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Here we characterised the nanoscopic tau aggregates in individual synaptosomes from AD cases and controls, measuring their number and size using SynPull with direct stochastic optical reconstruction microscopy (\n                    <jats:italic>d<\/jats:italic>\n                    STORM). A total of 7888 synaptosomes from pre-frontal cortex samples were studied, showing the presence of AT8-positive tau aggregates in a small fraction of synaptosomes (~\u20093%) from control brains, reaching\u2009~\u200920% by Braak stage 6. These key findings of the intra-synaptic localisation of aggregates and existence of synaptic tau pathology at Braak stage 3\u2014preceding tangle formation in this region, were confirmed using aggregate-specific single-molecule array (SIMOA) with proteinase K digestion, three-dimensional super-resolution microscopy, stimulated emission depletion microscopy (STED), and immunohistochemistry. The aggregates also grew in size with AD progression with an average length of 117\u00a0nm at stage 0, 154\u00a0nm at stage 3 and 182\u00a0nm at stage 6, however they mostly remained non-elongated (circular) with average eccentricity values remaining below 0.8. We then investigated the multi-phosphorylation of synaptic tau aggregates for AT8 and T181 and quantified their co-localisation with phosphatidylserine and CD47, synaptic \u201ceat me\u201d and \u201cdon\u2019t eat me\u201d signals respectively, along with synaptogyrin-3, which contributes to tau-mediated synaptic dysfunction. T181, phosphatidylserine, and synaptogyrin-3 co-localisation with AT8-positive tau were higher during stage 3 and CD47 was lower, indicating early synaptic pathology is associated with the formation of small tau aggregates, contributing to microglia-driven synaptic loss.\n                  <\/jats:p>","DOI":"10.1007\/s00401-026-02977-9","type":"journal-article","created":{"date-parts":[[2026,1,23]],"date-time":"2026-01-23T07:20:30Z","timestamp":1769152830000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Early synaptic pathology is associated with small tau aggregates in Alzheimer\u2019s disease"],"prefix":"10.1007","volume":"151","author":[{"given":"Emre","family":"Fertan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shekhar","family":"Kedia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"George","family":"Nolan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Georg","family":"Meisl","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew W.","family":"Cotton","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karin H.","family":"M\u00fcller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ziwei","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leila","family":"Muresan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annelies","family":"Quaegebeur","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Grazia","family":"Spillantini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Klenerman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,1,23]]},"reference":[{"key":"2977_CR1","doi-asserted-by":"publisher","first-page":"119","DOI":"10.1093\/brain\/awae234","volume":"148","author":"J Appleton","year":"2025","unstructured":"Appleton J, Finn Q, Zanotti-Fregonara P, Yu M, Faridar A, Nakawah MO et al (2025) Brain inflammation co-localizes highly with tau in mild cognitive impairment due to early-onset Alzheimer\u2019s disease. 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