CoChat
Sign Up
Cited by 348Alzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration MechanismsNeuroscience and Neuropharmacology Research

Beyond the neuron–cellular interactions early in Alzheimer disease pathogenesis

Open access
Henstridge, Christopher M., Hyman, Bradley T., Spires-Jones, Tara L.·2019·Nature Reviews Neuroscience
DOI 10.1038/s41583-018-0113-1PMC PMC6545070
Open this paper in CoChat — free account

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.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1038/s41583-018-0113-1

Cites

80 of 80 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Early-stage Alzheimer's disease is characterized primarily by Aβ plaque accumulation and subtle synaptic dysfunction, whereas late-stage disease involves extensive neurodegeneration, widespread neuroinflammation, and pronounced blood-brain barrier disruption.

    “Early-stage AD is characterized primarily by the accumulation of Aβ plaques and subtle synaptic dysfunction, whereas late-stage AD involves extensive neurodegeneration, widespread neuroinflammation, and pronounced BBB disruption [157, 158].”

    From Targeted Nanoparticles for Drug Delivery Across the Blood–Brain Barrier in Early and Late Stages of Alzheimer's Disease: A Review (2026) · cites this paper as [158]

    Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

1 retracted

Flagged first, then by citations

Research works printed but not linked: 153

  1. [3]Hardy JA & Higgins GA Alzheimer’s disease: the amyloid cascade hypothesis. Science 256, 184– 185 (1992). 1566067
  2. [4]Karran E & De Strooper B The amyloid cascade hypothesis: are we poised for success or failure? J. Neurochem 139, 237– 252 (2016). 27255958
  3. [6]Livingston G Dementia prevention, intervention, and care. Lancet 390, 2673– 2734 (2017). 28735855
  4. [8]Kisler K, Nelson AR, Montagne A & Zlokovic BV Cerebral blood flow regulation and neurovascular dysfunction in Alzheimer disease. Nat. Rev. Neurosci 18, 419– 434 (2017). 28515434 PMC5759779
  5. [9]Corder EH Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science 261, 921– 923 (1993). 8346443 This landmark paper identifies APOE4 as a genetic risk factor for late-onset AD.
  6. [11]Bennett RE Tau induces blood vessel abnormalities and angiogenesis-related geneexpression in P301L transgenic mice and human Alzheimer’s disease. Proc. Natl Acad. Sci. USA 115, E1289– E1298 (2018). 29358399 PMC5819390
  7. [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). 25630253 PMC4311408
  8. [14]Lue LF 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). 11520119
  9. [15]Zhao R, Hu W, Tsai J, Li W & Gan WB Microglia limit the expansion of beta-amyloid plaques in a mouse model of Alzheimer’s disease. Mol. Neurodegener 12, 47 (2017). 28606182 PMC5468952
  10. [21]Korin B High-dimensional, single-cell characterization of the brain’s immune compartment. Nat. Neurosci 20, 1300– 1309 (2017). 28758994
  11. [22]Korin B, Dubovik T & Rolls A Mass cytometry analysis of immune cells in the brain. Nat. Protoc 13, 377– 391 (2018). 29370157
  12. [25]Yeh FL, Wang Y, Tom I, Gonzalez LC & 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). 27477018
  13. [26]Jay TR Disease progression-dependent effects of TREM2 deficiency in a mouse model of Alzheimer’s disease. J. Neurosci 37, 637– 647 (2017). 28100745 PMC5242410
  14. [27]Yuan P 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). 27196974 PMC4898967
  15. [30]Song WM Humanized TREM2 mice reveal microglia-intrinsic and -extrinsic effects of R47H polymorphism. J. Exp. Med 215, 745– 760 (2018). 29321225 PMC5839761
  16. [33]Wyss-Coray T Adult mouse astrocytes degrade amyloid-beta in vitro and in situ. Nat. Med 9, 453– 457 (2003). 12612547
  17. [34]Leal MC 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). 17021402
  18. [35]Deb S, Wenjun Zhang J & Gottschall PE Beta-amyloid induces the production of active, matrix-degrading proteases in cultured rat astrocytes. Brain Res 970, 205– 213 (2003). 12706262
  19. [36]Yin KJ Matrix metalloproteinases expressed by astrocytes mediate extracellular amyloid-beta peptide catabolism. J. Neurosci 26, 10939– 10948 (2006). 17065436 PMC6674654
  20. [37]Mrak RE, Sheng JG & Griffin WS Correlation of astrocytic S100 beta expression with dystrophic neurites in amyloid plaques of Alzheimer’s disease. J. Neuropathol. Exp. Neurol 55, 273– 279 (1996). 8786385 PMC3833601
  21. [39]Bales KR Lack of apolipoprotein Edramatically reduces amyloid beta-peptide deposition. Nat. Genet 17, 263– 264 (1997). 9354781
  22. [40]Irizarry MC 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). 11045665
  23. [41]Lee L, Kosuri P & Arancio O Picomolar amyloid-beta peptides enhance spontaneous astrocyte calcium transients. J. Alzheimers Dis 38, 49– 62 (2014). 23948929 PMC4116306
  24. [43]Kuchibhotla KV, Lattarulo CR, Hyman BT& Bacskai BJ Synchronous hyperactivity and intercellular calcium waves in astrocytes in Alzheimer mice. Science 323, 1211– 1215 (2009). 19251629 PMC2884172
  25. [44]Spires-Jones TL, Attems J & Thal DR Interactions of pathological proteins in neurodegenerative diseases. Acta Neuropathol. 134, 187– 205 (2017). 28401333 PMC5508034
  26. [47]Hampton DW Cell-mediated neuroprotection in a mouse model of human tauopathy. J. Neurosci 30, 9973– 9983 (2010). 20668182 PMC6633376
  27. [48]Bemiller SM TREM2 deficiency exacerbates tau pathology through dysregulated kinase signaling in a mouse model of tauopathy. Mol. Neurodegener 12, 74 (2017). 29037207 PMC5644120
  28. [51]Asai H Depletion of microglia and inhibition of exosome synthesis halt tau propagation. Nat. Neurosci 18, 1584– 1593 (2015). 26436904 PMC4694577
  29. [54]Grabert K Microglial brain region-dependent diversity and selective regional sensitivities to aging. Nat. Neurosci 19, 504– 516 (2016). 26780511 PMC4768346
  30. [56]Tzioras M Assessing amyloid-β, tau, and glial features in Lothian Birth Cohort 1936 participants post-mortem. Matters (Zur). 10.19185/matters.201708000003 (2017). · DOI
  31. [59]Mathys H Temporal tracking of microglia activation in neurodegeneration at single-cell resolution. Cell Rep. 21, 366– 380 (2017). 29020624 PMC5642107
  32. [61]Henstridge CM & Spires-Jones TL Modeling Alzheimer’s disease brains in vitro. Nat. Neurosci 21, 899– 900 (2018). 29950667
  33. [62]Simard AR, Soulet D, Gowing G, Julien JP & Rivest S Bone marrow-derived microglia play a critical role in restricting senile plaque formation in Alzheimer’s disease. Neuron 49, 489– 502 (2006). 16476660
  34. [63]Stalder AK Invasion of hematopoietic cells into the brain of amyloid precursor protein transgenic mice. J. Neurosci 25, 11125– 11132 (2005). 16319312 PMC6725647
  35. [64]Zuroff L, Daley D, Black KL & 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). 28197669 PMC5425508
  36. [65]Buttini M Cellular source of apolipoprotein E4 determines neuronal susceptibility to excitotoxic injury in transgenic mice. Am. J. Pathol 177, 563– 569 (2010). 20595630 PMC2913361
  37. [67]Chakrabarty P IL-10 alters immunoproteostasis in APP mice, increasing plaque burden and worsening cognitive behavior. Neuron 85, 519– 533 (2015). 25619653 PMC4320003
  38. [69]Lian H Astrocyte-microglia cross talk through complement activation modulates amyloid pathology in mouse models of Alzheimer’s disease. J. Neurosci 36, 577– 589 (2016). 26758846 PMC4710776
  39. [70]Sekar S 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). 25448601 PMC4315763
  40. [71]Mosher KI & Wyss-Coray T Microglial dysfunction in brain aging and Alzheimer’s disease. Biochem. Pharmacol 88, 594– 604 (2014). 24445162 PMC3972294
  41. [73]Diniz LP Astrocyte transforming growth factor beta 1 protects synapses against Aβ oligomers in Alzheimer’s disease model. J. Neurosci 37, 6797– 6809 (2017). 28607171 PMC6596548
  42. [74]White JA, Manelli AM, Holmberg KH, Van Eldik LJ & Ladu MJ Differential effects of oligomeric and fibrillar amyloid-beta 1–42 on astrocyte-mediated inflammation. Neurobiol. Dis 18, 459– 465 (2005). 15755672
  43. [77]Wilkaniec A, Gassowska-Dobrowolska M, Strawski M, Adamczyk A & Czapski GA Inhibition of cyclin-dependent kinase 5 affects early neuroinflammatory signalling in murine model of amyloid beta toxicity. J. Neuroinflammation 15, 1 (2018). 29301548 PMC5753486
  44. [78]Patel NS Inflammatory cytokine levels correlate with amyloid load in transgenic mouse models of Alzheimer’s disease. J. Neuroinflammation 2, 9 (2005). 15762998 PMC555557
  45. [79]Wood LB Identification of neurotoxic cytokines by profiling Alzheimer’s disease tissues and neuron culture viability screening. Sci. Rep 5, 16622 (2015). 26564777 PMC4643219
  46. [80]Robinson SR, Dobson C & Lyons J Challengesand directions for the pathogen hypothesis of Alzheimer’s disease. Neurobiol. Aging 25, 629– 637 (2004). 15172741
  47. [81]Itzhaki RF Herpes simplex virus type 1 in brain and risk of Alzheimer’s disease. Lancet 349, 241– 244 (1997). 9014911
  48. [82]Readhead B Multiscale analysis of independent Alzheimer’s cohorts finds disruption of molecular, genetic, and clinical networks by human herpesvirus. Neuron 99, 64– 82 (2018). 29937276 PMC6551233
  49. [83]Eimer WA Alzheimer’s disease-associated beta-amyloid is rapidly seeded by herpesviridae to protect against brain infection. Neuron 99, 56– 63 (2018). 30001512 PMC6075814
  50. [84]Kumar DK Amyloid-beta peptide protects against microbial infection in mouse and worm models of Alzheimer’s disease. Sci. Transl Med 8, 340ra372 (2016). PMC5505565 27225182
  51. [86]McAleese KE Cortical tau load is associated with white matter hyperintensities. Acta Neuropathol. Commun 3, 60 (2015). 26419828 PMC4589169
  52. [87]Braak H & Braak E Development of Alzheimer-related neurofibrillary changes in the neocortex inversely recapitulates cortical myelogenesis. Acta Neuropathol. 92, 197– 201 (1996). 8841666
  53. [88]de Faria O Neuroglial interactions underpinning myelin plasticity. Dev. Neurobiol 78, 93– 107 (2018). 28941015
  54. [89]Xu J Amyloid-beta peptides are cytotoxic to oligodendrocytes. J. Neurosci 21, RC118 (2001). 11150354 PMC6762453
  55. [90]Jantaratnotai N, Ryu JK, Kim SU & McLarnon JG Amyloid beta peptide-induced corpus callosum damage and glial activation in vivo. Neuroreport 14, 1429– 1433 (2003). 12960758
  56. [92]Terry RD Physical basis of cognitive alterations in Alzheimer’s disease: synapse loss is the major correlate of cognitive impairment. Ann. Neurol 30, 572– 580 (1991). 1789684
  57. [93]Akram A 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). 17420070 PMC2569870
  58. [94]Mufson EJ Mild cognitive impairment: pathology and mechanisms. Acta Neuropathol. 123, 13– 30 (2012). 22101321 PMC3282485
  59. [96]DeKosky ST & Scheff SW Synapse loss in frontal cortex biopsies in Alzheimer’s disease: correlation with cognitive severity. Ann. Neurol 27, 457– 464 (1990). 2360787 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.
  60. [97]Spires-Jones TL & Hyman BT The intersection of amyloid beta and tau at synapses in Alzheimer’s disease. Neuron 82, 756– 771 (2014). 24853936 PMC4135182
  61. [98]Henstridge CM, Pickett E & Spires-Jones TL Synaptic pathology: A shared mechanism in neurological disease. Ageing Res. Rev 28, 72– 84 (2016). 27108053
  62. [100]Salter MW & Stevens B Microglia emerge as central players in brain disease. Nat. Med 23, 1018– 1027 (2017). 28886007
  63. [101]Schafer DP, Lehrman EK & Stevens B The “quad-partite” synapse: microglia-synapse interactions in the developing and mature CNS. Glia 61, 24– 36 (2013). 22829357 PMC4082974
  64. [105]Stevens B The classical complement cascade mediates CNS synapse elimination. Cell 1 31, 1164– 1178 (2007). 18083105
  65. [106]Stephan AH, Barres BA & Stevens B The complement system: an unexpected role in synaptic pruning during development and disease. Annu. Rev. Neurosci 35, 369– 389 (2012). 22715882
  66. [107]Bialas AR & Stevens B TGF-β signaling regulates neuronal C1q expression and developmental synaptic refinement. Nat. Neurosci 16, 1773– 1782 (2013). 24162655 PMC3973738
  67. [109]Lambert JC Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer’s disease. Nat. Genet 41, 1094– 1099 (2009). 19734903
  68. [110]Yasojima K, Schwab C, McGeer EG & McGeer PL Up-regulated production and activation of the complement system in Alzheimer’s disease brain. Am. J. Pathol 154, 927– 936 (1999). 10079271 PMC1866427
  69. [113]Weinhard L Microglia remodel synapses by presynaptic trogocytosis and spine head filopodia induction. Nat. Commun 9, 1228 (2018). 29581545 PMC5964317
  70. [114]Boulanger LM Immune proteins in brain development and synaptic plasticity. Neuron 64, 93– 109 (2009). 19840552
  71. [115]Syken J, Grandpre T, Kanold PO & Shatz CJ PirB restricts ocular-dominance plasticity in visual cortex. Science 313, 1795– 1800 (2006). 16917027
  72. [116]William CM Synaptic plasticity defect following visual deprivation in Alzheimer’s disease model transgenic mice. J. Neurosci 32, 8004– 8011 (2012). 22674275 PMC3493160
  73. [117]Kim T 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). 24052308 PMC3853120
  74. [118]Paolicelli RC TDP-43 depletion in microglia promotes amyloid clearance but also induces synapse loss. Neuron 95, 297– 308 (2017). 28669544 PMC5519492
  75. [119]Henstridge CM Synapse loss in the prefrontal cortex is associated with cognitive decline in amyotrophic lateral sclerosis. Acta Neuropathol. 135, 213– 226 (2018). 29273900 PMC5773656
  76. [120]Matos M, Augusto E, Agostinho P, Cunha RA & Chen JF Antagonistic interaction between adenosine A2A receptors and Na+/K+-ATPase-α2 controlling glutamate uptake in astrocytes. J. Neurosci 33, 18492– 18502 (2013). 24259572 PMC3834055
  77. [121]Orr AG Astrocytic adenosine receptor A2A and Gs-coupled signaling regulate memory. Nat. Neurosci 18, 423– 434 (2015). 25622143 PMC4340760
  78. [122]Mookherjee P GLT-1 loss accelerates cognitive deficit onset in an Alzheimer’s disease animal model. J. Alzheimers Dis 26, 447– 455 (2011). 21677376 PMC3256092
  79. [124]Zumkehr J 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). 25964214
  80. [125]Reisberg B Memantine in moderate-to-severe Alzheimer’s disease. N. Engl. J. Med 348, 1333– 1341 (2003). 12672860
  81. [128]Rebeck GW, Reiter JS, Strickland DK & Hyman, B. T. Apolipoprotein E in sporadic Alzheimer’s disease: allelic variation and receptor interactions. Neuron 11, 575– 580 (1993) 8398148
  82. [131]Klein W Synaptotoxic amyloid-β oligomers: a molecular basis for the cause, diagnosis, and treatment of Alzheimer’s disease? J. A¡zheimers Dis 33 (Suppl. 1), 49– 65 (2013). 22785404
  83. [134]Dumanis SB, DiBattista AM, Miessau M, Moussa CE & Rebeck GW APOE genotype affects the pre-synaptic compartment of glutamatergic nerve terminals. J. Neurochem 124, 4– 14 (2013). 22862561 PMC3509249
  84. [136]Schiepers OJ 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). 21263443
  85. [137]Henstridge CM 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). 26335101 PMC4559320
  86. [138]Kay KR Studying synapses in human brain with array tomography and electron microscopy. Nat. Protoc 8, 1366– 1380 (2013). 23787894 PMC3712649
  87. [140]Sidoryk-Wegrzynowicz M Astrocytes in mouse models of tauopathies acquire early deficits and lose neurosupportive functions. Acta Neuropathol. Commun 5, 89 (2017). 29187256 PMC6389177
  88. [141]Hunsberger HC, Rudy CC, Batten SR, Gerhardt GA & Reed MN P301L tau expression affects glutamate release and clearance in the hippocampal trisynaptic pathway. J. Neurochem 132, 169– 182 (2015). 25319522 PMC4302046
  89. [142]Piacentini R Reduced gliotransmitter release from astrocytes mediates tau-induced synaptic dysfunction in cultured hippocampal neurons. Glia 65, 1302– 1316 (2017). 28519902 PMC5520670
  90. [143]Dudvarski Stankovic N, Teodorczyk M, Ploen R, Zipp F & Schmidt MHH Microglia-blood vessel interactions: a double-edged sword in brain pathologies. Acta Neuropathol 131, 347– 363 (2016). 26711460
  91. [144]Shen Q, Goderie SK, Jin L, Karanth N & Sun Y Endothelial cells stimulate self-renewal and expand neurogenesis of neural stem cells. Science 304, 1338– 1340 (2004). 15060285
  92. [145]Arai K & Lo EH An oligovascular niche: cerebral endothelial cells promote the survival and proliferation, of oligodendrocyte precursor cells. J. Neurosci 29, 4351– 4355 (2009). 19357263 PMC3849498
  93. [146]Guo S, Kim WJ, Lok J & Lee SR Neuroprotection via matrix-trophic coupling between cerebral endothelial cells and neurons. Proc. Natl Acad. Sci. USA 105, 7582– 7587 (2008). 18495934 PMC2396701
  94. [147]Santos CY Pathophysiologic relationship between Alzheimer’s disease, cerebrovascular disease, and cardiovascular risk: a review and synthesis. Alzheimers Dement. (Amst.) 7, 69– 87 (2017). 28275702 PMC5328683
  95. [148]Matthews FE A two decade dementia incidence comparison from the cognitive function and ageing studies I and II. Nat. Commun 7, 11398 (2016). 27092707 PMC4838896
  96. [149]Iadecola C SOD1 rescues cerebral endothelial dysfunction in mice overexpressing amyloid precursor protein. Nat. Neurosci 2, 157– 161 (1999). 10195200
  97. [151]Kelly P Microvascular ultrastructural changes precede cognitive impairment in the murine APPswe/PS1dE9 model of Alzheimer’s disease. Angiogenesis 20, 567– 580 (2017). 28741167 PMC5660145
  98. [152]Wang H, Golob EJ & Su M-YY 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). 16878309
  99. [153]Starr JM, Farrall AJ, Armitage P & McGurn B Blood-brain barrier permeability in Alzheimer’s disease: a case-control MRI study. Psychiatry Res. 171, 232– 241 (2009). 19211227
  100. [154]Jagust WJ Diminished glucose transport in Alzheimer’s disease: dynamic PET studies. J. Cereb. Blood Flow Metab 11, 323– 330 (1991). 1997504
  101. [155]Iturria-Medina Y Early role of vascular dysregulation on late-onset Alzheimer’s disease based on multifactorial data-driven analysis. Nat. Commun 7, 11934 (2016). 27327500 PMC4919512
  102. [156]Wardlaw JM & Hernandez MCV What are white matter hyperintensities made of? Relevance to vascular cognitive impairment. J. Am. Heart Assoc 4, e001140 (2015). PMC4599520 26104658
  103. [157]McAleese KE 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). 28638989 PMC5563333
  104. [159]Bakker EN Lymphatic clearance of the brain: perivascular, paravascular and significance for neurodegenerative diseases. Cell. Mol. Neurobiol 36, 181– 194 (2016). 26993512 PMC4844641
  105. [160]Tarasoff-Conway JM Clearance systems in the brain-implications for Alzheimer disease. Nat. Rev. Neurol 11, 457– 470 (2015). 26195256 PMC4694579
  106. [161]Iadecola C The neurovascular unit coming of age: a journey through neurovascular coupling in health and disease. Neuron 96, 17– 42 (2017). 28957666 PMC5657612
  107. [163]Plog BA & Nedergaard M The glymphatic system in central nervous system health and disease: past, present, and future. Annu. Rev. Pathol 13, 379– 394 (2018). 29195051 PMC5803388
  108. [164]Da Mesquita S Functional aspects of meningeal lymphatics in ageing and Alzheimer’s disease. Nature 560, 185– 191 (2018). 30046111 PMC6085146
  109. [165]Lucey BP Associations between beta-amyloid kinetics and the beta-amyloid diurnal pattern in the central nervous system. JAMA Neurol. 74, 207– 215 (2017). 27992627 PMC5305432
  110. [166]Kang JE Amyloid-beta dynamics are regulated 1 91. by orexin and the sleep-wake cycle. Science 326, 1005– 1007 (2009). 19779148 PMC2789838
  111. [167]Bero AW Neuronal activity regulates the regional vulnerability to amyloid-beta deposition. Nat. Neurosci 14, 750– 756 (2011). 21532579 PMC3102784
  112. [170]Nelson AR, Sagare AP & Zlokovic BV Role of clusterin in the brain vascular clearance of amyloid-beta. Proc. Natl Acad. Sci. USA 114, 8681– 8682 (2017). 28765369 PMC5565473
  113. [171]Robert J Clearance of beta-amyloid is facilitated by apolipoprotein E and circulating high-density lipoproteins in bioengineered human vessels. eLife 6, e29595 (2017). 28994390 PMC5634784
  114. [172]Burfeind KG 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). PMC5651426 29067342
  115. [174]Hill RA 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). 26119027 PMC4487786
  116. [175]Faraco G 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). 25920959 PMC4758560
  117. [176]El Khoury J Ccr2 deficiency impairs microglial accumulation and accelerates progression of Alzheimer-like disease. Nat. Med 13, 432– 438 (2007). 17351623
  118. [177]Jiang T, Sun Q & Chen S Oxidative stress: a major 201 pathogenesis and potential therapeutic target of antioxidative agents in Parkinson’s disease and Alzheimer’s disease. Prog. Neurobiol 147, 1– 19 (2016). 27769868
  119. [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). 11440793
  120. [181]Nunomura A Oxidative damage is the earliest event in Alzheimer disease. J. Neuropathol. Exp. Neurol 60, 759– 767 (2001). 11487050
  121. [183]Park L Innate immunity receptor CD36 promotes cerebral amyloid angiopathy. Proc. Natl Acad. Sci. USA 110, 3089– 3094 (2013). 23382216 PMC3581946
  122. [188]LaClair KD Treatment with bexarotene, a compound that increases apolipoprotein-E, provides no cognitive benefit in mutant APP/PS1 mice. Mol. Neurodegener 8, 18 (2013). 23764200 PMC3693923
  123. [189]O’Hare E Lack of support for bexarotene as a treatment for Alzheimer’s disease. Neuropharmacology 100, 124– 130 (2016). 26025659
  124. [190]Cummings JL Double-blind, placebo-controlled, proof-of-concept trial of bexarotene Xin moderate Alzheimer’s disease. Alzheimers Res. Ther 8, 4 (2016). 26822146 PMC4731943
  125. [191]Huynh TV Age-dependent effects of apoE reduction using antisense oligonucleotides in a model of beta-amyloidosis. Neuron 96, 1013– 1023 (2017). 29216448 PMC5728673
  126. [193]Masgrau R, Guaza C, Ransohoff RM & Galea E Should we stop saying ‘glia’ and ‘neuroinflammation’? Trends Mol. Med 23, 486– 500 (2017). 28499701
  127. [194]Breitner JC Extended results of the Alzheimer’s disease anti-inflammatory prevention trial. Alzheimers Dement. 7, 402– 411 (2011). 21784351 PMC3149804
  128. [195]Lansita JA Nonclinical development of ANX005: a humanized anti-C1q antibody for treatment of autoimmune and neurodegenerative diseases. Int. J. Toxicol 36, 449– 462 (2017). 29202623
  129. [196]Femminella GD Antidiabetic drugs in Alzheimer’s disease: mechanisms of action and futureperspectives. J. Diabetes Res 2017, 7420796 (2017). 28656154 PMC5471577
  130. [197]Infante-Garcia C 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). 29224179
  131. [198]Ramos-Rodriguez JJ 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). 27177549
  132. [199]Harrington C 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). 21592048
  133. [201]Wu YT The changing prevalence and incidence of dementia over time - current evidence. Nat. Rev. Neurol 13, 327– 339 (2017). 28497805
  134. [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). 29434025 PMC5977988
  135. [203]Forbes D, Forbes SC, Blake CM, Thiessen EJ & Forbes S Exercise programs for people with dementia. Cochrane Database Syst. Rev 4, CD006489 (2015). PMC9426996 25874613
  136. [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). PMC10554155 25900537
  137. [208]De Strooper B Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein. Nature 391, 387– 390 (1998). 9450754
  138. [210]Thal DR, 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). 12084879
  139. [211]Jarosz-Griffiths HH, Noble E, Rushworth JV & Hooper NM Amyloid-β receptors: the good, the bad, and the prion protein. J. Biol. Chem 291, 3174– 3183 (2016). 26719327 PMC4751366
  140. [212]Goedert M, Spillantini MG, Cairns NJ & Crowther RA Tau proteins of Alzheimer paired helical filaments: abnormal phosphorylation of all six brain isoforms. Neuron 8, 159– 168 (1992). 1530909
  141. [213]Goedert M & Spillantini MG A century of Alzheimer’s disease. Science 314, 777– 781 (2006). 17082447
  142. [216]Ingelsson M Early Aβ accumulation and progressive synaptic loss, gliosis, and tangle formation in AD brain. Neurology 62, 925– 931 (2004). 15037694
  143. [219]Dickerson BC, Stoub TR, Shah RC & Sperling RA Alzheimer-signature MRI biomarker predicts AD dementia in cognitively normal adults. Neurology 76, 1395– 1402 (2011). 21490323 PMC3087406
  144. [222]Pekny M Astrocytes: a central element in neurological diseases. Acta Neuropathol. 131, 323– 345 (2016). 26671410
  145. [223]Rodriguez-Arellano JJ, Parpura V, Zorec R & Verkhratsky A Astrocytes in physiological aging and Alzheimer’s disease. Neuroscience 323, 170– 182 (2016). 25595973
  146. [224]Cai Z & Xiao M Oligodendrocytes and Alzheimer’s disease. Int. J. Neurosci 126, 97– 104 (2016). 26000818
  147. [225]Nasrabady SE, Rizvi B, Goldman JE & Brickman AM White matter changes in Alzheimer’s disease: a focus on myelin and oligodendrocytes. Acta Neuropathol. Commun 6, 22 (2018). 29499767 PMC5834839
  148. [226]Palop JJ & Mucke L Amyloid-beta-induced neuronal dysfunction in Alzheimer’s disease: from synapses toward neural networks. Nat. Neurosci 13, 812– 818 (2010). 20581818 PMC3072750
  149. [228]Hollingworth P Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer’s disease. Nat. Genet 43, 429– 435 (2011). 21460840 PMC3084173
  150. [230]Guerreiro R TREM2 variants in Alzheimer’s disease. N. Engl. J. Med 368, 117– 127 (2013). 23150934 PMC3631573
  151. [231]Jonsson T Variant of TREM2 associated with the risk of Alzheimer’s disease. N. Engl. J. Med 368, 107– 116 (2013). 23150908 PMC3677583
  152. [233]Robinson M, Lee BY & Hane FT Recent progress in Alzheimer’s disease research, part 2: genetics and epidemiology. J. Alzheimers Dis 57, 317– 330 (2017). 28211812 PMC5366246
  153. [234]Efthymiou AG & Goate AM Late onset Alzheimer’s disease genetics implicates microglial pathways in disease risk. Mol. Neurodegener 12, 43 (2017). 28549481 PMC5446752

Cited by

Sorted by citations

Authors
Henstridge, C. M., Hyman, B. T., & Spires-Jones, T. L.
Affiliations
  • UK Dementia Research Institute (GB)
  • Harvard University (US)
ORCID
Venue
Nature Reviews Neuroscience
Publisher
Springer Science and Business Media LLC
Published
2019-01-14
Volume
20
Issue
2
Pages
94-108
ISSN
  • 1471-003X (ISSN-L)
  • 1471-0048
DOI
10.1038/s41583-018-0113-1
PMC
PMC6545070
OpenAlex
W2908632279
Cited by
348
References
80
Citations by year
2026: 42 · 2025: 45 · 2024: 35 · 2023: 46 · 2022: 39 · 2021: 58 · 2020: 57 · 2019: 26
FWCI
5.51
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Nature reviews. Neuroscience (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • Discovery Research Portal (University of Dundee) (submittedVersion)
  • Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, other-oa)
Funders
  • MND Scotland
  • Alzheimer's Society
  • UK Dementia Research Institute
  • National Institute on Aging (RF1AG058674, P50AG005134, P30AG062421)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords
Alzheimer's disease, neurodegeneration, astrocytes, microglia, vascular cells, pathogenesis, neuroprotection, therapeutic target
MeSH terms
Alzheimer Disease, Animals, Astrocytes, Brain, Cell Communication, Humans, Neurons, Microglia

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review