biostudies-literatureIslam TNIA NIH HHSVetenskapsrådet (Swedish Research Council)U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)Alzheimer's Association574-588https://www.ebi.ac.uk/biostudies/studies/S-EPMC11835754biostudies-literatureUnknown31(2)Patients with Alzheimer's disease (AD) with little or no quantifiable insoluble brain tau neurofibrillary tangle (NFT) pathology demonstrate stronger clinical benefits of therapies than those with advanced NFTs. The formation of NFTs can be prevented by targeting the intermediate soluble tau assemblies (STAs). However, biochemical understanding and biomarkers of STAs are lacking. We show that Tris-buffered saline-soluble tau aggregates from autopsy-verified AD brain tissues include the core sequence ~tau_258-368. In neuropathological assessments, antibodies against the phosphorylation sites serine-262 and serine-356 within the STA core almost exclusively stained granular (that is, prefibrillar) tau aggregates in pre-NFTs while antibodies against phosphorylation at serine-202 and Nature medicinePhospho-tau serine-262 and serine-356 as biomarkers of pre-tangle soluble tau assemblies in Alzheimer's disease.PMC11835754U24 AG0829302021-03244R37 AG023651P01AG025204RF1 AG025516P01 AG014449R01 AG072641R01 AG073267RF1 AG052525P50 AG005133R01 AG053952P30 AG062429R01 AG075336P01 AG025204AARF-21-850325P01AG14449P30AG066468P30 AG066468R01 AG083874R01AG083874Islam TSmirnov DSLashley TOlsson MDel Popolo IZetterberg HHill ERichardson ASjons ESehrawat AGalasko DPascoal TAChen YTherriault JRahmouni NServaes SRosa-Neto PZeng XKac PRTissot CKvartsberg HMitchell VAbrahamson EEIkonomovic MDWall MJGonzalez-Ortiz FKarikari TKBlennow KfalsePhospho-tau serine-262 and serine-356 as biomarkers of pre-tangle soluble tau assemblies in Alzheimer's disease.Patients with Alzheimer's disease (AD) with little or no quantifiable insoluble brain tau neurofibrillary tangle (NFT) pathology demonstrate stronger clinical benefits of therapies than those with advanced NFTs. The formation of NFTs can be prevented by targeting the intermediate soluble tau assemblies (STAs). However, biochemical understanding and biomarkers of STAs are lacking. We show that Tris-buffered saline-soluble tau aggregates from autopsy-verified AD brain tissues include the core sequence ~tau_258-368. In neuropathological assessments, antibodies against the phosphorylation sites serine-262 and serine-356 within the STA core almost exclusively stained granular (that is, prefibrillar) tau aggregates in pre-NFTs while antibodies against phosphorylation at serine-202 and 2025-01-01T00:00:00Z2025 Feb2026-06-01T21:56:48.718Z2025-04-04T02:12:04.78ZS-EPMC118357543993014210.1038/s41591-024-03400-0