000265749 001__ 265749 000265749 005__ 20231119001739.0 000265749 0247_ $$2doi$$a10.1016/j.neuron.2023.05.031 000265749 0247_ $$2pmid$$apmid:37385247 000265749 0247_ $$2ISSN$$a0896-6273 000265749 0247_ $$2ISSN$$a1097-4199 000265749 0247_ $$2altmetric$$aaltmetric:150644309 000265749 037__ $$aDZNE-2023-01024 000265749 041__ $$aEnglish 000265749 082__ $$a610 000265749 1001_ $$0P:(DE-2719)2811642$$aSimons, Mikael$$b0$$eFirst author$$udzne 000265749 245__ $$aTipping points in neurodegeneration. 000265749 260__ $$aNew York, NY$$bElsevier$$c2023 000265749 3367_ $$2DRIVER$$aarticle 000265749 3367_ $$2DataCite$$aOutput Types/Journal article 000265749 3367_ $$0PUB:(DE-HGF)16$$2PUB:(DE-HGF)$$aJournal Article$$bjournal$$mjournal$$s1700060539_31971$$xReview Article 000265749 3367_ $$2BibTeX$$aARTICLE 000265749 3367_ $$2ORCID$$aJOURNAL_ARTICLE 000265749 3367_ $$00$$2EndNote$$aJournal Article 000265749 520__ $$aIn Alzheimer's disease (AD), Aβ deposits form slowly, several decades before further pathological events trigger neurodegeneration and dementia. However, a substantial proportion of affected individuals remains non-demented despite AD pathology, raising questions about the underlying factors that determine the transition to clinical disease. Here, we emphasize the critical function of resilience and resistance factors, which we extend beyond the concept of cognitive reserve to include the glial, immune, and vascular system. We review the evidence and use the metaphor of 'tipping points' to illustrate how gradually forming AD neuropathology in the preclinical stage can transition to dementia once adaptive functions of the glial, immune, and vascular system are lost and self-reinforcing pathological cascades are unleashed. Thus, we propose an expanded framework for pathomechanistic research that focuses on tipping points and non-neuronal resilience mechanisms, which may represent previously untapped therapeutic targets in preclinical AD. 000265749 536__ $$0G:(DE-HGF)POF4-353$$a353 - Clinical and Health Care Research (POF4-353)$$cPOF4-353$$fPOF IV$$x0 000265749 536__ $$0G:(DE-HGF)POF4-351$$a351 - Brain Function (POF4-351)$$cPOF4-351$$fPOF IV$$x1 000265749 588__ $$aDataset connected to CrossRef, PubMed, , Journals: pub.dzne.de 000265749 650_7 $$2Other$$aAlzheimer's disease 000265749 650_7 $$2Other$$aglia 000265749 650_7 $$2Other$$ainflammation 000265749 650_7 $$2Other$$aneurodegeneration 000265749 650_7 $$2Other$$avasculature 000265749 650_7 $$2NLM Chemicals$$aAmyloid beta-Peptides 000265749 650_2 $$2MeSH$$aHumans 000265749 650_2 $$2MeSH$$aAlzheimer Disease: pathology 000265749 650_2 $$2MeSH$$aNeuroglia: pathology 000265749 650_2 $$2MeSH$$aAmyloid beta-Peptides 000265749 7001_ $$0P:(DE-2719)2811659$$aLevin, Johannes$$b1$$udzne 000265749 7001_ $$0P:(DE-2719)2000030$$aDichgans, Martin$$b2$$eLast author$$udzne 000265749 773__ $$0PERI:(DE-600)2001944-0$$a10.1016/j.neuron.2023.05.031$$gVol. 111, no. 19, p. 2954 - 2968$$n19$$p2954 - 2968$$tNeuron$$v111$$x0896-6273$$y2023 000265749 8564_ $$uhttps://pub.dzne.de/record/265749/files/DZNE-2023-01024.pdf$$yOpenAccess 000265749 8564_ $$uhttps://pub.dzne.de/record/265749/files/DZNE-2023-01024.pdf?subformat=pdfa$$xpdfa$$yOpenAccess 000265749 909CO $$ooai:pub.dzne.de:265749$$pdnbdelivery$$pdriver$$pVDB$$popen_access$$popenaire 000265749 9101_ $$0I:(DE-588)1065079516$$6P:(DE-2719)2811642$$aDeutsches Zentrum für Neurodegenerative Erkrankungen$$b0$$kDZNE 000265749 9101_ $$0I:(DE-588)1065079516$$6P:(DE-2719)2811659$$aDeutsches Zentrum für Neurodegenerative Erkrankungen$$b1$$kDZNE 000265749 9101_ $$0I:(DE-588)1065079516$$6P:(DE-2719)2000030$$aDeutsches Zentrum für Neurodegenerative Erkrankungen$$b2$$kDZNE 000265749 9131_ $$0G:(DE-HGF)POF4-353$$1G:(DE-HGF)POF4-350$$2G:(DE-HGF)POF4-300$$3G:(DE-HGF)POF4$$4G:(DE-HGF)POF$$aDE-HGF$$bGesundheit$$lNeurodegenerative Diseases$$vClinical and Health Care Research$$x0 000265749 9131_ $$0G:(DE-HGF)POF4-351$$1G:(DE-HGF)POF4-350$$2G:(DE-HGF)POF4-300$$3G:(DE-HGF)POF4$$4G:(DE-HGF)POF$$aDE-HGF$$bGesundheit$$lNeurodegenerative Diseases$$vBrain Function$$x1 000265749 9141_ $$y2023 000265749 915__ $$0StatID:(DE-HGF)0150$$2StatID$$aDBCoverage$$bWeb of Science Core Collection$$d2023-08-28 000265749 915__ $$0StatID:(DE-HGF)0160$$2StatID$$aDBCoverage$$bEssential Science Indicators$$d2023-08-28 000265749 915__ $$0StatID:(DE-HGF)1050$$2StatID$$aDBCoverage$$bBIOSIS Previews$$d2023-08-28 000265749 915__ $$0StatID:(DE-HGF)1190$$2StatID$$aDBCoverage$$bBiological Abstracts$$d2023-08-28 000265749 915__ $$0StatID:(DE-HGF)0600$$2StatID$$aDBCoverage$$bEbsco Academic Search$$d2023-08-28 000265749 915__ $$0StatID:(DE-HGF)9915$$2StatID$$aIF >= 15$$bNEURON : 2022$$d2023-08-28 000265749 915__ $$0StatID:(DE-HGF)0100$$2StatID$$aJCR$$bNEURON : 2022$$d2023-08-28 000265749 915__ $$0StatID:(DE-HGF)0113$$2StatID$$aWoS$$bScience Citation Index Expanded$$d2023-08-28 000265749 915__ $$0StatID:(DE-HGF)1030$$2StatID$$aDBCoverage$$bCurrent Contents - Life Sciences$$d2023-08-28 000265749 915__ $$0StatID:(DE-HGF)0510$$2StatID$$aOpenAccess 000265749 915__ $$0StatID:(DE-HGF)0030$$2StatID$$aPeer Review$$bASC$$d2023-08-28 000265749 915__ $$0StatID:(DE-HGF)0300$$2StatID$$aDBCoverage$$bMedline$$d2023-08-28 000265749 915__ $$0StatID:(DE-HGF)0200$$2StatID$$aDBCoverage$$bSCOPUS$$d2023-08-28 000265749 915__ $$0LIC:(DE-HGF)CCBY4$$2HGFVOC$$aCreative Commons Attribution CC BY 4.0 000265749 915__ $$0StatID:(DE-HGF)0420$$2StatID$$aNationallizenz$$d2023-08-28$$wger 000265749 915__ $$0StatID:(DE-HGF)0199$$2StatID$$aDBCoverage$$bClarivate Analytics Master Journal List$$d2023-08-28 000265749 9201_ $$0I:(DE-2719)5000022$$kAG Dichgans$$lVascular Cognitive Impairment & Post-Stroke Dementia$$x0 000265749 9201_ $$0I:(DE-2719)1110008$$kAG Simons$$lMolecular Neurobiology$$x1 000265749 9201_ $$0I:(DE-2719)1111016$$kAG Levin$$lClinical Neurodegeneration$$x2 000265749 9201_ $$0I:(DE-2719)1111015$$kClinical Research (Munich)$$lClinical Research (Munich)$$x3 000265749 980__ $$ajournal 000265749 980__ $$aVDB 000265749 980__ $$aUNRESTRICTED 000265749 980__ $$aI:(DE-2719)5000022 000265749 980__ $$aI:(DE-2719)1110008 000265749 980__ $$aI:(DE-2719)1111016 000265749 980__ $$aI:(DE-2719)1111015 000265749 9801_ $$aFullTexts