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A caveat with this hypothesis is the spatio-temporal divide between plaques and NFTs. This has been addressed by the inclusion of soluble A\u03b2 and tau species in the revised amyloid cascade hypothesis. Nevertheless, despite the potential for non-plaque A\u03b2 to contribute to tau pathology, few studies have examined relative correlative strengths between total A\u03b2, plaque A\u03b2 and intracellular A\u03b2 with tau pathology within a single tissue cohort. Employing frozen and fixed frontal cortex grey and white matter tissue from non-AD controls (Con; <jats:italic>n<\/jats:italic>\u2009=\u200939) and Alzheimer\u2019s disease (AD) cases (<jats:italic>n<\/jats:italic>\u2009=\u200921), biochemical and immunohistochemical (IHC) measures of A\u03b2 and AT-8 phosphorylated tau were assessed. Biochemical native-state dot blots from crude tissue lysates demonstrated robust correlations between total A\u03b2 and AT-8 tau, when considered as a combined cohort (Con and AD) and when as Con and AD cases, separately. In contrast, no associations between A\u03b2 plaques and AT-8 were reported when using IHC measurements in either Con or AD cases. However, when intracellular A\u03b2 was measured via the A\u03b2 specific antibody MOAB-2, a correlative relationship with AT-8 tau was reported in non-AD controls but not in AD cases. Collectively the data suggests that accumulating intracellular A\u03b2 may influence AT-8 pathology, early in AD-related neuropathological change. Despite the lower levels of phospho-tau and A\u03b2 in controls, the robust correlative relationships observed suggest a physiological association of A\u03b2 production and tau phosphorylation, which may be modified during disease. This study is supportive of a revised amyloid cascade hypothesis and demonstrates regional associative relationships between tau pathology and intracellular A\u03b2, but not extracellular A\u03b2 plaques.<\/jats:p>","DOI":"10.1007\/s00401-024-02691-4","type":"journal-article","created":{"date-parts":[[2024,2,14]],"date-time":"2024-02-14T12:02:16Z","timestamp":1707912136000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Regional AT-8 reactive tau species correlate with intracellular A\u03b2 levels in cases of low AD neuropathologic change"],"prefix":"10.1007","volume":"147","author":[{"given":"Nauman","family":"Malik","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohi-Uddin","family":"Miah","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandro","family":"Galgani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kirsty","family":"McAleese","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lauren","family":"Walker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fiona E.","family":"LeBeau","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johannes","family":"Attems","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tiago F.","family":"Outeiro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alan","family":"Thomas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8034-9880","authenticated-orcid":false,"given":"David J.","family":"Koss","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,2,14]]},"reference":[{"key":"2691_CR1","doi-asserted-by":"publisher","first-page":"1085","DOI":"10.1097\/WNR.0b013e328302c858","volume":"19","author":"M Aoki","year":"2008","unstructured":"Aoki M, Volkmann I, Tjernberg LO, Winblad B, Bogdanovic N (2008) Amyloid beta-peptide levels in laser capture microdissected cornu ammonis 1 pyramidal neurons of Alzheimer\u2019s brain. 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