease model. Cell 160, 1061–1071 (2015). The first demonstration that AD genetic risk loci affect microglia, which play an important part in modulating the AD state.
Orre, M. et al. Isolation of glia from Alzheimer's mice reveals inflammation and dysfunction. Neurobiol. Aging 35, 2746–2760 (2014).
Mandrekar, S. et al. Microglia mediate the clearance of soluble Aβ through fluid phase macropinocytosis. J. Neurosci. 29, 4252–4262 (2009).
Chen, Z. et al. Microglial displacement of inhibitory synapses provides neuroprotection in the adult brain. Nature Commun. 5, 4486 (2014).
Cacucci, F., Yi, M., Wills, T. J., Chapman, P. & O'Keefe, J. Place cell firing correlates with memory deficits and amyloid plaque burden in Tg2576 Alzheimer mouse model. Proc. Natl Acad. Sci. USA 105, 7863–7868 (2008).
Ciupek, S. M., Cheng, J., Ali, Y. O., Lu, H.-C. & Ji, D. Progressive functional impairments of hippocampal neurons in a tauopathy mouse model. J. Neurosci. 35, 8118–8131 (2015).
Morris, R. G., Garrud, P., Rawlins, J. N. & O'Keefe, J. Place navigation impaired in rats with hippocampal lesions. Nature 297, 681–683 (1982).
Wilson, M. A. & McNaughton, B. L. Dynamics of the hippocampal ensemble code for space. Science 261, 1055–1058 (1993).
Whitehouse, P. J., Price, D. L., Clark, A. W., Coyle, J. T. & DeLong, M. R. Alzheimer disease: evidence for selective loss of cholinergic neurons in the nucleus basalis. Ann. Neurol. 10, 122–126 (1981).
Metherate, R., Cox, C. L. & Ashe, J. H. Cellular bases of neocortical activation: modulation of neural oscillations by the nucleus basalis and endogenous acetylcholine. J. Neurosci. 12, 4701–4711 (1992).
Mesulam, M., Shaw, P., Mash, D. & Weintraub, S. Cholinergic nucleus basalis tauopathy emerges early in the aging–MCI–AD continuum. Ann. Neurol. 55, 815–828 (2004).
Bartus, R. T., Dean, R. L., Beer, B. & Lippa, A. The cholinergic hypothesis of geriatric memory dysfunction. Science 217, 408–414 (1982).
Hangya, B., Ranade, S. P., Lorenc, M. & Kepecs, A. Central cholinergic neurons are rapidly recruited by reinforcement feedback. Cell 162, 1155–1168 (2015).
Zhu, C. W. et al. Long-term associations between cholinesterase inhibitors and memantine use and health outcomes among patients with Alzheimer's disease. Alzheimers Dement. 9, 733–740 (2013).
Mattson, M. P. Pathways towards and away from Alzheimer's disease. Nature 430, 631–639 (2004).
Braak, H. & Del Tredici, K. The pathological process underlying Alzheimer's disease in individuals under thirty. Acta Neuropathol. 121, 171–181 (2011).
Braak, H. & Braak, E. Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol. 82, 239–259 (1991). The first comprehensive hierarchical staging of AD, which suggested a stereotypical path of progression and highlighted correlations between pathological observations of the brain and cognitive decline.
Johnson, K. A. et al. Tau positron emission tomographic imaging in aging and early Alzheimer disease. Ann. Neurol. 79, 110–119 (2016).
Steffenach, H. A., Witter, M., Moser, M. B. & Moser, E. I. Spatial memory in the rat requires the dorsolateral band of the entorhinal cortex. Neuron 45, 301–313 (2005).
Vargha-Khadem, F. et al. Differential effects of early hippocampal pathology on episodic and semantic memory. Science 277, 376–380 (1997).
Schöll, M. et al. PET imaging of tau deposition in the aging human brain. Neuron 89, 971–982 (2016).
Ossenkoppele, R. et al. Tau PET patterns mirror clinical and neuroanatomical variability in Alzheimer's disease. Brain 139, 1551–1567 (2016).
Ye, L. et al. Progression of seed-induced Aβ deposition within the limbic connectome. Brain Pathol. 25, 743–752 (2015).
Bruen, P. D., McGeown, W. J., Shanks, M. F. & Venneri, A. Neuroanatomical correlates of neuropsychiatric symptoms in Alzheimer's disease. Brain 131, 2455–2463 (2008).
Iba, M. et al. Tau pathology spread in PS19 tau transgenic mice following locus coeruleus (LC) injections of synthetic tau fibrils is determined by the LC's afferent and efferent connections. Acta Neuropathol. 130, 349–362 (2015).
Nestor, P. J., Fryer, T. D., Smielewski, P. & Hodges, J. R. Limbic hypometabolism in Alzheimer's disease and mild cognitive impairment. Ann. Neurol. 54, 343–351 (2003).
Fletcher, E., Carmichael, O., Pasternak, O., Maier-Hein, K. H. & DeCarli, C. Early brain loss in circuits affected by Alzheimer's disease is predicted by fornix microstructure but may be independent of gray matter. Front. Aging Neurosci. 6, 106 (2014).
Laxton, A. W. et al. A phase I trial of deep brain stimulation of memory circuits in Alzheimer's disease. Ann. Neurol. 68, 521–534 (2010). This paper describes the feasibility of deep-brain stimulation in people and targets regions that are not typically described in studies of disrupted processes in AD; it suggests that complex brain-wide network effects occur in AD.
McEwen, B. S. Central effects of stress hormones in health and disease: understanding the protective and damaging effects of stress and stress mediators. Eur. J. Pharmacol. 583, 174–185 (2008).
Diano, S. et al. Ghrelin controls hippocampal spine synapse density and memory performance. Nature Neurosci. 9, 381–388 (2006).
Lupien, S. J. et al. Cortisol levels during human aging predict hippocampal atrophy and memory deficits. Nature Neurosci. 1, 69–73 (1998).
Baglietto-Vargas, D. et al. Short-term modern life-like stress exacerbates Aβ-pathology and synapse loss in 3xTg-AD mice. J. Neurochem. 134, 915–926 (2015).
Rei, D. et al. Basolateral amygdala bidirectionally modulates stress-induced hippocampal learning and memory deficits through a p25/Cdk5-dependent pathway. Proc. Natl Acad. Sci. USA 112, 7291–7296 (2015).
Roy, D. S. et al. Memory retrieval by activating engram cells in mouse models of early Alzheimer's disease. Nature 531, 508–512 (2016).
Fischer, A., Sananbenesi, F., Wang, X., Dobbin, M. & Tsai, L.-H. Recovery of learning and memory is associated with chromatin remodelling. Nature 447, 178–182 (2007). One of the first papers to highlight the importance of epigenetic alterations in AD and the first to demonstrate experimentally that memories can be recovered through treatment, even after considerable neurodegeneration has occurred.
Talantova, M. et al. Aβ induces astrocytic glutamate release, extrasynaptic NMDA receptor activation, and synaptic loss. Proc. Natl Acad. Sci. USA 110, E2518–E2527 (2013).
Shytle, R. D. et al. Cholinergic modulation of microglial activation by α7 nicotinic receptors. J. Neurochem. 89, 337–343 (2004).
Pedersen, J. T. & Sigurdsson, E. M. Tau immunotherapy for Alzheimer's disease. Trends Mol. Med. 21, 394–402 (2015).
Kuhn, J. et al. Deep brain stimulation of the nucleus basalis of meynert in early stage of Alzheimer's dementia. Brain Stimul. 8, 838–839 (2015).
Sankar, T. et al. Deep brain stimulation influences brain structure in Alzheimer's disease. Brain Stimul. 8, 645–654 (2015).
Hamelin, L. et al. Early and protective microglial activation in Alzheimer's disease: a prospective study using 18F-DPA-714 PET imaging. Brain 139, 1252–1264 (2016).
Nhan, H. S., Chiang, K. & Koo, E. H. The multifaceted nature of amyloid precursor protein and its proteolytic fragments: friends and foes. Acta Neuropathol. 129, 1–19 (2015).
Lammich, S. et al. Constitutive and regulated α-secretase cleavage of Alzheimer's amyloid precursor protein by a disintegrin metalloprotease. Proc. Natl Acad. Sci. USA 96, 3922–3927 (1999).
De Jonghe, C. et al. Pathogenic APP mutations near the γ-secretase cleavage site differentially affect Aβ secretion and APP C-terminal fragment stability. Hum. Mol. Genet. 10, 1665–1671 (2001).
Willem, M. et al. η-Secretase processing of APP inhibits neuronal activity in the hippocampus. Nature 526, 443–447 (2015).
We thank the US National Institutes of Health for grants R01 NS051874, R01 NS078839, RF1 AG042978 and RF1 AG047661 in support of L.-H.T. We thank the Barbara J. Weedon Fellowship and Norman B. Leventhal Fellowship for supporting R.G.C. and the Human Frontier Science Program for supporting J.P. We also thank the JPB Foundation, the Belfer Neurodegeneration Consortium, the Glenn Foundation for Medical Research, the Cure Alzheimer's Fund and the Alana Foundation for support of L.-H.T. and for continued championship of ageing and neurodegenerative disease research. We thank C. Yao for contributions to the original figure artwork. Last, we express profound gratitude to A. Watson, H. Meharena, W. Raja and N. Dedic for insightful comments on the manuscript.
The authors declare no competing financial interests.
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Canter, R., Penney, J. & Tsai, LH. The road to restoring neural circuits for the treatment of Alzheimer's disease. Nature 539, 187–196 (2016). https://doi.org/10.1038/nature20412
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