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Whether or not neuroinflammation occurs in such nondemented individuals is unknown. We evaluated the medial temporal lobe of 66 nondemented subjects, aged 42\u201393, in terms of tau pathology, A\u03b2 deposition, and microglial activation. We show that 100% of subjects had neurofibrillary degeneration (NFD), 35% had A\u03b2 deposits, and 8% revealed microglial activation in individuals where early amyloid formation was apparent by Congo Red staining. Amyloid\u2010induced neuroinflammatory clusters of Iba1, CD68, and ferritin\u2010positive microglia were evident in the immediate vicinity of aggregated A\u03b2. Microglia in the adjacent neuropil were nonactivated. Thus, neuroinflammation in AD represents a highly localized phagocyte reaction, essentially a foreign body response, geared toward removal of insoluble A\u03b2. Because clustered microglia in some amyloid plaques were dystrophic and ferritin\u2010positive, we hypothesize that these cells were exhausted by their attempts to remove the aggregated, insoluble A\u03b2. Our findings show that the sequence of pathologic events in AD begins with tau pathology, followed by A\u03b2 deposition, and then by microglial activation. Because only 8% of our subjects revealed all three hallmark pathologic features, we propose that these nondemented individuals were near the threshold of transitioning from nonsymptomatic to symptomatic disease. The onset of neuroinflammation in AD may thus represent a tipping point in AD pathogenesis. Our study suggests that the role of microglia in AD pathogenesis entails primarily the attempted removal of potentially toxic, extracellular material.<\/jats:p>","DOI":"10.1002\/glia.23510","type":"journal-article","created":{"date-parts":[[2018,11,12]],"date-time":"2018-11-12T02:20:16Z","timestamp":1541989216000},"page":"2550-2562","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":77,"title":["Microglial activation occurs late during preclinical Alzheimer's disease"],"prefix":"10.1002","volume":"66","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4973-9052","authenticated-orcid":false,"given":"Wolfgang J.","family":"Streit","sequence":"first","affiliation":[{"name":"Department of Neuroscience University of Florida College of Medicine  Gainesville Florida"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heiko","family":"Braak","sequence":"additional","affiliation":[{"name":"Clinical Neuroanatomy (Department of Neurology) Center for Biomedical Research, University of Ulm  Ulm Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kelly","family":"Del Tredici","sequence":"additional","affiliation":[{"name":"Clinical Neuroanatomy (Department of Neurology) Center for Biomedical Research, University of Ulm  Ulm Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Judith","family":"Leyh","sequence":"additional","affiliation":[{"name":"Institute of Anatomy Leipzig University  Leipzig Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia","family":"Lier","sequence":"additional","affiliation":[{"name":"Institute of Anatomy Leipzig University  Leipzig Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Habibeh","family":"Khoshbouei","sequence":"additional","affiliation":[{"name":"Department of Neuroscience University of Florida College of Medicine  Gainesville Florida"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Eisenl\u00f6ffel","sequence":"additional","affiliation":[{"name":"Department of Neuropathology Leipzig University  Leipzig Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wolf","family":"M\u00fcller","sequence":"additional","affiliation":[{"name":"Department of Neuropathology Leipzig University  Leipzig Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ingo","family":"Bechmann","sequence":"additional","affiliation":[{"name":"Institute of Anatomy Leipzig University  Leipzig Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2018,11,11]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0046-8177(97)90196-9"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2990.2006.00756.x"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/jnr.490380402"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jalz.2015.05.016"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnagi.2013.00050"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-006-0127-z"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF00308809"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0197-4580(97)00056-0"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-010-0789-4"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-014-1356-1"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awv236"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1097\/NEN.0b013e318232a379"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-014-1349-0"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1186\/1742-2094-9-179"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.38.11.1682"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neurobiolaging.2003.12.026"},{"issue":"3","key":"e_1_2_7_18_1","first-page":"589","article-title":"The heterogeneity of mononuclear phagocytes in lymphoid organs: Distinct macrophage subpopulations in the rat recognized by monoclonal antibodies ED1, ED2 and ED3","volume":"54","author":"Dijkstra C. 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