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Beyond the neuron–cellular interactions early in Alzheimer disease pathogenesis

Nature Reviews Neuroscience volume 20, pages 94–108 (2019)Cite this article

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Abstract

The symptoms of Alzheimer disease reflect a loss of neural circuit integrity in the brain, but neurons do not work in isolation. Emerging evidence suggests that the intricate balance of interactions between neurons, astrocytes, microglia and vascular cells required for healthy brain function becomes perturbed during the disease, with early changes likely protecting neural circuits from damage, followed later by harmful effects when the balance cannot be restored. Moving beyond a neuronal focus to understand the complex cellular interactions in Alzheimer disease and how these change throughout the course of the disease may provide important insight into developing effective therapeutics.

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Fig. 1: Synapse loss occurs early in Alzheimer disease pathogenesis.
Fig. 2: Schematic of the neurovascular unit and early changes in Alzheimer disease.

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References

  1. World Health Organization. Dementia, a global health priority. https://www.who.int/mental_health/publications/dementia_report_2012/en/ (WHO, 2017).

  2. De Strooper, B. & Karran, E. The cellular phase of Alzheimer’s disease. Cell 164, 603–615 (2016).

    PubMed  Google Scholar 

  3. Hardy, J. A. & Higgins, G. A. Alzheimer’s disease: the amyloid cascade hypothesis. Science 256, 184–185 (1992).

    CAS  PubMed  Google Scholar 

  4. Karran, E. & De Strooper, B. The amyloid cascade hypothesis: are we poised for success or failure? J. Neurochem. 139, 237–252 (2016).

    CAS  PubMed  Google Scholar 

  5. Villegas-Llerena, C., Phillips, A., Garcia-Reitboeck, P., Hardy, J. & Pocock, J. M. Microglial genes regulating neuroinflammation in the progression of Alzheimer’s disease. Curr. Opin. Neurobiol. 36, 74–81 (2016).

    CAS  PubMed  Google Scholar 

  6. Livingston, G. et al. Dementia prevention, intervention, and care. Lancet 390, 2673–2734 (2017).

    PubMed  Google Scholar 

  7. Iadecola, C. The pathobiology of vascular dementia. Neuron 80, 844–866 (2013).

    CAS  PubMed  Google Scholar 

  8. Kisler, K., Nelson, A. R., Montagne, A. & Zlokovic, B. V. Cerebral blood flow regulation and neurovascular dysfunction in Alzheimer disease. Nat. Rev. Neurosci. 18, 419–434 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. 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). This landmark paper identifies APOE4 as a genetic risk factor for late-onset AD.

    CAS  PubMed  Google Scholar 

  10. Zlokovic, B. V. Neurovascular pathways to neurodegeneration in Alzheimer’s disease and other disorders. Nat. Rev. Neurosci. 12, 723–738 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Bennett, R. E. et al. Tau induces blood vessel abnormalities and angiogenesis-related gene expression in P301L transgenic mice and human Alzheimer’s disease. Proc. Natl Acad. Sci. USA 115, E1289–E1298 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Condello, C., Yuan, P., Schain, A. & Grutzendler, J. Microglia constitute a barrier that prevents neurotoxic protofibrillar Aβ42 hotspots around plaques. Nat. Commun. 6, 6176 (2015).

    CAS  PubMed  Google Scholar 

  13. Heneka, M. T. et al. Neuroinflammation in Alzheimer’s disease. Lancet. Neurol. 14, 388–405 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Lue, L. F. et al. Involvement of microglial receptor for advanced glycation endproducts (RAGE) in Alzheimer’s disease: identification of a cellular activation mechanism. Exp. Neurol. 171, 29–45 (2001).

    CAS  PubMed  Google Scholar 

  15. Zhao, R., Hu, W., Tsai, J., Li, W. & Gan, W. B. Microglia limit the expansion of beta-amyloid plaques in a mouse model of Alzheimer’s disease. Mol. Neurodegener. 12, 47 (2017).

    PubMed  PubMed Central  Google Scholar 

  16. Grathwohl, S. A. et al. Formation and maintenance of Alzheimer’s disease beta-amyloid plaques in the absence of microglia. Nat. Neurosci. 12, 1361–1363 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Spangenberg, E. E. et al. Eliminating microglia in Alzheimer’s mice prevents neuronal loss without modulating amyloid-beta pathology. Brain 139, 1265–1281 (2016).

    PubMed  PubMed Central  Google Scholar 

  18. Olmos-Alonso, A. et al. Pharmacological targeting of CSF1R inhibits microglial proliferation and prevents the progression of Alzheimer’s-like pathology. Brain 139, 891–907 (2016).

    PubMed  PubMed Central  Google Scholar 

  19. Czirr, E. et al. Microglial complement receptor 3 regulates brain Aβ levels through secreted proteolytic activity. J. Exp. Med. 214, 1081–1092 (2017).

    PubMed  PubMed Central  Google Scholar 

  20. Tay, T. L. et al. A new fate mapping system reveals context-dependent random or clonal expansion of microglia. Nat. Neurosci. 20, 793–803 (2017).

    CAS  PubMed  Google Scholar 

  21. Korin, B. et al. High-dimensional, single-cell characterization of the brain’s immune compartment. Nat. Neurosci. 20, 1300–1309 (2017).

    CAS  PubMed  Google Scholar 

  22. Korin, B., Dubovik, T. & Rolls, A. Mass cytometry analysis of immune cells in the brain. Nat. Protoc. 13, 377–391 (2018).

    CAS  PubMed  Google Scholar 

  23. Keren-Shaul, H. et al. A unique microglia type associated with restricting development of Alzheimer’s disease. Cell 169, 1276–1290 (2017). This study uses single-cell transcriptomics to identify a subset of microglia surrounding plaques in an AD mouse model. Activation of these DAMs requires TREM2.

    CAS  PubMed  Google Scholar 

  24. Krasemann, S. et al. The TREM2-APOE pathway drives the transcriptional phenotype of dysfunctional microglia in neurodegenerative diseases. Immunity 47, 566–581 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Yeh, F. L., Wang, Y., Tom, I., Gonzalez, L. C. & Sheng, M. TREM2 binds to apolipoproteins, including APOE and CLU/APOJ, and thereby facilitates uptake of amyloid-beta by microglia. Neuron 91, 328–340 (2016).

    CAS  PubMed  Google Scholar 

  26. Jay, T. R. et al. Disease progression-dependent effects of TREM2 deficiency in a mouse model of Alzheimer’s disease. J. Neurosci. 37, 637–647 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Yuan, P. et al. TREM2 haplodeficiency in mice and humans impairs the microglia barrier function leading to decreased amyloid compaction and severe axonal dystrophy. Neuron 90, 724–739 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Ulrich, J. D. et al. Altered microglial response to Aβ plaques in APPPS1-21 mice heterozygous for TREM2. Mol. Neurodegener. 9, 20 (2014).

    PubMed  PubMed Central  Google Scholar 

  29. Jay, T. R. et al. TREM2 deficiency eliminates TREM2+inflammatory macrophages and ameliorates pathology in Alzheimer’s disease mouse models. J. Exp. Med. 212, 287–295 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Song, W. M. et al. Humanized TREM2 mice reveal microglia-intrinsic and -extrinsic effects of R47H polymorphism. J. Exp. Med. 215, 745–760 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Wang, Y. et al. TREM2-mediated early microglial response limits diffusion and toxicity of amyloid plaques. J. Exp. Med. 213, 667–675 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Kim, S. M. et al. TREM2 promotes Aβ phagocytosis by upregulating C/EBPα-dependent CD36 expression in microglia. Sci. Rep. 7, 11118 (2017).

    PubMed  PubMed Central  Google Scholar 

  33. Wyss-Coray, T. et al. Adult mouse astrocytes degrade amyloid-beta in vitro and in situ. Nat. Med. 9, 453–457 (2003).

    CAS  PubMed  Google Scholar 

  34. Leal, M. C. et al. Plaque-associated overexpression of insulin-degrading enzyme in the cerebral cortex of aged transgenic tg2576 mice with Alzheimer pathology. J. Neuropathol. Exp. Neurol. 65, 976–987 (2006).

    CAS  PubMed  Google Scholar 

  35. Deb, S., Wenjun Zhang, J. & Gottschall, P. E. Beta-amyloid induces the production of active, matrix-degrading proteases in cultured rat astrocytes. Brain Res. 970, 205–213 (2003).

    PubMed  Google Scholar 

  36. Yin, K. J. et al. Matrix metalloproteinases expressed by astrocytes mediate extracellular amyloid-beta peptide catabolism. J. Neurosci. 26, 10939–10948 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Mrak, R. E., Sheng, J. G. & Griffin, W. S. Correlation of astrocytic S100 beta expression with dystrophic neurites in amyloid plaques of Alzheimer’s disease. J. Neuropathol. Exp. Neurol. 55, 273–279 (1996).

    CAS  PubMed  Google Scholar 

  38. 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).

    PubMed  PubMed Central  Google Scholar 

  39. Bales, K. R. et al. Lack of apolipoprotein E dramatically reduces amyloid beta-peptide deposition. Nat. Genet. 17, 263–264 (1997).

    CAS  PubMed  Google Scholar 

  40. Irizarry, M. C. et al. Apolipoprotein E affects the amount, form, and anatomical distribution of amyloid beta-peptide deposition in homozygous APP(V717F) transgenic mice. Acta Neuropathol. 100, 451–458 (2000).

    CAS  PubMed  Google Scholar 

  41. Lee, L., Kosuri, P. & Arancio, O. Picomolar amyloid-beta peptides enhance spontaneous astrocyte calcium transients. J. Alzheimers Dis. 38, 49–62 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Lim, D. et al. Amyloid beta deregulates astroglial mGluR5-mediated calcium signaling via calcineurin and Nf-kB. Glia 61, 1134–1145 (2013).

    PubMed  Google Scholar 

  43. Kuchibhotla, K. V., Lattarulo, C. R., Hyman, B. T. & Bacskai, B. J. Synchronous hyperactivity and intercellular calcium waves in astrocytes in Alzheimer mice. Science 323, 1211–1215 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Spires-Jones, T. L., Attems, J. & Thal, D. R. Interactions of pathological proteins in neurodegenerative diseases. Acta Neuropathol. 134, 187–205 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Serrano-Pozo, A. et al. Reactive glia not only associates with plaques but also parallels tangles in Alzheimer’s disease. Am. J. Pathol. 179, 1373–1384 (2011).

    PubMed  PubMed Central  Google Scholar 

  46. Leyns, C. E. G. et al. TREM2 deficiency attenuates neuroinflammation and protects against neurodegeneration in a mouse model of tauopathy. Proc. Natl Acad. Sci. USA 114, 11524–11529 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Hampton, D. W. et al. Cell-mediated neuroprotection in a mouse model of human tauopathy. J. Neurosci. 30, 9973–9983 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Bemiller, S. M. et al. TREM2 deficiency exacerbates tau pathology through dysregulated kinase signaling in a mouse model of tauopathy. Mol. Neurodegener. 12, 74 (2017).

    PubMed  PubMed Central  Google Scholar 

  49. Jiang, T. et al. TREM2 modifies microglial phenotype and provides neuroprotection in P301S tau transgenic mice. Neuropharmacology 105, 196–206 (2016).

    CAS  PubMed  Google Scholar 

  50. Shi, Y. et al. ApoE4 markedly exacerbates tau-mediated neurodegeneration in a mouse model of tauopathy. Nature 549, 523–527 (2017).

    PubMed  PubMed Central  Google Scholar 

  51. Asai, H. et al. Depletion of microglia and inhibition of exosome synthesis halt tau propagation. Nat. Neurosci. 18, 1584–1593 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Bhaskar, K. et al. Regulation of tau pathology by the microglial fractalkine receptor. Neuron 68, 19–31 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Nash, K. R. et al. Fractalkine overexpression suppresses tau pathology in a mouse model of tauopathy. Neurobiol. Aging 34, 1540–1548 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Grabert, K. et al. Microglial brain region-dependent diversity and selective regional sensitivities to aging. Nat. Neurosci. 19, 504–516 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Clarke, L. E. et al. Normal aging induces A1-like astrocyte reactivity. Proc. Natl Acad. Sci. 115, E1896–E1905 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Tzioras, M. et al. Assessing amyloid-β, tau, and glial features in Lothian Birth Cohort 1936 participants post-mortem. Matters (Zur). https://doi.org/10.19185/matters.201708000003 (2017).

    Article  Google Scholar 

  57. Kang, S. S. et al. Microglial translational profiling reveals a convergent APOE pathway from aging, amyloid, and tau. J. Exp. Med. 215, 2235–2245 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Gomez-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).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Mathys, H. et al. Temporal tracking of microglia activation in neurodegeneration at single-cell resolution. Cell Rep. 21, 366–380 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Park, J. et al. A 3D human triculture system modeling neurodegeneration and neuroinflammation in Alzheimer’s disease. Nat. Neurosci. 21, 941–951 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Henstridge, C. M. & Spires-Jones, T. L. Modeling Alzheimer’s disease brains in vitro. Nat. Neurosci. 21, 899–900 (2018).

    CAS  PubMed  Google Scholar 

  62. Simard, A. R., Soulet, D., Gowing, G., Julien, J. P. & Rivest, S. Bone marrow-derived microglia play a critical role in restricting senile plaque formation in Alzheimer’s disease. Neuron 49, 489–502 (2006).

    CAS  PubMed  Google Scholar 

  63. Stalder, A. K. et al. Invasion of hematopoietic cells into the brain of amyloid precursor protein transgenic mice. J. Neurosci. 25, 11125–11132 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Zuroff, L., Daley, D., Black, K. L. & Koronyo-Hamaoui, M. Clearance of cerebral Aβ in Alzheimer’s disease: reassessing the role of microglia and monocytes. Cell. Mol. Life Sci. 74, 2167–2201 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Buttini, M. et al. Cellular source of apolipoprotein E4 determines neuronal susceptibility to excitotoxic injury in transgenic mice. Am. J. Pathol. 177, 563–569 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Liddelow, S. A. et al. Neurotoxic reactive astrocytes are induced by activated microglia. Nature 541, 481–487 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Chakrabarty, P. et al. IL-10 alters immunoproteostasis in APP mice, increasing plaque burden and worsening cognitive behavior. Neuron 85, 519–533 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Guillot-Sestier, M. V. et al. Il10 deficiency rebalances innate immunity to mitigate Alzheimer-like pathology. Neuron 85, 534–548 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Lian, H. et al. Astrocyte-microglia cross talk through complement activation modulates amyloid pathology in mouse models of Alzheimer’s disease. J. Neurosci. 36, 577–589 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Sekar, S. et al. Alzheimer’s disease is associated with altered expression of genes involved in immune response and mitochondrial processes in astrocytes. Neurobiol. Aging 36, 583–591 (2015).

    CAS  PubMed  Google Scholar 

  71. Mosher, K. I. & Wyss-Coray, T. Microglial dysfunction in brain aging and Alzheimer’s disease. Biochem. Pharmacol. 88, 594–604 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Liao, Y. F., Wang, B. J., Cheng, H. T., Kuo, L. H. & Wolfe, M. S. Tumor necrosis factor-alpha, interleukin-1beta, and interferon-gamma stimulate gamma-secretase-mediated cleavage of amyloid precursor protein through a JNK-dependent MAPK pathway. J. Biol. Chem. 279, 49523–49532 (2004).

    CAS  PubMed  Google Scholar 

  73. Diniz, L. P. et al. Astrocyte transforming growth factor beta 1 protects synapses against Aβ oligomers in Alzheimer’s disease model. J. Neurosci. 37, 6797–6809 (2017).

    CAS  PubMed  Google Scholar 

  74. White, J. A., Manelli, A. M., Holmberg, K. H., Van Eldik, L. J. & Ladu, M. J. Differential effects of oligomeric and fibrillar amyloid-beta 1–42 on astrocyte-mediated inflammation. Neurobiol. Dis. 18, 459–465 (2005).

    CAS  PubMed  Google Scholar 

  75. Rodriguez, G. A., Tai, L. M. & LaDu, M. J. & Rebeck, G. W. Human APOE4 increases microglia reactivity at Aβ plaques in a mouse model of Aβ deposition. J. Neuroinflammation 11, 111 (2014).

    PubMed  PubMed Central  Google Scholar 

  76. He, P. et al. Deletion of tumor necrosis factor death receptor inhibits amyloid beta generation and prevents learning and memory deficits in Alzheimer’s mice. J. Cell Biol. 178, 829–841 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Wilkaniec, A., Gassowska-Dobrowolska, M., Strawski, M., Adamczyk, A. & Czapski, G. A. Inhibition of cyclin-dependent kinase 5 affects early neuroinflammatory signalling in murine model of amyloid beta toxicity. J. Neuroinflammation 15, 1 (2018).

    PubMed  PubMed Central  Google Scholar 

  78. Patel, N. S. et al. Inflammatory cytokine levels correlate with amyloid load in transgenic mouse models of Alzheimer’s disease. J. Neuroinflammation 2, 9 (2005).

    PubMed  PubMed Central  Google Scholar 

  79. Wood, L. B. et al. Identification of neurotoxic cytokines by profiling Alzheimer’s disease tissues and neuron culture viability screening. Sci. Rep. 5, 16622 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Robinson, S. R., Dobson, C. & Lyons, J. Challenges and directions for the pathogen hypothesis of Alzheimer’s disease. Neurobiol. Aging 25, 629–637 (2004).

    CAS  PubMed  Google Scholar 

  81. Itzhaki, R. F. et al. Herpes simplex virus type 1 in brain and risk of Alzheimer’s disease. Lancet 349, 241–244 (1997).

    CAS  PubMed  Google Scholar 

  82. Readhead, B. et al. Multiscale analysis of independent Alzheimer’s cohorts finds disruption of molecular, genetic, and clinical networks by human herpesvirus. Neuron 99, 64–82 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Eimer, W. A. et al. Alzheimer’s disease-associated beta-amyloid is rapidly seeded by herpesviridae to protect against brain infection. Neuron 99, 56–63 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Kumar, D. K. et al. Amyloid-beta peptide protects against microbial infection in mouse and worm models of Alzheimer’s disease. Sci. Transl Med. 8, 340ra372 (2016).

    Google Scholar 

  85. Dean, D. C. 3rd et al. Association of amyloid pathology with myelin alteration in preclinical Alzheimer disease. JAMA Neurol. 74, 41–49 (2017).

    PubMed  PubMed Central  Google Scholar 

  86. McAleese, K. E. et al. Cortical tau load is associated with white matter hyperintensities. Acta Neuropathol. Commun. 3, 60 (2015).

    PubMed  PubMed Central  Google Scholar 

  87. Braak, H. & Braak, E. Development of Alzheimer-related neurofibrillary changes in the neocortex inversely recapitulates cortical myelogenesis. Acta Neuropathol. 92, 197–201 (1996).

    CAS  PubMed  Google Scholar 

  88. de Faria, O. et al. Neuroglial interactions underpinning myelin plasticity. Dev. Neurobiol. 78, 93–107 (2018).

    PubMed  Google Scholar 

  89. Xu, J. et al. Amyloid-beta peptides are cytotoxic to oligodendrocytes. J. Neurosci. 21, RC118 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Jantaratnotai, N., Ryu, J. K., Kim, S. U. & McLarnon, J. G. Amyloid beta peptide-induced corpus callosum damage and glial activation in vivo. Neuroreport 14, 1429–1433 (2003).

    CAS  PubMed  Google Scholar 

  91. Miron, V. E. et al. M2 microglia and macrophages drive oligodendrocyte differentiation during CNS remyelination. Nat. Neurosci. 16, 1211–1218 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. 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).

    CAS  PubMed  Google Scholar 

  93. Akram, A. et al. Stereologic estimates of total spinophilin-immunoreactive spine number in area 9 and the CA1 field: relationship with the progression of Alzheimer’s disease. Neurobiol. Aging 29, 1296–1307 (2008).

    CAS  PubMed  Google Scholar 

  94. Mufson, E. J. et al. Mild cognitive impairment: pathology and mechanisms. Acta Neuropathol. 123, 13–30 (2012).

    CAS  PubMed  Google Scholar 

  95. Scheff, S. W., DeKosky, S. T. & Price, D. A. Quantitative assessment of cortical synaptic density in Alzheimer’s disease. Neurobiol. Aging 11, 29–37 (1990).

    CAS  PubMed  Google Scholar 

  96. 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). This paper presents the first study to demonstrate that loss of synapses correlates with cognitive decline in AD using elegant electron microscopy imaging of frontal cortex biopsy sample tissue.

    CAS  PubMed  Google Scholar 

  97. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Henstridge, C. M., Pickett, E. & Spires-Jones, T. L. Synaptic pathology: A shared mechanism in neurological disease. Ageing Res. Rev. 28, 72–84 (2016).

    CAS  PubMed  Google Scholar 

  99. Chung, W. S. et al. Astrocytes mediate synapse elimination through MEGF10 and MERTK pathways. Nature 504, 394–400 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Salter, M. W. & Stevens, B. Microglia emerge as central players in brain disease. Nat. Med. 23, 1018–1027 (2017).

    CAS  PubMed  Google Scholar 

  101. Schafer, D. P., Lehrman, E. K. & Stevens, B. The “quad-partite” synapse: microglia-synapse interactions in the developing and mature CNS. Glia 61, 24–36 (2013).

    PubMed  Google Scholar 

  102. Tremblay, M. E., Lowery, R. L. & Majewska, A. K. Microglial interactions with synapses are modulated by visual experience. PLOS Biol. 8, e1000527 (2010).

    PubMed  PubMed Central  Google Scholar 

  103. Paolicelli, R. C. et al. Synaptic pruning by microglia is necessary for normal brain development. Science 333, 1456–1458 (2011).

    CAS  PubMed  Google Scholar 

  104. Schafer, D. P. et al. Microglia sculpt postnatal neural circuits in an activity and complement-dependent manner. Neuron 74, 691–705 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Stevens, B. et al. The classical complement cascade mediates CNS synapse elimination. Cell 131, 1164–1178 (2007).

    CAS  PubMed  Google Scholar 

  106. Stephan, A. H., Barres, B. A. & Stevens, B. The complement system: an unexpected role in synaptic pruning during development and disease. Annu. Rev. Neurosci. 35, 369–389 (2012).

    CAS  PubMed  Google Scholar 

  107. Bialas, A. R. & Stevens, B. TGF-β signaling regulates neuronal C1q expression and developmental synaptic refinement. Nat. Neurosci. 16, 1773–1782 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Chung, W. S. et al. Novel allele-dependent role for APOE in controlling the rate of synapse pruning by astrocytes. Proc. Natl Acad. Sci. USA 113, 10186–10191 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Lambert, J. C. et al. Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer’s disease. Nat. Genet. 41, 1094–1099 (2009).

    CAS  PubMed  Google Scholar 

  110. Yasojima, K., Schwab, C., McGeer, E. G. & McGeer, P. L. Up-regulated production and activation of the complement system in Alzheimer’s disease brain. Am. J. Pathol. 154, 927–936 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. Hong, S. et al. Complement and microglia mediate early synapse loss in Alzheimer mouse models. Science 352, 712–716 (2016). This study is the first demonstration of complement-mediated microglial engulfment of synapses in AD mouse models.

    CAS  PubMed  PubMed Central  Google Scholar 

  112. Shi, Q. et al. Complement C3 deficiency protects against neurodegeneration in aged plaque-rich APP/PS1 mice. Sci. Transl Med. 9, eaaf6295 (2017). This paper establishes the first link between APOE and tau-induced neurodegeneration in an FTD model. APOE knockout was protective whereas APOE2<APOE3<APOE4 expression was associated with reduced homeostatic and increased pro-inflammatory gene expression in both microglia and astrocytes.

    Google Scholar 

  113. Weinhard, L. et al. Microglia remodel synapses by presynaptic trogocytosis and spine head filopodia induction. Nat. Commun. 9, 1228 (2018).

    PubMed  PubMed Central  Google Scholar 

  114. Boulanger, L. M. Immune proteins in brain development and synaptic plasticity. Neuron 64, 93–109 (2009).

    CAS  PubMed  Google Scholar 

  115. Syken, J., Grandpre, T., Kanold, P. O. & Shatz, C. J. PirB restricts ocular-dominance plasticity in visual cortex. Science 313, 1795–1800 (2006).

    CAS  PubMed  Google Scholar 

  116. William, C. M. et al. Synaptic plasticity defect following visual deprivation in Alzheimer’s disease model transgenic mice. J. Neurosci. 32, 8004–8011 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  117. Kim, T. et al. Human LilrB2 is a beta-amyloid receptor and its murine homolog PirB regulates synaptic plasticity in an Alzheimer’s model. Science 341, 1399–1404 (2013).

    CAS  PubMed  Google Scholar 

  118. Paolicelli, R. C. et al. TDP-43 depletion in microglia promotes amyloid clearance but also induces synapse loss. Neuron 95, 297–308 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  119. Henstridge, C. M. et al. Synapse loss in the prefrontal cortex is associated with cognitive decline in amyotrophic lateral sclerosis. Acta Neuropathol. 135, 213–226 (2018).

    CAS  PubMed  Google Scholar 

  120. Matos, M., Augusto, E., Agostinho, P., Cunha, R. A. & Chen, J. F. Antagonistic interaction between adenosine A2A receptors and Na+/K+-ATPase-α2 controlling glutamate uptake in astrocytes. J. Neurosci. 33, 18492–18502 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  121. Orr, A. G. et al. Astrocytic adenosine receptor A2A and Gs-coupled signaling regulate memory. Nat. Neurosci. 18, 423–434 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  122. Mookherjee, P. et al. GLT-1 loss accelerates cognitive deficit onset in an Alzheimer’s disease animal model. J. Alzheimers Dis. 26, 447–455 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  123. Scimemi, A. et al. Amyloid-β1-42 slows clearance of synaptically released glutamate by mislocalizing astrocytic GLT-1. J. Neurosci. 33, 5312–5318 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  124. Zumkehr, J. et al. Ceftriaxone ameliorates tau pathology and cognitive decline via restoration of glial glutamate transporter in a mouse model of Alzheimer’s disease. Neurobiol. Aging 36, 2260–2271 (2015).

    CAS  PubMed  Google Scholar 

  125. Reisberg, B. et al. Memantine in moderate-to-severe Alzheimer’s disease. N. Engl. J. Med. 348, 1333–1341 (2003).

    CAS  PubMed  Google Scholar 

  126. Pitas, R. E., Boyles, J. K., Lee, S. H., Foss, D. & Mahley, R. W. Astrocytes synthesize apolipoprotein E and metabolize apolipoprotein E-containing lipoproteins. Biochim. Biophys. Acta 917, 148–161 (1987).

    CAS  PubMed  Google Scholar 

  127. Koffie, R. M. et al. Apolipoprotein E4 effects in Alzheimer’s disease are mediated by synaptotoxic oligomeric amyloid-beta. Brain: J. Neurol. 135, 2155–2168 (2012). This study applies, for the first time, the high-resolution imaging technique of array tomography to human brain tissue. APOE4 was observed to increase the presence of oligomeric Aβ at synapses in the AD brain.

    Google Scholar 

  128. Rebeck, G. W., Reiter, J. S., Strickland, D. K. & Hyman, B. T. Apolipoprotein E in sporadic Alzheimer’s disease: allelic variation and receptor interactions. Neuron 11, 575–580 (1993).

    CAS  PubMed  Google Scholar 

  129. Castellano, J. M. et al. Human apoE isoforms differentially regulate brain amyloid-β peptide clearance. Sci. Transl Med. 3, 89ra57 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  130. Hashimoto, T. et al. Apolipoprotein E, especially apolipoprotein E4, increases the oligomerization of amyloid β peptide. J. Neurosci. 32, 15181–15192 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  131. Klein, W. Synaptotoxic amyloid-β oligomers: a molecular basis for the cause, diagnosis, and treatment of Alzheimer’s disease? J. Alzheimers Dis. 33 (Suppl. 1), 49–65 (2013).

    PubMed  Google Scholar 

  132. Perez-Nievas, B. G. et al. Dissecting phenotypic traits linked to human resilience to Alzheimer’s pathology. Brain 136, 2510–2526 (2013).

    PubMed  PubMed Central  Google Scholar 

  133. Dumanis, S. B. et al. ApoE4 decreases spine density and dendritic complexity in cortical neurons in vivo. J. Neurosci. 29, 15317–15322 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  134. Dumanis, S. B., DiBattista, A. M., Miessau, M., Moussa, C. E. & Rebeck, G. W. APOE genotype affects the pre-synaptic compartment of glutamatergic nerve terminals. J. Neurochem. 124, 4–14 (2013).

    CAS  PubMed  Google Scholar 

  135. Korwek, K. M., Trotter, J. H., Ladu, M. J., Sullivan, P. M. & Weeber, E. J. ApoE isoform-dependent changes in hippocampal synaptic function. Mol. Neurodegener. 4, 21 (2009).

    PubMed  PubMed Central  Google Scholar 

  136. Schiepers, O. J. et al. APOE E4 status predicts age-related cognitive decline in the ninth decade: longitudinal follow-up of the Lothian Birth Cohort 1921. Mol. Psychiatry 17, 315–324 (2012).

    CAS  PubMed  Google Scholar 

  137. Henstridge, C. M. et al. Post-mortem brain analyses of the Lothian Birth Cohort 1936: extending lifetime cognitive and brain phenotyping to the level of the synapse. Acta Neuropathol. Commun. 3, 53 (2015).

    PubMed  PubMed Central  Google Scholar 

  138. Kay, K. R. et al. Studying synapses in human brain with array tomography and electron microscopy. Nat. Protoc. 8, 1366–1380 (2013).

    PubMed  PubMed Central  Google Scholar 

  139. Yoshiyama, Y. et al. Synapse loss and microglial activation precede tangles in a P301S tauopathy mouse model. Neuron 53, 337–351 (2007).

    CAS  PubMed  Google Scholar 

  140. Sidoryk-Wegrzynowicz, M. et al. Astrocytes in mouse models of tauopathies acquire early deficits and lose neurosupportive functions. Acta Neuropathol. Commun. 5, 89 (2017).

    PubMed  PubMed Central  Google Scholar 

  141. Hunsberger, H. C., Rudy, C. C., Batten, S. R., Gerhardt, G. A. & Reed, M. N. P301L tau expression affects glutamate release and clearance in the hippocampal trisynaptic pathway. J. Neurochem. 132, 169–182 (2015).

    CAS  PubMed  Google Scholar 

  142. Piacentini, R. et al. Reduced gliotransmitter release from astrocytes mediates tau-induced synaptic dysfunction in cultured hippocampal neurons. Glia 65, 1302–1316 (2017).

    PubMed  PubMed Central  Google Scholar 

  143. Dudvarski Stankovic, N., Teodorczyk, M., Ploen, R., Zipp, F. & Schmidt, M. H. H. Microglia-blood vessel interactions: a double-edged sword in brain pathologies. Acta Neuropathol. 131, 347–363 (2016).

    PubMed  Google Scholar 

  144. Shen, Q., Goderie, S. K., Jin, L., Karanth, N. & Sun, Y. Endothelial cells stimulate self-renewal and expand neurogenesis of neural stem cells. Science 304, 1338–1340 (2004).

    CAS  PubMed  Google Scholar 

  145. Arai, K. & Lo, E. H. An oligovascular niche: cerebral endothelial cells promote the survival and proliferation of oligodendrocyte precursor cells. J. Neurosci. 29, 4351–4355 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  146. Guo, S., Kim, W. J., Lok, J. & Lee, S. R. Neuroprotection via matrix-trophic coupling between cerebral endothelial cells and neurons. Proc. Natl Acad. Sci. USA 105, 7582–7587 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  147. Santos, C. Y. et al. Pathophysiologic relationship between Alzheimer’s disease, cerebrovascular disease, and cardiovascular risk: a review and synthesis. Alzheimers Dement. (Amst.) 7, 69–87 (2017).

    Google Scholar 

  148. Matthews, F. E. et al. A two decade dementia incidence comparison from the cognitive function and ageing studies I and II. Nat. Commun. 7, 11398 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  149. Iadecola, C. et al. SOD1 rescues cerebral endothelial dysfunction in mice overexpressing amyloid precursor protein. Nat. Neurosci. 2, 157–161 (1999).

    CAS  PubMed  Google Scholar 

  150. Iadecola, C. Neurovascular regulation in the normal brain and in Alzheimer’s disease. Nat. Rev. Neurosci. 5, 347–360 (2004).

    CAS  PubMed  Google Scholar 

  151. Kelly, P. et al. Microvascular ultrastructural changes precede cognitive impairment in the murine APPswe/PS1dE9 model of Alzheimer’s disease. Angiogenesis 20, 567–580 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  152. Wang, H., Golob, E. J. & Su, M.-Y. Y. Vascular volume and blood-brain barrier permeability measured by dynamic contrast enhanced MRI in hippocampus and cerebellum of patients with MCI and normal controls. J. Magn. Reson. Imaging 24, 695–700 (2006).

    PubMed  Google Scholar 

  153. Starr, J. M., Farrall, A. J., Armitage, P. & McGurn, B. Blood–brain barrier permeability in Alzheimer’s disease: a case–control MRI study. Psychiatry Res. 171, 232–241 (2009).

    CAS  PubMed  Google Scholar 

  154. Jagust, W. J. et al. Diminished glucose transport in Alzheimer’s disease: dynamic PET studies. J. Cereb. Blood Flow Metab. 11, 323–330 (1991).

    CAS  PubMed  Google Scholar 

  155. Iturria-Medina, Y. et al. Early role of vascular dysregulation on late-onset Alzheimer’s disease based on multifactorial data-driven analysis. Nat. Commun. 7, 11934 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  156. Wardlaw, J. M. & Hernández, M. C. V. What are white matter hyperintensities made of? Relevance to vascular cognitive impairment. J. Am. Heart Assoc. 4, e001140 (2015).

    PubMed Central  Google Scholar 

  157. McAleese, K. E. et al. Parietal white matter lesions in Alzheimer’s disease are associated with cortical neurodegenerative pathology, but not with small vessel disease. Acta Neuropathol. 134, 459–473 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  158. Lee, S. et al. White matter hyperintensities are a core feature of Alzheimer’s disease: evidence from the dominantly inherited Alzheimer network. Ann. Neurol. 79, 929–939 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  159. Bakker, E. N. et al. Lymphatic clearance of the brain: perivascular, paravascular and significance for neurodegenerative diseases. Cell. Mol. Neurobiol. 36, 181–194 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  160. Tarasoff-Conway, J. M. et al. Clearance systems in the brain-implications for Alzheimer disease. Nat. Rev. Neurol. 11, 457–470 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  161. Iadecola, C. The neurovascular unit coming of age: a journey through neurovascular coupling in health and disease. Neuron 96, 17–42 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  162. Iliff, J. J. et al. A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid beta. Sci. Transl Med. 4, 147ra111 (2012).

    PubMed  PubMed Central  Google Scholar 

  163. Plog, B. A. & Nedergaard, M. The glymphatic system in central nervous system health and disease: past, present, and future. Annu. Rev. Pathol. 13, 379–394 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  164. Da Mesquita, S. et al. Functional aspects of meningeal lymphatics in ageing and Alzheimer’s disease. Nature 560, 185–191 (2018).

    PubMed  PubMed Central  Google Scholar 

  165. Lucey, B. P. et al. Associations between beta-amyloid kinetics and the beta-amyloid diurnal pattern in the central nervous system. JAMA Neurol. 74, 207–215 (2017).

    PubMed  PubMed Central  Google Scholar 

  166. Kang, J. E. et al. Amyloid-beta dynamics are regulated by orexin and the sleep-wake cycle. Science 326, 1005–1007 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  167. Bero, A. W. et al. Neuronal activity regulates the regional vulnerability to amyloid-beta deposition. Nat. Neurosci. 14, 750–756 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  168. Xie, L. et al. Sleep drives metabolite clearance from the adult brain. Science 342, 373–377 (2013).

    CAS  PubMed  Google Scholar 

  169. Zhao, Z. et al. Central role for PICALM in amyloid-beta blood-brain barrier transcytosis and clearance. Nat. Neurosci. 18, 978–987 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  170. Nelson, A. R., Sagare, A. P. & Zlokovic, B. V. Role of clusterin in the brain vascular clearance of amyloid-beta. Proc. Natl Acad. Sci. USA 114, 8681–8682 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  171. Robert, J. et al. Clearance of beta-amyloid is facilitated by apolipoprotein E and circulating high-density lipoproteins in bioengineered human vessels. eLife 6, e29595 (2017).

    PubMed  PubMed Central  Google Scholar 

  172. Burfeind, K. G. et al. The effects of noncoding aquaporin-4 single-nucleotide polymorphisms on cognition and functional progression of Alzheimer’s disease. Alzheimers Dement. (NY) 3, 348–359 (2017).

    Google Scholar 

  173. Sagare, A. P. et al. Pericyte loss influences Alzheimer-like neurodegeneration in mice. Nat. Commun. 4, 2932 (2013).

    PubMed  Google Scholar 

  174. Hill, R. A. et al. Regional blood flow in the normal and ischemic brain is controlled by arteriolar smooth muscle cell contractility and not by capillary pericytes. Neuron 87, 95–110 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  175. Faraco, G. et al. Hypertension enhances Aβ-induced neurovascular dysfunction, promotes β-secretase activity, and leads to amyloidogenic processing of APP. J. Cereb. Blood Flow Metab. 36, 241–252 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  176. El Khoury, J. et al. Ccr2 deficiency impairs microglial accumulation and accelerates progression of Alzheimer-like disease. Nat. Med. 13, 432–438 (2007).

    CAS  PubMed  Google Scholar 

  177. Jiang, T., Sun, Q. & Chen, S. Oxidative stress: a major pathogenesis and potential therapeutic target of antioxidative agents in Parkinson’s disease and Alzheimer’s disease. Prog. Neurobiol. 147, 1–19 (2016).

    CAS  PubMed  Google Scholar 

  178. Pratico, D. Oxidative stress hypothesis in Alzheimer’s disease: a reappraisal. Trends Pharmacol. Sci. 29, 609–615 (2008).

    CAS  PubMed  Google Scholar 

  179. Pratico, 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  180. Matsuoka, Y., Picciano, M., La Francois, J. & Duff, K. Fibrillar beta-amyloid evokes oxidative damage in a transgenic mouse model of Alzheimer’s disease. Neuroscience 104, 609–613 (2001).

    CAS  PubMed  Google Scholar 

  181. Nunomura, A. et al. Oxidative damage is the earliest event in Alzheimer disease. J. Neuropathol. Exp. Neurol. 60, 759–767 (2001).

    CAS  PubMed  Google Scholar 

  182. Park, L. et al. Nox2-derived radicals contribute to neurovascular and behavioral dysfunction in mice overexpressing the amyloid precursor protein. Proc. Natl Acad. Sci. USA 105, 1347–1352 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  183. Park, L. et al. Innate immunity receptor CD36 promotes cerebral amyloid angiopathy. Proc. Natl Acad. Sci. USA 110, 3089–3094 (2013).

    PubMed  PubMed Central  Google Scholar 

  184. Park, L. et al. Brain perivascular macrophages initiate the neurovascular dysfunction of Alzheimer Aβ peptides. Circ. Res. 121, 258–269 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  185. Lane-Donovan, C. & Herz, J. ApoE, ApoE receptors, and the synapse in Alzheimer’s disease. Trends Endocrinol. Metab. 28, 273–284 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  186. Cramer, P. E. et al. ApoE-directed therapeutics rapidly clear beta-amyloid and reverse deficits in AD mouse models. Science 335, 1503–1506 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  187. Tesseur, I. et al. Comment on “ApoE-directed therapeutics rapidly clear beta-amyloid and reverse deficits in AD mouse models”. Science 340, 924 (2013).

    CAS  PubMed  Google Scholar 

  188. LaClair, K. D. et al. Treatment with bexarotene, a compound that increases apolipoprotein-E, provides no cognitive benefit in mutant APP/PS1 mice. Mol. Neurodegener. 8, 18 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  189. O’Hare, E. et al. Lack of support for bexarotene as a treatment for Alzheimer’s disease. Neuropharmacology 100, 124–130 (2016).

    PubMed  Google Scholar 

  190. Cummings, J. L. et al. Double-blind, placebo-controlled, proof-of-concept trial of bexarotene Xin moderate Alzheimer’s disease. Alzheimers Res. Ther. 8, 4 (2016).

    PubMed  PubMed Central  Google Scholar 

  191. Huynh, T. V. et al. Age-dependent effects of apoE reduction using antisense oligonucleotides in a model of beta-amyloidosis. Neuron 96, 1013–1023 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  192. in t’ Veld, B. A. et al. Nonsteroidal antiinflammatory drugs and the risk of Alzheimer’s disease. N. Engl. J. Med. 345, 1515–1521 (2001).

    PubMed  Google Scholar 

  193. Masgrau, R., Guaza, C., Ransohoff, R. M. & Galea, E. Should we stop saying ‘glia’ and ‘neuroinflammation’? Trends Mol. Med. 23, 486–500 (2017).

    CAS  PubMed  Google Scholar 

  194. Breitner, J. C. et al. Extended results of the Alzheimer’s disease anti-inflammatory prevention trial. Alzheimers Dement. 7, 402–411 (2011).

    PubMed  PubMed Central  Google Scholar 

  195. Lansita, J. A. et al. Nonclinical development of ANX005: a humanized anti-C1q antibody for treatment of autoimmune and neurodegenerative diseases. Int. J. Toxicol. 36, 449–462 (2017).

    CAS  PubMed  Google Scholar 

  196. Femminella, G. D. et al. Antidiabetic drugs in Alzheimer’s disease: mechanisms of action and future perspectives. J. Diabetes Res. 2017, 7420796 (2017).

    PubMed  PubMed Central  Google Scholar 

  197. Infante-Garcia, C. et al. Antidiabetic polypill improves central pathology and cognitive impairment in a mixed model of Alzheimer’s disease and type 2 diabetes. Mol. Neurobiol. 55, 6130–6144 (2017).

    PubMed  Google Scholar 

  198. Ramos-Rodriguez, J. J. et al. Progressive neuronal pathology and synaptic loss induced by prediabetes and type 2 diabetes in a mouse model of Alzheimer’s disease. Mol. Neurobiol. 54, 3428–3438 (2017).

    CAS  PubMed  Google Scholar 

  199. Harrington, C. et al. Rosiglitazone does not improve cognition or global function when used as adjunctive therapy to AChE inhibitors in mild-to-moderate Alzheimer’s disease: two phase 3 studies. Curr. Alzheimer Res. 8, 592–606 (2011).

    CAS  PubMed  Google Scholar 

  200. Takeda Pharmaceutical Company. Takeda and Zinfandel pharmaceuticals discontinue TOMMORROW trial following planned futility analysis. Takeda https://www.takeda.com/newsroom/newsreleases/2018/takeda-tommorrow-trial/ (2018).

  201. Wu, Y. T. et al. The changing prevalence and incidence of dementia over time - current evidence. Nat. Rev. Neurol. 13, 327–339 (2017).

    PubMed  Google Scholar 

  202. Hamer, M., Muniz Terrera, G. & Demakakos, P. Physical activity and trajectories in cognitive function: English longitudinal study of ageing. J. Epidemiol. Community Health 72, 477–483 (2018).

    PubMed  Google Scholar 

  203. Forbes, D., Forbes, S. C., Blake, C. M., Thiessen, E. J. & Forbes, S. Exercise programs for people with dementia. Cochrane Database Syst. Rev. 4, CD006489 (2015).

    Google Scholar 

  204. Young, J., Angevaren, M., Rusted, J. & Tabet, N. Aerobic exercise to improve cognitive function in older people without known cognitive impairment. Cochrane Database Syst. Rev. 4, CD005381 (2015).

    Google Scholar 

  205. Serrano-Pozo, A., Frosch, M. P., Masliah, E. & Hyman, B. T. Neuropathological alterations in Alzheimer disease. Cold Spring Harb. Perspect. Med. 1, a006189 (2011).

    PubMed  PubMed Central  Google Scholar 

  206. Alzheimer, A. Ubereine eigenartige Erkrankung der Hirnrinde [German]. Allgemeine Zeitschrift Psychiatrie Psychisch-Gerichtliche Medizin 64, 146–148 (1907).

    Google Scholar 

  207. 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).

    PubMed  PubMed Central  Google Scholar 

  208. De Strooper, B. et al. Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein. Nature 391, 387–390 (1998).

    PubMed  Google Scholar 

  209. Vassar, R. et al. Beta-secretase cleavage of Alzheimer’s amyloid precursor protein by the transmembrane aspartic protease BACE. Science 286, 735–741 (1999).

    CAS  PubMed  Google Scholar 

  210. 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).

    PubMed  Google Scholar 

  211. Jarosz-Griffiths, H. H., Noble, E., Rushworth, J. V. & Hooper, N. M. Amyloid-β receptors: the good, the bad, and the prion protein. J. Biol. Chem. 291, 3174–3183 (2016).

    CAS  PubMed  Google Scholar 

  212. Goedert, M., Spillantini, M. G., Cairns, N. J. & Crowther, R. A. Tau proteins of Alzheimer paired helical filaments: abnormal phosphorylation of all six brain isoforms. Neuron 8, 159–168 (1992).

    CAS  PubMed  Google Scholar 

  213. Goedert, M. & Spillantini, M. G. A century of Alzheimer’s disease. Science 314, 777–781 (2006).

    CAS  PubMed  Google Scholar 

  214. 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).

    CAS  PubMed  Google Scholar 

  215. Braak, H. & Braak, E. Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol. 82, 239–259 (1991).

    CAS  PubMed  Google Scholar 

  216. Ingelsson, M. et al. Early Aβ accumulation and progressive synaptic loss, gliosis, and tangle formation in AD brain. Neurology 62, 925–931 (2004).

    CAS  PubMed  Google Scholar 

  217. Nelson, P. T. et al. Correlation of Alzheimer disease neuropathologic changes with cognitive status: a review of the literature. J. Neuropathol. Exp. Neurol. 71, 362–381 (2012).

    PubMed  Google Scholar 

  218. Gomez-Isla, T. et al. Neuronal loss correlates with but exceeds neurofibrillary tangles in Alzheimer’s disease. Ann. Neurol. 41, 17–24 (1997).

    CAS  PubMed  Google Scholar 

  219. Dickerson, B. C., Stoub, T. R., Shah, R. C. & Sperling, R. A. Alzheimer-signature MRI biomarker predicts AD dementia in cognitively normal adults. Neurology 76, 1395–1402 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  220. Hickman, S., Izzy, S., Sen, P., Morsett, L. & El Khoury, J. Microglia in neurodegeneration. Nat. Neurosci. 21, 1359–1369 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  221. Heppner, F. L., Ransohoff, R. M. & Becher, B. Immune attack: the role of inflammation in Alzheimer disease. Nat. Rev. Neurosci. 16, 358–372 (2015).

    CAS  PubMed  Google Scholar 

  222. Pekny, M. et al. Astrocytes: a central element in neurological diseases. Acta Neuropathol. 131, 323–345 (2016).

    CAS  PubMed  Google Scholar 

  223. Rodriguez-Arellano, J. J., Parpura, V., Zorec, R. & Verkhratsky, A. Astrocytes in physiological aging and Alzheimer’s disease. Neuroscience 323, 170–182 (2016).

    CAS  PubMed  Google Scholar 

  224. Cai, Z. & Xiao, M. Oligodendrocytes and Alzheimer’s disease. Int. J. Neurosci. 126, 97–104 (2016).

    CAS  PubMed  Google Scholar 

  225. Nasrabady, S. E., Rizvi, B., Goldman, J. E. & Brickman, A. M. White matter changes in Alzheimer’s disease: a focus on myelin and oligodendrocytes. Acta Neuropathol. Commun. 6, 22 (2018).

    PubMed  PubMed Central  Google Scholar 

  226. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  227. Lambert, J. C. et al. Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer’s disease. Nat. Genet. 45, 1452–1458 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  228. Hollingworth, P. et al. Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer’s disease. Nat. Genet. 43, 429–435 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  229. Harold, D. et al. Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer’s disease. Nat. Genet. 41, 1088–1093 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  230. Guerreiro, R. et al. TREM2 variants in Alzheimer’s disease. N. Engl. J. Med. 368, 117–127 (2013).

    CAS  PubMed  Google Scholar 

  231. Jonsson, T. et al. Variant of TREM2 associated with the risk of Alzheimer’s disease. N. Engl. J. Med. 368, 107–116 (2013).

    CAS  PubMed  Google Scholar 

  232. Sims, R. et al. Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer’s disease. Nat. Genet. 49, 1373–1384 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  233. Robinson, M., Lee, B. Y. & Hane, F. T. Recent progress in Alzheimer’s disease research, part 2: genetics and epidemiology. J. Alzheimers Dis. 57, 317–330 (2017).

    PubMed  PubMed Central  Google Scholar 

  234. Efthymiou, A. G. & Goate, A. M. Late onset Alzheimer’s disease genetics implicates microglial pathways in disease risk. Mol. Neurodegener. 12, 43 (2017).

    PubMed  PubMed Central  Google Scholar 

  235. Zhang, Y. et al. An RNA-sequencing transcriptome and splicing database of glia, neurons, and vascular cells of the cerebral cortex. J. Neurosci. 34, 11929–11947 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

T.L.S.-J. and C.M.H. gratefully acknowledge funding from the UK Dementia Research Institute, the European Research Council (ALZSYN), Alzheimer’s Research UK, the Alzheimer’s Society, MND Scotland and the Euan MacDonald Centre for Motorneurone Disease Research. T.L.S.-J. is a member of the FENS Kavli Network of Excellence. The authors thank M. Tzioras for excellent critical review of the manuscript.

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Nature Reviews Neuroscience thanks O. Arancio and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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  1. The University of Edinburgh Centre for Discovery Brain Sciences, UK Dementia Research Institute, Edinburgh, UK

    Christopher M. Henstridge & Tara L. Spires-Jones

  2. MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA

    Bradley T. Hyman

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T.L.S.-J., B.T.H. and C.M.H. made substantial contributions to the discussion of content, writing, review and editing of the manuscript before submission.

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Glossary

Amyloid cascade hypothesis

Initially proposed in 1992, this hypothesis posits that the accumulation of amyloid-β (Aβ) is the initiating factor in Alzheimer disease pathogenesis, leading to the formation of amyloid plaques, neurofibrillary tangles, neuron loss and clinical dementia.

Innate immune system

Reactive response that utilizes chemical mediators to fight infection and clear foreign substances from the body by recruiting specialized immune cells. It can also activate a second wave of adaptive immune response by presenting antigens to adaptive immune cells.

Secretomes

The secretome includes all secretable factors released from a cell.

Oligomeric Aβ

Single molecules of Aβ are known as monomers. These monomers can aggregate to form oligomeric structures of two or more monomers, which can then accumulate into larger fibrillar forms of Aβ and deposit as the hallmark amyloid plaques.

Cytokine

Small releasable signalling proteins that often have immunomodulatory effects. These include chemokines, interleukins and interferons and they can be released by numerous immune cell types, endothelial cells and fibroblasts.

Homeostatic genes

Genes encoding a protein involved in a homeostatic mechanism within the cell.

Glymphatic system

Drainage pathway found in the vertebrate CNS that allows cerebrospinal fluid to enter the brain alongside penetrating arteries and facilitates the removal of interstitial fluid and waste products from the brain.

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Henstridge, C.M., Hyman, B.T. & Spires-Jones, T.L. Beyond the neuron–cellular interactions early in Alzheimer disease pathogenesis. Nat Rev Neurosci 20, 94–108 (2019). https://doi.org/10.1038/s41583-018-0113-1

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