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Acta Neuropathologica

Erschienen in:

07.08.2019 | Review

The basis of cellular and regional vulnerability in Alzheimer’s disease

verfasst von: Dunja Mrdjen, Edward J. Fox, Syed A. Bukhari, Kathleen S. Montine, Sean C. Bendall, Thomas J. Montine

Erschienen in: Acta Neuropathologica | Ausgabe 5/2019

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Abstract

Alzheimer’s disease (AD) differentially and specifically affects brain regions and neuronal cell types in a predictable pattern. Damage to the brain appears to spread and worsens with time, taking over more regions and activating multiple stressors that can converge to promote vulnerability of certain cell types. At the same time, other cell types and brain regions remain intact in the face of this onslaught of neuropathology. Although neuropathologic descriptions of AD have been extensively expanded and mapped over the last several decades, our understanding of the mechanisms underlying how certain regions and cell populations are specifically vulnerable or resistant has lagged behind. In this review, we detail what is known about the selectivity of local initiation of AD pathology in the hippocampus, its proposed spread via synaptic connections, and the diversity of clinical phenotypes and brain atrophy patterns that may arise from different fibrillar strains of pathologic proteins or genetic predispositions. We summarize accumulated and emerging knowledge of the cellular and molecular basis for neuroanatomic selectivity, consider potential disease-relevant differences between vulnerable and resistant neuronal cell types and isolate molecular markers to identify them.

Aleksis R, Oleskovs F, Jaudzems K, Pahnke J, Biverstål H (2017) Structural studies of amyloid-β peptides: unlocking the mechanism of aggregation and the associated toxicity. Biochimie 140:176–192. https://doi.org/10.1016/j.biochi.2017.07.011 CrossRefPubMed

Amaral DG, Witter MP (1989) The three-dimensional organization of the hippocampal formation: a review of anatomical data. Neuroscience 31:571–591. https://doi.org/10.1016/0306-4522(89)90424-7 CrossRefPubMed

Anderton BH, Brion JP, Flament-Durand J, Haugh MC, Kahn J, Miller CC et al (1987) Neurofibrillary tangles and the neuronal cytoskeleton. J Neural Transm Suppl 24:191–196PubMed

Angelo M, Bendall SC, Finck R, Hale MB, Hitzman C, Borowsky AD et al (2014) Multiplexed ion beam imaging of human breast tumors. Nat Med 20:436–442. https://doi.org/10.1038/nm.3488 CrossRefPubMedPubMedCentral

Avila J, Lucas JJ, Perez M, Hernandez F (2004) Role of tau protein in both physiological and pathological conditions. Physiol Rev 84:361–384. https://doi.org/10.1152/physrev.00024.2003 CrossRefPubMed

Ballatore C, Lee VMY, Trojanowski JQ (2007) Tau-mediated neurodegeneration in Alzheimer’s disease and related disorders. Nat Rev Neurosci 8:663–672. https://doi.org/10.1038/nrn2194 CrossRefPubMed

Barker WW, Luis CA, Kashuba A, Luis M, Harwood DG, Loewenstein D et al (2016) Relative frequencies of Alzheimer disease, Lewy body, vascular and frontotemporal dementia, and hippocampal sclerosis in the State of Florida Brain Bank. Alzheimer Dis Assoc Disord 16:203–212CrossRef

Bendall SC, Simonds EF, Qiu P, Amir ED, Krutzik PO, Finck R et al (2011) Single-cell mass cytometry of differential immune and drug responses across a human hematopoietic continuum. Science 332:687–696. https://doi.org/10.1126/science.1198704 CrossRefPubMedPubMedCentral

Blacker D, Haines JL, Rodes L, Terwedow H, Go RC, Harrell LE et al (1997) ApoE-4 and age at onset of Alzheimer’s disease: the NIMH genetics initiative. Neurology 48:139–147CrossRefPubMed

10.

Boldrini M, Fulmore CA, Tartt AN, Simeon LR, Pavlova I, Poposka V et al (2018) Human hippocampal neurogenesis persists throughout aging. Cell Stem Cell 22:589–599.e5. https://doi.org/10.1016/j.stem.2018.03.015 CrossRefPubMedPubMedCentral

11.

Boluda S, Iba M, Zhang B, Raible KM, Lee VMY, Trojanowski JQ (2015) Differential induction and spread of tau pathology in young PS19 tau transgenic mice following intracerebral injections of pathological tau from Alzheimer’s disease or corticobasal degeneration brains. Acta Neuropathol 129:221–237. https://doi.org/10.1007/s00401-014-1373-0 CrossRefPubMed

12.

Botcher NA, Falck JE, Thomson AM, Mercer A (2014) Distribution of interneurons in the CA2 region of the rat hippocampus. Front Neuroanat 8:1–16. https://doi.org/10.3389/fnana.2014.00104 CrossRef

13.

Bouwman FH, Schoonenboom NSM, Verwey NA, van Elk EJ, Kok A, Blankenstein MA et al (2009) CSF biomarker levels in early and late onset Alzheimer’s disease. Neurobiol Aging 30:1895–1901. https://doi.org/10.1016/j.neurobiolaging.2008.02.007 CrossRefPubMed

14.

Braak H, Alafuzoff I, Arzberger T, Kretzschmar H, Tredici K (2006) Staging of Alzheimer disease-associated neurofibrillary pathology using paraffin sections and immunocytochemistry. Acta Neuropathol 112:389–404. https://doi.org/10.1007/s00401-006-0127-z CrossRefPubMedPubMedCentral

15.

Braak H, Braak E (1991) Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol 82:239–259. https://doi.org/10.1109/ICINIS.2015.10 CrossRefPubMed

16.

Braak H, Braak E (1998) Evolution of neuronal changes in the course of Alzheimer’s disease. In: Jellinger K, Fazekas F, Windisch M (eds) Ageing and dementia. Springer, Vienna, pp 127–140CrossRef

17.

Braak H, Thal DR, Ghebremedhin E, Del Tredici K (2011) Stages of the pathologic process in Alzheimer disease: age categories from 1 to 100 years. J Neuropathol Exp Neurol 70:960–969. https://doi.org/10.1097/NEN.0b013e318232a379 CrossRefPubMed

18.

Brecht WJ (2004) Neuron-specific apolipoprotein E4 proteolysis is associated with increased tau phosphorylation in brains of transgenic mice. J Neurosci 24:2527–2534. https://doi.org/10.1523/JNEUROSCI.4315-03.2004 CrossRefPubMedPubMedCentral

19.

Brundin P, Melki R, Kopito R (2010) Prion-like transmission of protein aggregates in neurodegenerative diseases. Nat Rev Mol Cell Biol 11:301–307. https://doi.org/10.1038/nrm2873 CrossRefPubMedPubMedCentral

20.

Busche MA, Wegmann S, Dujardin S, Commins C, Schiantarelli J, Klickstein N et al (2019) Tau impairs neural circuits, dominating amyloid-β effects, in Alzheimer models in vivo. Nat Neurosci 22:57–64. https://doi.org/10.1038/s41593-018-0289-8 CrossRefPubMed

21.

Bushman DM, Kaeser GE, Siddoway B, Westra JW, Rivera RR, Rehen SK et al (2015) Genomic mosaicism with increased amyloid precursor protein (APP) gene copy number in single neurons from sporadic Alzheimer’s disease brains. Elife 2015:1–26. https://doi.org/10.7554/eLife.05116.001 CrossRef

22.

Buttini M, Masliah E, Yu GQ, Palop JJ, Chang S, Bernardo A et al (2010) Cellular source of apolipoprotein E4 determines neuronal susceptibility to excitotoxic injury in transgenic mice. Am J Pathol 177:563–569. https://doi.org/10.2353/ajpath.2010.090973 CrossRefPubMedPubMedCentral

23.

Byun MS, Kim SE, Park J, Yi D, Choe YM, Sohn BK et al (2015) Heterogeneity of regional brain atrophy patterns associated with distinct progression rates in Alzheimer’s disease. PLoS One 10:e0142756. https://doi.org/10.1371/journal.pone.0142756 CrossRefPubMedPubMedCentral

24.

Cacace R, Sleegers K, Van Broeckhoven C (2016) Molecular genetics of early-onset Alzheimer’s disease revisited. Alzheimer’s Dement 12:733–748. https://doi.org/10.1016/j.jalz.2016.01.012 CrossRef

25.

Cali I, Cohen ML, Haїk S, Parchi P, Giaccone G, Collins SJ et al (2018) Iatrogenic Creutzfeldt-Jakob disease with Amyloid-β pathology: an international study. Acta Neuropathol Commun 6:5. https://doi.org/10.1186/s40478-017-0503-z CrossRefPubMedPubMedCentral

26.

Carter SF, Herholz K, Rosa-Neto P, Pellerin L, Nordberg A, Zimmer ER (2019) Astrocyte biomarkers in Alzheimer’s disease. Trends Mol Med 25:77–95. https://doi.org/10.1016/j.molmed.2018.11.006 CrossRefPubMed

27.

Cembrowski MS, Wang L, Sugino K, Shields BC, Spruston N (2016) Hipposeq: a comprehensive RNA-seq database of gene expression in hippocampal principal neurons. Elife 5:1–22. https://doi.org/10.7554/eLife.14997 CrossRef

28.

Chartier-Harlin M-C, Crawford F, Houlden H, Warren A, Hughes D, Fidani L et al (1991) Early-onset Alzheimer’s disease caused by mutations at codon 717 of the β-amyloid precursor protein gene. Nature 353:844–846. https://doi.org/10.1038/353844a0 CrossRefPubMed

29.

Chen F, Guan Q, Nie Z-Y, Jin L-J (2013) Gene expression profile and functional analysis of Alzheimer’s disease. Am J Alzheimers Dis Other Demen 28:693–701. https://doi.org/10.1177/1533317513500838 CrossRefPubMed

30.

Chen M-K, Mecca AP, Naganawa M, Finnema SJ, Toyonaga T, Lin S et al (2018) Assessing synaptic density in Alzheimer disease with synaptic vesicle glycoprotein 2A positron emission tomographic imaging. JAMA Neurol 75:1215. https://doi.org/10.1001/jamaneurol.2018.1836 CrossRefPubMedPubMedCentral

31.

Chevaleyre V, Piskorowski RA (2016) Hippocampal area CA2: an overlooked but promising therapeutic target. Trends Mol Med 22:645–655. https://doi.org/10.1016/j.molmed.2016.06.007 CrossRefPubMed

32.

Ciryam P, Tartaglia GG, Morimoto RI, Dobson CM, Vendruscolo M (2013) Widespread aggregation and neurodegenerative diseases are associated with supersaturated proteins. Cell Rep 5:781–790. https://doi.org/10.1016/j.celrep.2013.09.043 CrossRefPubMed

33.

Clavaguera F, Akatsu H, Fraser G, Crowther RA, Frank S, Hench J et al (2013) Brain homogenates from human tauopathies induce tau inclusions in mouse brain. Proc Natl Acad Sci USA 110:9535–9540. https://doi.org/10.1073/pnas.1301175110 CrossRefPubMedPubMedCentral

34.

Clavaguera F, Hench J, Lavenir I, Schweighauser G, Frank S, Goedert M et al (2014) Peripheral administration of tau aggregates triggers intracerebral tauopathy in transgenic mice. Acta Neuropathol 127:299–301. https://doi.org/10.1007/s00401-013-1231-5 CrossRefPubMed

35.

Cohen ML, Kim C, Haldiman T, ElHag M, Mehndiratta P, Pichet T et al (2015) Rapidly progressive Alzheimer’s disease features distinct structures of amyloid-β. Brain. https://doi.org/10.1093/brain/awv006 CrossRefPubMedPubMedCentral

36.

Corces MR, Trevino AE, Hamilton EG, Greenside PG, Sinnott-Armstrong NA, Vesuna S et al (2017) An improved ATAC-seq protocol reduces background and enables interrogation of frozen tissues. Nat Methods 14:959–962. https://doi.org/10.1038/nmeth.4396 CrossRefPubMedPubMedCentral

37.

Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small GW et al (1993) Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science 261:921–923CrossRefPubMed

38.

Crary JF, Trojanowski JQ, Schneider JA, Abisambra JF, Abner EL, Alafuzoff I et al (2014) Primary age-related tauopathy (PART): a common pathology associated with human aging. Acta Neuropathol 128:755–766. https://doi.org/10.1007/s00401-014-1349-0 CrossRefPubMedPubMedCentral

39.

Cummings JL (2004) Alzheimer’s Disease. N Engl J Med 351:56–67. https://doi.org/10.1056/NEJMra040223 CrossRefPubMed

40.

Davies P (1976) Selective loss of central cholinergic neurons in Alzheimer’s Disease. Lancet 308:1403. https://doi.org/10.1016/S0140-6736(76)91936-X CrossRef

41.

DeKosky ST, Scheff SW (1990) Synapse loss in frontal cortex biopsies in Alzheimer’s disease: correlation with cognitive severity. Ann Neurol 27:457–464. https://doi.org/10.1002/ana.410270502 CrossRefPubMed

42.

Diamond MI, Kaufman SK, Sanders DW, Thomas TL, Ruchinskas AJ, Vaquer-Alicea J et al (2016) Tau prion strains dictate patterns of cell pathology, progression rate, and regional vulnerability in vivo. Neuron. https://doi.org/10.1016/j.neuron.2016.09.055 CrossRefPubMedPubMedCentral

43.

Dickerson BC, Wolk DA (2011) Dysexecutive versus amnesic phenotypes of very mild Alzheimer’s disease are associated with distinct clinical, genetic and cortical thinning characteristics. J Neurol Neurosurg Psychiatry 82:45–51. https://doi.org/10.1136/jnnp.2009.199505 CrossRefPubMed

44.

Dudek SM, Alexander GM, Farris S (2016) Rediscovering area CA2: unique properties and functions. Nat Rev Neurosci 17:89–102. https://doi.org/10.1038/nrn.2015.22 CrossRefPubMedPubMedCentral

45.

Dueck H, Khaladkar M, Kim TK, Spaethling JM, Francis C, Suresh S et al (2015) Deep sequencing reveals cell-type-specific patterns of single-cell transcriptome variation. Genome Biol 16:1–17. https://doi.org/10.1186/s13059-015-0683-4 CrossRef

46.

Duyckaerts C, Sazdovitch V, Ando K, Seilhean D, Privat N, Yilmaz Z et al (2018) Neuropathology of iatrogenic Creutzfeldt-Jakob disease and immunoassay of French cadaver-sourced growth hormone batches suggest possible transmission of tauopathy and long incubation periods for the transmission of Abeta pathology. Acta Neuropathol 135:201–212. https://doi.org/10.1007/s00401-017-1791-x CrossRefPubMed

47.

Eckerström C, Klasson N, Olsson E, Selnes P, Rolstad S, Wallin A (2018) Similar pattern of atrophy in early- and late-onset Alzheimer’s disease. Alzheimer’s Dement Diagnosis. Assess Dis Monit 10:253–259. https://doi.org/10.1016/j.dadm.2018.02.001 CrossRef

48.

Eimer WA, Vijaya Kumar DK, Navalpur Shanmugam NK, Rodriguez AS, Mitchell T, Washicosky KJ et al (2018) Alzheimer’s disease-associated β-amyloid is rapidly seeded by herpesviridae to protect against brain infection. Neuron 99:56–63.e3. https://doi.org/10.1016/j.neuron.2018.06.030 CrossRefPubMedPubMedCentral

49.

Eisenberg D, Jucker M (2012) The amyloid state of proteins in human diseases. Cell 148:1188–1203. https://doi.org/10.1016/j.cell.2012.02.022 CrossRefPubMedPubMedCentral

50.

Farrer LA, Cupples LA, Haines JL, Hyman B, Kukull WA, Mayeux R et al (1997) Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. A meta-analysis. APOE and Alzheimer Disease Meta Analysis Consortium. JAMA 278:1349–1356. https://doi.org/10.1001/jama.1997.03550160069041 CrossRefPubMed

51.

Ferreira D, Verhagen C, Hernández-Cabrera JA, Cavallin L, Guo C-J, Ekman U et al (2017) Distinct subtypes of Alzheimer’s disease based on patterns of brain atrophy: longitudinal trajectories and clinical applications. Sci Rep 7:46263. https://doi.org/10.1038/srep46263 CrossRefPubMedPubMedCentral

52.

van der Flier WM, Pijnenburg YAL, Fox NC, Scheltens P (2011) Early-onset versus late-onset Alzheimer’s disease: the case of the missing APOE ɛ4 allele. Lancet Neurol 10:280–288. https://doi.org/10.1016/S1474-4422(10)70306-9 CrossRefPubMed

53.

van der Flier WM, Schoonenboom SNM, Pijnenburg YAL, Fox NC, Scheltens P (2006) The effect of APOE genotype on clinical phenotype in Alzheimer disease. Neurology 67:526–527. https://doi.org/10.1212/01.wnl.0000228222.17111.2a CrossRefPubMed

54.

Freer R, Sormanni P, Vecchi G, Ciryam P, Dobson CM, Vendruscolo M (2016) A protein homeostasis signature in healthy brains recapitulates tissue vulnerability to Alzheimer’s disease. Sci Adv 2:e1600947. https://doi.org/10.1126/sciadv.1600947 CrossRefPubMedPubMedCentral

55.

Frost B, Jacks RL, Diamond MI (2009) Propagation of Tau misfolding from the outside to the inside of a cell. J Biol Chem. https://doi.org/10.1074/jbc.m808759200 CrossRefPubMedPubMedCentral

56.

Fu H, Hardy J, Duff KE (2018) Selective vulnerability in neurodegenerative diseases. Nat Neurosci 21:1350–1358. https://doi.org/10.1038/s41593-018-0221-2 CrossRefPubMedPubMedCentral

57.

Fu H, Possenti A, Freer R, Nakano Y, Villegas NCH, Tang M et al (2019) A tau homeostasis signature is linked with the cellular and regional vulnerability of excitatory neurons to tau pathology. Nat Neurosci 22:47–56. https://doi.org/10.1038/s41593-018-0298-7 CrossRefPubMed

58.

Gajera CR, Fernandez R, Postupna N, Montine KS, Fox EJ, Tebaykin D et al (2019) Mass synaptometry: high-dimensional multi parametric assay for single synapses. J Neurosci Methods 312:73–83. https://doi.org/10.1016/j.jneumeth.2018.11.008 CrossRefPubMed

59.

Gaugler J, James B, Johnson T, Scholz K, Weuve J (2018) 2018 Alzheimer’s disease facts and figures. Alzheimer’s Dement 14:367–429. https://doi.org/10.1016/j.jalz.2018.02.001 CrossRef

60.

Giovacchini G, Giovannini E, Borsò E, Lazzeri P, Riondato M, Leoncini R et al (2019) The brain cognitive reserve hypothesis: a review with emphasis on the contribution of nuclear medicine neuroimaging techniques. J Cell Physiol 234:14865–14872. https://doi.org/10.1002/jcp.28308 CrossRef

61.

Goedert M, Spillantini MG, Jakes R, Rutherford D, Crowther RA (1989) Multiple isoforms of human microtubule-associated protein tau: sequences and localization in neurofibrillary tangles of Alzheimer’s disease. Neuron 3:519–526. https://doi.org/10.1016/0896-6273(89)90210-9 CrossRefPubMed

62.

Gómez-Isla T, Hollister R, West H, Mui S, Growdon JH, Petersen RC et al (1997) Neuronal loss correlates with but exceeds neurofibrillary tangles in Alzheimer’s disease. Ann Neurol 41:17–24. https://doi.org/10.1002/ana.410410106 CrossRefPubMed

63.

Gosztyla ML, Brothers HM, Robinson SR (2018) Alzheimer’s amyloid-β is an antimicrobial peptide: a review of the evidence. J Alzheimer’s Dis 62:1495–1506. https://doi.org/10.3233/JAD-171133 CrossRef

64.

Guerreiro R, Wojtas A, Bras J, Carrasquillo M, Rogaeva E, Majounie E et al (2013) TREM2 variants in Alzheimer’s disease. N Engl J Med 368:117–127. https://doi.org/10.1056/NEJMoa1211851 CrossRefPubMed

65.

Guo JL, Lee VMY (2011) Seeding of normal tau by pathological tau conformers drives pathogenesis of Alzheimer-like tangles. J Biol Chem 286:15317–15331. https://doi.org/10.1074/jbc.M110.209296 CrossRefPubMedPubMedCentral

66.

Hara M, Hirokawa K, Kamei S, Uchihara T (2013) Isoform transition from four-repeat to three-repeat tau underlies dendrosomatic and regional progression of neurofibrillary pathology. Acta Neuropathol 125:565–579. https://doi.org/10.1007/s00401-013-1097-6 CrossRefPubMed

67.

Hardy J (1997) Amyloid, the presenilins and Alzheimer’s disease. Trends Neurosci 20:154–159. https://doi.org/10.1016/S0166-2236(96)01030-2 CrossRefPubMed

68.

Hartmann FJ, Bernard-Valnet R, Quériault C, Mrdjen D, Weber LM, Galli E et al (2016) High-dimensional single-cell analysis reveals the immune signature of narcolepsy. J Exp Med. https://doi.org/10.1084/jem.20160897 CrossRefPubMedPubMedCentral

69.

Head E, Powell D, Gold BT, Schmitt FA (2012) Alzheimer’s disease in down syndrome. Eur J Neurodegener Dis 1:353–364PubMedPubMedCentral

70.

Hellvard A, Ryder MI, Hasturk H, Walker GD, Benedyk M, Lee A et al (2019) Porphyromonas gingivalis in Alzheimer’s disease brains: evidence for disease causation and treatment with small-molecule inhibitors. Sci Adv 5:eaau3333. https://doi.org/10.1126/sciadv.aau3333 CrossRefPubMedPubMedCentral

71.

Heneka MT, Kummer MP, Stutz A, Delekate A, Schwartz S, Vieira-Saecker A et al (2013) NLRP3 is activated in Alzheimer’s disease and contributes to pathology in APP/PS1 mice. Nature 493:674–678. https://doi.org/10.1038/nature11729 CrossRefPubMed

72.

Hervé D, Porché M, Cabrejo L, Guidoux C, Tournier-Lasserve E, Nicolas G et al (2018) Fatal Aβ cerebral amyloid angiopathy 4 decades after a dural graft at the age of 2 years. Acta Neuropathol. https://doi.org/10.1007/s00401-018-1828-9 CrossRefPubMed

73.

Hiltunen M, van Groen T, Jolkkonen J (2009) Functional roles of amyloid-beta protein precursor and amyloid-beta peptides: evidence from experimental studies. J Alzheimers Dis 18:401–412. https://doi.org/10.3233/JAD-2009-1154 CrossRefPubMed

74.

Hof P, Morrison J (1990) Quantitative analysis of a vulnerable subset of pyramidal neurons in Alzheimer’s disease. J Comp Neurol 301:55–64CrossRefPubMed

75.

Hof PR, Bussière T, Gold G, Kövari E, Giannakopoulos P, Bouras C et al (2003) Stereologic evidence for persistence of viable neurons in layer II of the entorhinal cortex and the CA1 field in Alzheimer disease. J Neuropathol Exp Neurol 62:55–67CrossRefPubMed

76.

Holmes BB, Furman JL, Mahan TE, Yamasaki TR, Mirbaha H, Eades WC et al (2014) Proteopathic tau seeding predicts tauopathy in vivo. Proc Natl Acad Sci. https://doi.org/10.1073/pnas.1411649111 CrossRefPubMedPubMedCentral

77.

Hoover BR, Reed MN, Su J, Penrod RD, Kotilinek LA, Grant MK et al (2010) Tau mislocalization to dendritic spines mediates synaptic dysfunction independently of neurodegeneration. Neuron 68:1067–1081. https://doi.org/10.1016/j.neuron.2010.11.030 CrossRefPubMedPubMedCentral

78.

Hu M, Robertson NP (2018) Transmissible amyloid protein: evidence from iatrogenic CJD. J Neurol 265:1726–1729. https://doi.org/10.1007/s00415-018-8927-3 CrossRefPubMedPubMedCentral

79.

Huang Y (2010) Aβ-independent roles of apolipoprotein E4 in the pathogenesis of Alzheimer’s disease. Trends Mol Med 16:287–294CrossRefPubMed

80.

Hwang J, Kim CM, Jeon S, Lee JM, Hong YJ, Roh JH, Lee JH et al (2016) Prediction of Alzheimer’s disease pathophysiology based on cortical thickness patterns. Alzheimer’s Dement Diagnosis. Assess Dis Monit 2:58–67. https://doi.org/10.1016/j.dadm.2015.11.008 CrossRef

81.

Hyman BT, Van Hoesen GW, Damasio AR, Barnes CL (1984) Alzheimer’s disease: cell-specific pathology isolates the hippocampal formation. Science 225:1168–1170. https://doi.org/10.1126/science.6474172 CrossRefPubMed

82.

Hyman BT, Phelps CH, Beach TG, Bigio EH, Cairns NJ, Carrillo MC et al (2012) National Institute on Aging–Alzheimer’s Association guidelines for the neuropathologic assessment of Alzheimer’s disease. Alzheimer’s Dement 8:1–13. https://doi.org/10.1016/j.jalz.2011.10.007 CrossRef

83.

Iseki E, Yamamoto R, Murayama N, Minegishi M, Togo T, Katsuse O et al (2006) Immunohistochemical investigation of neurofibrillary tangles and their tau isoforms in brains of limbic neurofibrillary tangle dementia. Neurosci Lett 405:29–33. https://doi.org/10.1016/j.neulet.2006.06.036 CrossRefPubMed

84.

Jack CR, Bennett DA, Blennow K, Carrillo MC, Dunn B, Haeberlein SB et al (2018) NIA-AA Research Framework: toward a biological definition of Alzheimer’s disease. Alzheimer’s Dement 14:535–562. https://doi.org/10.1016/j.jalz.2018.02.018 CrossRef

85.

Jack CR, Lowe VJ, Weigand SD, Wiste HJ, Senjem ML, Knopman DS et al (2009) 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. https://doi.org/10.1093/brain/awp062 CrossRefPubMedPubMedCentral

86.

Jacobs HIL, Hopkins DA, Mayrhofer HC, Bruner E, Van Leeuwen FW, Raaijmakers W et al (2018) The cerebellum in Alzheimer’s disease: evaluating its role in cognitive decline. Brain 141:37–47. https://doi.org/10.1093/brain/awx194 CrossRefPubMed

87.

Jaunmuktane Z, Mead S, Ellis M, Wadsworth JDF, Nicoll AJ, Kenny J et al (2015) Evidence for human transmission of amyloid-β pathology and cerebral amyloid angiopathy. Nature 525:247–250. https://doi.org/10.1038/nature15369 CrossRefPubMed

88.

Jaunmuktane Z, Quaegebeur A, Taipa R, Viana-Baptista M, Barbosa R, Koriath C et al (2018) Evidence of amyloid-β cerebral amyloid angiopathy transmission through neurosurgery. Acta Neuropathol 135:671–679. https://doi.org/10.1007/s00401-018-1822-2 CrossRefPubMedPubMedCentral

89.

Josephs KA, Murray ME, Tosakulwong N, Whitwell JL, Knopman DS, Machulda MM et al (2017) Tau aggregation influences cognition and hippocampal atrophy in the absence of beta-amyloid: a clinico-imaging-pathological study of primary age-related tauopathy (PART). Acta Neuropathol 133:705–715. https://doi.org/10.1007/s00401-017-1681-2 CrossRefPubMedPubMedCentral

90.

Josephs KA, Whitwell JL, Ahmed Z, Shiung MM, Weigand SD, Knopman DS et al (2008) β-amyloid burden is not associated with rates of brain atrophy. Ann Neurol 63:204–212. https://doi.org/10.1002/ana.21223 CrossRefPubMedPubMedCentral

91.

Kaufman SK, Sanders DW, Thomas TL, Ruchinskas AJ, Vaquer-Alicea J, Sharma AM et al (2016) Tau prion strains dictate patterns of cell pathology, progression rate, and regional vulnerability in vivo. Neuron. https://doi.org/10.1016/j.neuron.2016.09.055 CrossRefPubMedPubMedCentral

92.

Kelly SC, He B, Perez SE, Ginsberg SD, Mufson EJ, Counts SE (2017) Locus coeruleus cellular and molecular pathology during the progression of Alzheimer’s disease. Acta Neuropathol Commun 5:8. https://doi.org/10.1186/s40478-017-0411-2 CrossRefPubMedPubMedCentral

93.

Keren-Shaul H, Spinrad A, Weiner A, Matcovitch-Natan O, Dvir-Szternfeld R, Ulland TK et al (2017) A unique microglia type associated with restricting development of Alzheimer’s disease. Cell 169:1276–1290.e17. https://doi.org/10.1016/j.cell.2017.05.018 CrossRefPubMed

94.

Keren L, Bosse M, Marquez D, Angoshtari R, Jain S, Varma S et al (2018) A structured tumor-immune microenvironment in triple negative breast cancer revealed by multiplexed ion beam imaging. Cell 174:1373–1387.e19. https://doi.org/10.1016/j.cell.2018.08.039 CrossRefPubMedPubMedCentral

95.

Kisler K, Nelson AR, Montagne A, Zlokovic BV (2017) Cerebral blood flow regulation and neurovascular dysfunction in Alzheimer disease. Nat Rev Neurosci 18:419–434. https://doi.org/10.1038/nrn.2017.48 CrossRefPubMedPubMedCentral

96.

Klein H-U, McCabe C, Gjoneska E, Sullivan SE, Kaskow BJ, Tang A et al (2019) Epigenome-wide study uncovers large-scale changes in histone acetylation driven by tau pathology in aging and Alzheimer’s human brains. Nat Neurosci 22:37–46. https://doi.org/10.1038/s41593-018-0291-1 CrossRefPubMed

97.

Koedam ELGE, Lauffer V, Van Der Vlies AE, Van Der Flier WM, Scheltens P, Pijnenburg YAL (2010) Early-versus late-onset Alzheimer’s disease: more than age alone. J Alzheimer’s Dis 19:1401–1408. https://doi.org/10.3233/JAD-2010-1337 CrossRef

98.

Kovacs GG, Lutz MI, Ricken G, Ströbel T, Höftberger R, Preusser M et al (2016) Dura mater is a potential source of Aβ seeds. Acta Neuropathol. https://doi.org/10.1007/s00401-016-1565-x CrossRefPubMedPubMedCentral

99.

Lambert JC, Ibrahim-Verbaas CA, Harold D, Naj AC, Sims R, Bellenguez C et al (2013) Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer’s disease. Nat Genet 45:1452–1458. https://doi.org/10.1038/ng.2802 CrossRefPubMedPubMedCentral

100.

Lee M-H, Siddoway B, Kaeser GE, Segota I, Rivera R, Romanow WJ et al (2018) Somatic APP gene recombination in Alzheimer’s disease and normal neurons. Nature 563:639–645. https://doi.org/10.1038/s41586-018-0718-6 CrossRefPubMedPubMedCentral

101.

Lehmann M, Ghosh PM, Madison C, Laforce R, Corbetta-Rastelli C, Weiner MW et al (2013) Diverging patterns of amyloid deposition and hypometabolism in clinical variants of probable Alzheimer’s disease. Brain 136:844–858. https://doi.org/10.1093/brain/aws327 CrossRefPubMedPubMedCentral

102.

Leuba G, Saini K (1995) Pathology of subcortical visual centres in relation to cortical degeneration in Alzheimer’s disease. Neuropathol Appl Neurobiol 21:410–422. https://doi.org/10.1111/j.1365-2990.1995.tb01078.x CrossRefPubMed

103.

Li J-Q, Yu J-T, Jiang T, Tan L (2015) Endoplasmic reticulum dysfunction in Alzheimer’s disease. Mol Neurobiol 51:383–395. https://doi.org/10.1007/s12035-014-8695-8 CrossRefPubMed

104.

Li Y, Sun H, Chen Z, Xu H, Bu G, Zheng H (2016) Implications of GABAergic neurotransmission in Alzheimer’s disease. Front Aging Neurosci 8:1–12. https://doi.org/10.3389/fnagi.2016.00031 CrossRef

105.

Liang D, Han G, Feng X, Sun J, Duan Y, Lei H (2012) Concerted perturbation observed in a hub network in Alzheimer’s disease. PLoS One. https://doi.org/10.1371/journal.pone.0040498 CrossRefPubMedPubMedCentral

106.

Liang WS, Dunckley T, Beach TG, Grover A, Mastroeni D, Ramsey K et al (2008) Altered neuronal gene expression in brain regions differentially affected by Alzheimer’s disease: a reference data set. Physiol Genom 33:240–256. https://doi.org/10.1152/physiolgenomics.00242.2007 CrossRef

107.

Liddelow SA, Guttenplan KA, Clarke LE, Bennett FC, Bohlen CJ, Schirmer L et al (2017) Neurotoxic reactive astrocytes are induced by activated microglia. Nature 541:481–487. https://doi.org/10.1038/nature21029 CrossRefPubMedPubMedCentral

108.

Liu C-C, Kanekiyo T, Xu H, Bu G (2013) Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy. Nat Rev Neurol 9:106–118. https://doi.org/10.1038/nrneurol.2012.263 CrossRefPubMedPubMedCentral

109.

Liu F, Gong CX (2008) Tau exon 10 alternative splicing and tauopathies. Mol Neurodegener 3:1–10. https://doi.org/10.1186/1750-1326-3-8 CrossRef

110.

Liu L, Drouet V, Wu JW, Witter MP, Small SA, Clelland C et al (2012) Trans-synaptic spread of tau pathology in vivo. PLoS ONE 7:1–9. https://doi.org/10.1371/journal.pone.0031302 CrossRef

111.

Liu ZP, Wang Y, Zhang XS, Chen L (2010) Identifying dysfunctional crosstalk of pathways in various regions of Alzheimer’s disease brains. BMC Syst Biol. https://doi.org/10.1186/1752-0509-4-11 CrossRefPubMedPubMedCentral

112.

Loring JF, Wen X, Lee JM, Seilhamer J, Somogyi R (2002) A gene expression profile of Alzheimer’s disease. DNA Cell Biol. https://doi.org/10.1089/10445490152717541 CrossRef

113.

Lowe VJ, Wiste HJ, Senjem ML, Weigand SD, Therneau TM, Boeve BF et al (2018) Widespread brain tau and its association with ageing, Braak stage and Alzheimer’s dementia. Brain 141:271–287. https://doi.org/10.1093/brain/awx320 CrossRefPubMed

114.

Lowenberg K, Waggoner RW (1934) Familial organic psychosis (Alzheimer’s type). Arch Neurol Psychiatry 31:737. https://doi.org/10.1001/archneurpsyc.1934.02250040061004 CrossRef

115.

Marshall GA, Fairbanks LA, Tekin S, Vinters HV, Cummings JL (2007) Early-onset Alzheimer’s disease is associated with greater pathologic burden. J Geriatr Psychiatry Neurol 20:29–33. https://doi.org/10.1177/0891988706297086 CrossRefPubMed

116.

Mesulam M, Shaw P, Mash D, Weintraub S (2004) Cholinergic nucleus basalis tauopathy emerges early in the aging-MCI-AD continuum. Ann Neurol 55:815–828. https://doi.org/10.1002/ana.20100 CrossRefPubMed

117.

Ming G, Song H (2011) Adult neurogenesis in the mammalian brain: significant answers and significant questions. Neuron 70:687–702. https://doi.org/10.1016/j.neuron.2011.05.001 CrossRefPubMedPubMedCentral

118.

Montagne A, Nation DA, Pa J, Sweeney MD, Toga AW, Zlokovic BV (2016) Brain imaging of neurovascular dysfunction in Alzheimer’s disease. Acta Neuropathol 131:687–707. https://doi.org/10.1007/s00401-016-1570-0 CrossRefPubMedPubMedCentral

119.

Montine TJ, Phelps CH, Beach TG, Bigio EH, Cairns NJ, Dickson DW et al (2012) National Institute on Aging–Alzheimer’s Association guidelines for the neuropathologic assessment of Alzheimer’s disease: a practical approach. Acta Neuropathol 123:1–11. https://doi.org/10.1007/s00401-011-0910-3 CrossRefPubMed

120.

Morris M, Maeda S, Vossel K, Mucke L (2011) The many faces of tau. Neuron 70:410–426. https://doi.org/10.1016/j.neuron.2011.04.009 CrossRefPubMedPubMedCentral

121.

Morrison BM, Hof PR, Morrison JH (1998) Determinants of neuronal vulnerability in neurodegenerative diseases. Ann Neurol 44:S32–S44. https://doi.org/10.1002/ana.410440706 CrossRefPubMed

122.

Morrison JH, Hof PR (2002) Chapter 37 selective vulnerability of corticocortical and hippocampal circuits in aging and Alzheimer’s disease. In: Progress in brain research, pp 467–486

123.

Mrdjen D, Hartmann FJ, Becher B (2017) High dimensional cytometry of central nervous system leukocytes during neuroinflammation. Humana, New YorkCrossRef

124.

Mrdjen D, Pavlovic A, Hartmann FJ, Schreiner B, Utz SG, Leung BP et al (2018) High-dimensional single-cell mapping of central nervous system immune cells reveals distinct myeloid subsets in health, aging, and disease. Immunity. https://doi.org/10.1016/j.immuni.2018.01.011 CrossRefPubMed

125.

Mrdjen D, Pavlovic A, Hartmann FJ, Schreiner B, Utz SG, Leung BP et al (2018) High-dimensional single-cell mapping of central nervous system immune cells reveals distinct myeloid subsets in health, aging, and disease. Immunity 48:380–395.e6. https://doi.org/10.1016/j.immuni.2018.01.011 CrossRefPubMed

126.

Mufson EJ, Binder L, Counts SE, DeKosky ST, de Toledo-Morrell L, Ginsberg SD et al (2012) Mild cognitive impairment: pathology and mechanisms. Acta Neuropathol 123:13–30. https://doi.org/10.1007/s00401-011-0884-1 CrossRefPubMed

127.

Murray ME, Graff-Radford NR, Ross OA, Petersen RC, Duara R, Dickson DW (2011) Neuropathologically defined subtypes of Alzheimer’s disease with distinct clinical characteristics: a retrospective study. Lancet Neurol 10:785–796. https://doi.org/10.1016/S1474-4422(11)70156-9 CrossRefPubMedPubMedCentral

128.

Nalivaeva NN, Turner AJ (2013) The amyloid precursor protein: a biochemical enigma in brain development, function and disease. FEBS Lett 587:2046–2054. https://doi.org/10.1016/J.FEBSLET.2013.05.010 CrossRefPubMed

129.

Nation D, Sweeney M, Montagne A, Sagare A, D’Orazio L, Pachicano M et al (2018) Blood-brain barrier breakdown is an early biomarker of human cognitive dysfunction. Nat Med. https://doi.org/10.1038/s41591-018-0297-y (in press) CrossRef

130.

Neal M, Richardson JR (2018) Epigenetic regulation of astrocyte function in neuroinflammation and neurodegeneration. Biochim Biophys Acta Mol Basis Dis 1864:432–443. https://doi.org/10.1016/j.bbadis.2017.11.004 CrossRefPubMed

131.

Noh Y, Jeon S, Lee JM, Seo SW, Kim GH, Cho H et al (2014) Anatomical heterogeneity of Alzheimer disease: based on cortical thickness on MRIs. Neurology 83:1936–1944. https://doi.org/10.1212/WNL.0000000000001003 CrossRefPubMedPubMedCentral

132.

Nonaka T, Watanabe ST, Iwatsubo T, Hasegawa M (2010) Seeded aggregation and toxicity of α-synuclein and tau: Cellular models of neurodegenerative diseases. J Biol Chem. https://doi.org/10.1074/jbc.m110.148460 CrossRefPubMedPubMedCentral

133.

Pascoal TA, Mathotaarachchi S, Shin M, Benedet AL, Mohades S, Wang S et al (2017) Synergistic interaction between amyloid and tau predicts the progression to dementia. Alzheimer’s Dement 13:644–653. https://doi.org/10.1016/j.jalz.2016.11.005 CrossRef

134.

Persson K, Eldholm RS, Barca ML, Cavallin L, Ferreira D, Knapskog A-B et al (2017) MRI-assessed atrophy subtypes in Alzheimer’s disease and the cognitive reserve hypothesis. PLoS One 12:e0186595. https://doi.org/10.1371/journal.pone.0186595 CrossRefPubMedPubMedCentral

135.

Petkova AT, Leapman RD, Guo Z, Yau WM, Mattson MP, Tycko R (2005) Self-propagating, molecular-level polymorphism in Alzheimer’s β-amyloid fibrils. Science (80-) 80:2. https://doi.org/10.1126/science.1105850 CrossRef

136.

Pini L, Pievani M, Bocchetta M, Altomare D, Bosco P, Cavedo E et al (2016) Brain atrophy in Alzheimer’s disease and aging. Ageing Res Rev 30:25–48. https://doi.org/10.1016/j.arr.2016.01.002 CrossRefPubMed

137.

Pluta R, Ułamek-Kozioł M, Januszewski S, Czuczwar SJ (2018) Exosomes as possible spread factor and potential biomarkers in Alzheimer’s disease: current concepts. Biomark Med 12:1025–1033. https://doi.org/10.2217/bmm-2018-0034 CrossRef

138.

Polanco JC, Li C, Bodea L-G, Martinez-Marmol R, Meunier FA, Götz J (2018) Amyloid-β and tau complexity—towards improved biomarkers and targeted therapies. Nat Rev Neurol 14:22–39. https://doi.org/10.1038/nrneurol.2017.162 CrossRefPubMed

139.

Price JL, Ko AI, Wade MJ, Tsou SK, McKeel DW, Morris JC (2001) Neuron number in the entorhinal cortex and CA1 in preclinical alzheimer disease. Arch Neurol 58:1395. https://doi.org/10.1001/archneur.58.9.1395 CrossRefPubMed

140.

Purro SA, Farrow MA, Linehan J, Nazari T, Thomas DX, Chen Z et al (2018) Transmission of amyloid-β protein pathology from cadaveric pituitary growth hormone. Nature. https://doi.org/10.1038/s41586-018-0790-y CrossRefPubMedPubMedCentral

141.

Qazi TJ, Quan Z, Mir A, Qing H (2018) Epigenetics in Alzheimer’s disease: perspective of DNA methylation. Mol Neurobiol 55:1026–1044. https://doi.org/10.1007/s12035-016-0357-6 CrossRefPubMed

142.

Qiang W, Yau W-M, Lu J-X, Collinge J, Tycko R (2017) Structural variation in amyloid-β fibrils from Alzheimer’s disease clinical subtypes. Nature 541:217–221. https://doi.org/10.1038/nature20814 CrossRefPubMedPubMedCentral

143.

Qiang W, Yau WM, Lu JX, Collinge J, Tycko R (2017) Structural variation in amyloid-β fibrils from Alzheimer’s disease clinical subtypes. Nature. https://doi.org/10.1038/nature20814 CrossRefPubMedPubMedCentral

144.

Rabinovici GD, Furst AJ, Alkalay A, Racine CA, O’Neil JP, Janabi M et al (2010) Increased metabolic vulnerability in early-onset Alzheimer’s disease is not related to amyloid burden. Brain 133:512–528. https://doi.org/10.1093/brain/awp326 CrossRefPubMedPubMedCentral

145.

Ray M, Zhang W (2010) Analysis of Alzheimer’s disease severity across brain regions by topological analysis of gene co-expression networks. BMC Syst Biol. https://doi.org/10.1186/1752-0509-4-136 CrossRefPubMedPubMedCentral

146.

Rice HC, de Malmazet D, Schreurs A, Frere S, Van Molle I, Volkov AN et al (2019) Secreted amyloid-β precursor protein functions as a GABA B R1a ligand to modulate synaptic transmission. Science (80-) 363:eaao4827. https://doi.org/10.1126/science.aao4827 CrossRef

147.

Risacher SL, Anderson WH, Charil A, Castelluccio PF, Shcherbinin S, Saykin AJ et al (2017) Alzheimer disease brain atrophy subtypes are associated with cognition and rate of decline. Neurology 89:2176–2186. https://doi.org/10.1212/WNL.0000000000004670 CrossRefPubMedPubMedCentral

148.

Roberson ED, Scearce-Levie K, Palop JJ, Yan F, Cheng IH, Wu T et al (2007) Reducing endogenous tau ameliorates amyloid beta-induced deficits in an Alzheimer’s disease mouse model. Science 316:750–754. https://doi.org/10.1126/science.1141736 CrossRefPubMed

149.

Rodriguez RD, Grinberg LT (2015) Argyrophilic grain disease: an underestimated tauopathy. Dement Neuropsychol 9:2–8. https://doi.org/10.1590/S1980-57642015DN91000002 CrossRefPubMedPubMedCentral

150.

Rohrback S, Siddoway B, Liu CS, Chun J (2018) Genomic mosaicism in the developing and adult brain. Dev Neurobiol 78:1026–1048. https://doi.org/10.1002/dneu.22626 CrossRefPubMedPubMedCentral

151.

Rosenbloom MH, Alkalay A, Agarwal N, Baker SL, O’Neil JP, Janabi M et al (2011) Distinct clinical and metabolic deficits in PCA and AD are not related to amyloid distribution. Neurology 76:1789–1796. https://doi.org/10.1212/WNL.0b013e31821cccad CrossRefPubMedPubMedCentral

152.

Rossor MN, Garrett NJ, Johnson AL, Mountjoy CQ, Roth M, Iversen LL (1982) A post-mortem study of the cholinergic and GABA systems in senile dementia. Brain 105:313–330CrossRefPubMed

153.

Roubroeks JAY, Smith RG, van den Hove DLA, Lunnon K (2017) Epigenetics and DNA methylomic profiling in Alzheimer’s disease and other neurodegenerative diseases. J Neurochem 143:158–170. https://doi.org/10.1111/jnc.14148 CrossRefPubMed

154.

Roussarie J, Yao V, Plautz Z, Kasturia S, Albornoz C, Eric F et al (2018) Selective neuronal vulnerability in Alzheimer’s disease: a network-based analysis. bioRxiv. https://doi.org/10.1101/499897 CrossRef

155.

Ryan NS, Rossor MN (2010) Correlating familial Alzheimer’s disease gene mutations with clinical phenotype. Biomark Med 4:99–112. https://doi.org/10.2217/bmm.09.92 CrossRefPubMed

156.

Saman S, Kim W, Raya M, Visnick Y, Miro S, Saman S et al (2012) Exosome-associated tau is secreted in tauopathy models and is selectively phosphorylated in cerebrospinal fluid in early Alzheimer disease. J Biol Chem 287:3842–3849. https://doi.org/10.1074/jbc.M111.277061 CrossRefPubMed

157.

Sanders DW, Kaufman SK, DeVos SL, Sharma AM, Mirbaha H, Li A et al (2014) Distinct tau prion strains propagate in cells and mice and define different tauopathies. Neuron. https://doi.org/10.1016/j.neuron.2014.04.047 CrossRefPubMedPubMedCentral

158.

Saxena S, Caroni P (2011) Selective neuronal vulnerability in neurodegenerative diseases: from stressor thresholds to degeneration. Neuron 71:35–48. https://doi.org/10.1016/j.neuron.2011.06.031 CrossRefPubMed

159.

Scharfman HE (2016) The enigmatic mossy cell of the dentate gyrus. Nat Rev Neurosci 17:562–575. https://doi.org/10.1038/nrn.2016.87 CrossRefPubMedPubMedCentral

160.

Scheff SW, Price DA, Schmitt FA, Dekosky ST, Mufson EJ (2007) Synaptic alterations in CA1 in mild Alzheimer disease and mild cognitive impairment. Neurology 68:1501–1508. https://doi.org/10.1212/01.wnl.0000260698.46517.8f CrossRefPubMed

161.

Scheff SW, Price DA, Schmitt FA, Mufson EJ (2006) Hippocampal synaptic loss in early Alzheimer’s disease and mild cognitive impairment. Neurobiol Aging 27:1372–1384. https://doi.org/10.1016/j.neurobiolaging.2005.09.012 CrossRefPubMed

162.

Selkoe DJ (1999) Translating cell biology into therapeutic advances in Alzheimer’s disease. Nature 399:A23–A31. https://doi.org/10.1038/399a023 CrossRefPubMed

163.

Selkoe DJ, Hardy J (2016) The amyloid hypothesis of Alzheimer’s disease at 25 years. EMBO Mol Med 8:595–608. https://doi.org/10.15252/emmm.201606210 CrossRefPubMedPubMedCentral

164.

Shiino A, Watanabe T, Maeda K, Kotani E, Akiguchi I, Matsuda M (2006) Four subgroups of Alzheimer’s disease based on patterns of atrophy using VBM and a unique pattern for early onset disease. Neuroimage 33:17–26. https://doi.org/10.1016/j.neuroimage.2006.06.010 CrossRefPubMed

165.

Simón D, García-García E, Gómez-Ramos A, Falcón-Pérez JM, Daz-Hernández M, Hernández F et al (2012) Tau overexpression results in its secretion via membrane vesicles. Neurodegener Dis 10:73–75. https://doi.org/10.1159/000334915 CrossRefPubMed

166.

Solodkin A, Veldhuizen SD, Van Hoesen GW (1996) Contingent vulnerability of entorhinal parvalbumin-containing neurons in Alzheimer’s disease. J Neurosci 16:3311–3321. https://doi.org/10.1523/JNEUROSCI.16-10-03311.1996 CrossRefPubMedPubMedCentral

167.

Soscia SJ, Kirby JE, Washicosky KJ, Tucker SM, Ingelsson M, Hyman B et al (2010) The Alzheimer’s disease-associated amyloid β-protein is an antimicrobial peptide. PLoS One 5:1–10. https://doi.org/10.1371/journal.pone.0009505 CrossRef

168.

Stancu I-C, Vasconcelos B, Ris L, Wang P, Villers A, Peeraer E et al (2015) Templated misfolding of Tau by prion-like seeding along neuronal connections impairs neuronal network function and associated behavioral outcomes in Tau transgenic mice. Acta Neuropathol 129:875–894. https://doi.org/10.1007/s00401-015-1413-4 CrossRefPubMedPubMedCentral

169.

Stern Y (2012) Cognitive reserve in ageing and Alzheimer’s disease. Lancet Neurol 11:1006–1012. https://doi.org/10.1016/S1474-4422(12)70191-6 CrossRefPubMedPubMedCentral

170.

Stranahan AM, Mattson MP (2010) Selective vulnerability of neurons in layer II of the entorhinal cortex during aging and Alzheimer’s disease. Neural Plast 2010:1–8. https://doi.org/10.1155/2010/108190 CrossRef

171.

Streit WJ, Sammons NW, Kuhns AJ, Sparks DL (2004) Dystrophic microglia in the aging human brain. Glia 45:208–212. https://doi.org/10.1002/glia.10319 CrossRefPubMed

172.

Tardivel M, Bégard S, Bousset L, Dujardin S, Coens A, Melki R et al (2016) Tunneling nanotube (TNT)-mediated neuron-to neuron transfer of pathological Tau protein assemblies. Acta Neuropathol Commun 4:117. https://doi.org/10.1186/s40478-016-0386-4 CrossRefPubMedPubMedCentral

173.

Tensaouti Y, Stephanz EP, Yu T-S, Kernie SG (2018) ApoE regulates the development of adult newborn hippocampal neurons. Eneuro 5:ENEURO.0155-18.2018. https://doi.org/10.1523/eneuro.0155-18.2018 CrossRefPubMedPubMedCentral

174.

Terry RD, Masliah E, Salmon DP, Butters N, DeTeresa R, Hill R et al (1991) Physical basis of cognitive alterations in alzheimer’s disease: synapse loss is the major correlate of cognitive impairment. Ann Neurol 30:572–580. https://doi.org/10.1002/ana.410300410 CrossRefPubMed

175.

Thal DR, Rüb U, Orantes M, Braak H (2002) Phases of Aβ-deposition in the human brain and its relevance for the development of AD. Neurology 58:1791–1800. https://doi.org/10.1212/WNL.58.12.1791 CrossRefPubMed

176.

Varol E, Sotiras A, Davatzikos C (2017) HYDRA: revealing heterogeneity of imaging and genetic patterns through a multiple max-margin discriminative analysis framework. Neuroimage 145:346–364. https://doi.org/10.1016/j.neuroimage.2016.02.041 CrossRefPubMed

177.

Verheijen BM, Vermulst M, van Leeuwen FW (2018) Somatic mutations in neurons during aging and neurodegeneration. Acta Neuropathol 135:811–826. https://doi.org/10.1007/s00401-018-1850-y CrossRefPubMedPubMedCentral

178.

Verheijen J, Sleegers K (2018) Understanding Alzheimer disease at the interface between genetics and transcriptomics. Trends Genet 34:434–447. https://doi.org/10.1016/j.tig.2018.02.007 CrossRefPubMed

179.

Vieira RT, Caixeta L, Machado S, Silva AC, Nardi AE, Arias-Carrión O et al (2013) Epidemiology of early-onset dementia: a review of the literature. Clin Pract Epidemiol Ment Health 9:88–95. https://doi.org/10.2174/1745017901309010088 CrossRefPubMedPubMedCentral

180.

Walker LC, Jucker M (2015) Neurodegenerative diseases: expanding the prion concept. Annu Rev Neurosci 38:87–103. https://doi.org/10.1146/annurev-neuro-071714-033828 CrossRefPubMedPubMedCentral

181.

Walker LC, Schelle J, Jucker M (2016) The prion-like properties of amyloid-β assemblies: implications for Alzheimer’s disease. Cold Spring Harb Perspect Med. https://doi.org/10.1101/cshperspect.a024398 CrossRefPubMedPubMedCentral

182.

Wang R, Reddy PH (2017) Role of glutamate and NMDA receptors in Alzheimer’s disease. J Alzheimer’s Dis 57:1041–1048. https://doi.org/10.3233/JAD-160763 CrossRef

183.

Wang Y, Balaji V, Kaniyappan S, Krüger L, Irsen S, Tepper K et al (2017) The release and trans-synaptic transmission of Tau via exosomes. Mol Neurodegener 12:5. https://doi.org/10.1186/s13024-016-0143-y CrossRefPubMedPubMedCentral

184.

Warren JD, Fletcher PD, Golden HL (2012) The paradox of syndromic diversity in Alzheimer disease. Nat Rev Neurol 8:451–464. https://doi.org/10.1038/nrneurol.2012.135 CrossRefPubMed

185.

Wegiel J, Wisniewski HM, Dziewiatkowski J, Badmajew E, Tarnawski M, Reisberg B et al (1999) Cerebellar atrophy in Alzheimer’s disease—clinicopathological correlations. Brain Res 818:41–50. https://doi.org/10.1016/S0006-8993(98)01279-7 CrossRefPubMed

186.

Wei P, Blundon JA, Rong Y, Zakharenko SS, Morgan JI (2011) Impaired locomotor learning and altered cerebellar synaptic plasticity in pep-19/pcp4-null mice. Mol Cell Biol 31:2838–2844. https://doi.org/10.1128/MCB.05208-11 CrossRefPubMedPubMedCentral

187.

Wendeln A-C, Degenhardt K, Kaurani L, Gertig M, Ulas T, Jain G et al (2018) Innate immune memory in the brain shapes neurological disease hallmarks. Nature 556:332–338. https://doi.org/10.1038/s41586-018-0023-4 CrossRefPubMedPubMedCentral

188.

West MJ, Coleman PD, Flood DG, Troncoso JC (1994) Differences in the pattern of hippocampal neuronal loss in normal ageing and Alzheimer’s disease. Lancet (London, England) 344:769–772CrossRef

189.

Whitehouse P, Price D, Struble R, Clark A, Coyle J, Delon M (1982) Alzheimer’s disease and senile dementia: loss of neurons in the basal forebrain. Science (80-) 215:1237–1239. https://doi.org/10.1126/science.7058341 CrossRef

190.

Whitwell JL, Dickson DW, Murray ME, Weigand SD, Tosakulwong N, Senjem ML et al (2012) Neuroimaging correlates of pathologically defined subtypes of Alzheimer’s disease: a case–control study. Lancet Neurol 11:868–877. https://doi.org/10.1016/S1474-4422(12)70200-4 CrossRefPubMedPubMedCentral

191.

Wingo TS, Lah JJ, Levey AI, Cutler DJ (2012) Autosomal recessive causes likely in early-onset Alzheimer disease. Arch Neurol 69:59–64. https://doi.org/10.1001/archneurol.2011.221 CrossRefPubMed

192.

Witter MP, Wouterlood FG, Naber PA, Van Haeften T (2000) Anatomical organization of the parahippocampal-hippocampal network. Ann N Y Acad Sci 911:1–24. https://doi.org/10.1111/j.1749-6632.2000.tb06716.x CrossRefPubMed

193.

Wu JW, Hussaini SA, Bastille IM, Rodriguez GA, Mrejeru A, Rilett K et al (2016) Neuronal activity enhances tau propagation and tau pathology in vivo. Nat Neurosci 19:1085–1092. https://doi.org/10.1038/nn.4328 CrossRefPubMedPubMedCentral

194.

Xu J, Patassini S, Rustogi N, Riba-Garcia I, Hale BD, Phillips AM et al (2019) Regional protein expression in human Alzheimer’s brain correlates with disease severity. Commun Biol. https://doi.org/10.1038/s42003-018-0254-9 CrossRefPubMedPubMedCentral

195.

Yamada K, Holth JK, Liao F, Stewart FR, Mahan TE, Jiang H et al (2014) Neuronal activity regulates extracellular tau in vivo. J Exp Med 211:387–393. https://doi.org/10.2214/AJR.17.18574 CrossRefPubMedPubMedCentral

196.

Zeisel A, Munoz-Manchado AB, Codeluppi S, Lonnerberg P, La Manno G, Jureus A et al (2015) Cell types in the mouse cortex and hippocampus revealed by single-cell RNA-seq. Science (80-) 347:1138–1142. https://doi.org/10.1126/science.aaa1934 CrossRef

197.

Zeng H, Shen EH, Hohmann JG, Oh SW, Bernard A, Royall JJ et al (2012) Large-scale cellular-resolution gene profiling in human neocortex reveals species-specific molecular signatures. Cell 149:483–496. https://doi.org/10.1016/j.cell.2012.02.052 CrossRefPubMedPubMedCentral

198.

Zhang Y, Li P, Feng J, Wu M (2016) Dysfunction of NMDA receptors in Alzheimer’s disease. Neurol Sci 37:1039–1047. https://doi.org/10.1007/s10072-016-2546-5 CrossRefPubMedPubMedCentral

199.

Zhao X, Lein ES, He A, Smith SC, Aston C, Gage FH (2001) Transcriptional profiling reveals strict boundaries between hippocampal subregions. J Comp Neurol 441:187–196. https://doi.org/10.1002/cne.1406 CrossRefPubMed

200.

Zhu X, Tan L, Wang H, Jiang T, Cao L, Wang C et al (2015) Rate of early onset Alzheimer’s disease: a systematic review and meta-analysis. Ann Transl Med. https://doi.org/10.3978/j.issn.2305-5839.2015.01.19 CrossRefPubMedPubMedCentral

Titel: The basis of cellular and regional vulnerability in Alzheimer’s disease
verfasst von: Dunja Mrdjen
Edward J. Fox
Syed A. Bukhari
Kathleen S. Montine
Sean C. Bendall
Thomas J. Montine
Publikationsdatum: 07.08.2019
Verlag: Springer Berlin Heidelberg
Erschienen in: Acta Neuropathologica / Ausgabe 5/2019
Print ISSN: 0001-6322
Elektronische ISSN: 1432-0533
DOI: https://doi.org/10.1007/s00401-019-02054-4

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