{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T13:05:37Z","timestamp":1785762337231,"version":"3.56.0"},"reference-count":92,"publisher":"Oxford University Press (OUP)","issue":"6","license":[{"start":{"date-parts":[[2025,12,18]],"date-time":"2025-12-18T00:00:00Z","timestamp":1766016000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/501100014065","name":"Bright Focus Foundation","doi-asserted-by":"publisher","award":["A2021026S"],"award-info":[{"award-number":["A2021026S"]}],"id":[{"id":"10.13039\/501100014065","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000957","name":"Alzheimer\u2019s Association","doi-asserted-by":"publisher","award":["AARG-22-973496"],"award-info":[{"award-number":["AARG-22-973496"]}],"id":[{"id":"10.13039\/100000957","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000957","name":"Alzheimer\u2019s Association","doi-asserted-by":"publisher","award":["ABA-25-1376130"],"award-info":[{"award-number":["ABA-25-1376130"]}],"id":[{"id":"10.13039\/100000957","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Gerhard and Ilse Schick Foundation"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,6,3]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>In Alzheimer\u2019s disease, carriage of the apolipoprotein E \u03b54 (ApoE4) risk allele is linked to faster tau accumulation at lower amyloid-PET levels, thereby accelerating disease progression. However, it remains unclear whether this ApoE4-facilitated transition from amyloidosis to tauopathy is mechanistically promoted by increased secretion of phosphorylated tau (ptau), a key intermediate that drives the amyloid-to-tauopathy transition, or alternatively by increased ptau-driven tau aggregation. Therefore, we investigated where along the amyloid-to-tau axis ApoE4 accelerates tau aggregation and assessed: (i) whether ApoE4 increases ptau secretion; or (ii) whether ApoE4 increases ptau-associated tau aggregation.<\/jats:p>\n                  <jats:p>To this end, we analysed two large-scale APOE-genotyped cohorts covering the full Alzheimer\u2019s disease spectrum (Alzheimer\u2019s Disease Neuroimaging Initiative; ADNI: n = 201) as well as a preclinical cohort (Anti-Amyloid Treatment in Asymptomatic Alzheimer\u2019s and Longitudinal Evaluation of Amyloid Risk and Neurodegeneration study; A4-LEARN: n = 200), integrating baseline amyloid-PET, plasma ptau217 and CSF ptau181 with longitudinal tau-PET. Using linear regression, we tested whether ApoE4 carriage moderates: (i) amyloid-PET-associated plasma ptau217 increases; or (ii) ptau217-associated tau spreading from local epicentres across patient-tailored tau spreading stages. All analyses were independently validated across both cohorts, including an additional replication in an ADNI subset (n = 115) with available CSF ptau181 measures as an alternative marker of ptau secretion. Finally, we used logistic regression to determine ApoE4 allele count-stratified plasma ptau217 thresholds marking early pathological tau-PET increases.<\/jats:p>\n                  <jats:p>We found that ApoE4 did not facilitate amyloid-PET-associated ptau increases, suggesting that amyloid-related ptau secretion is not altered by ApoE4 carriage. Contrastingly, we found that plasma ptau217 elevations were linked to faster tau-PET spread from local epicentres across connected brain regions in an ApoE4 allele dose-dependent manner, independent of amyloid [ADNI\/A4-LEARN: mean standardized beta (\u03b2) = 0.44\/0.56, P &amp;lt; 0.001\/P &amp;lt; 0.001]. Lastly, we found that a higher ApoE4 allele count was linked to lower ptau217 thresholds marking transition to tauopathy, i.e. early abnormal tau-PET increases, consistently across both samples (ADNI: 0\/1\/2 ApoE4 alleles = 0.62\/0.34\/0.15\u2005pg\/ml, representing \u223c45% and \u223c76% reductions from non-carriers; Fujirebio ptau217 assay; A4-LEARN: 0\/1\/2 ApoE4 alleles = 0.31\/0.23\/0.18\u2005pg\/ml, representing \u223c26% and \u223c42% reductions; Eli Lilly ptau217 assay).<\/jats:p>\n                  <jats:p>These findings suggest that ApoE4, i.e. the key genetic risk factor for sporadic Alzheimer\u2019s disease, facilitates amyloid-dependent tau aggregation in an allele dose-dependent manner by enhancing the ptau-driven spread of fibrillar tau, leading to an earlier transition from amyloidosis to tauopathy at lower ptau217 levels. This has implications for plasma ptau-based screening approaches and therapeutic timing of anti-amyloid drugs in ApoE4 carriers. Specifically, ApoE4 carriers may require genotype-adjusted ptau thresholds to detect Alzheimer\u2019s disease pathophysiology, as well as anti-amyloid treatment at lower ptau levels to prevent the transition to tauopathy, which ultimately drives neurodegeneration and cognitive decline.<\/jats:p>","DOI":"10.1093\/brain\/awaf463","type":"journal-article","created":{"date-parts":[[2025,12,11]],"date-time":"2025-12-11T13:09:35Z","timestamp":1765458575000},"page":"1902-1914","source":"Crossref","is-referenced-by-count":6,"title":["ApoE4 lowers the ptau217 threshold for tau aggregation and spread in an allele dose-dependent manner"],"prefix":"10.1093","volume":"149","author":[{"given":"Anna","family":"Steward","sequence":"first","affiliation":[{"name":"Institute for Stroke and Dementia Research (ISD), University Hospital LMU , Munich 81377 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5636-196X","authenticated-orcid":false,"given":"Anna","family":"Dewenter","sequence":"additional","affiliation":[{"name":"Institute for Stroke and Dementia Research (ISD), University Hospital LMU , Munich 81377 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabian","family":"Hirsch","sequence":"additional","affiliation":[{"name":"Institute for Stroke and Dementia Research (ISD), University Hospital LMU , Munich 81377 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3423-457X","authenticated-orcid":false,"given":"Sebastian N","family":"Roemer-Cassiano","sequence":"additional","affiliation":[{"name":"Institute for Stroke and Dementia Research (ISD), University Hospital LMU , Munich 81377 ,","place":["Germany"]},{"name":"Department of Neurology, University Hospital LMU , Munich 81377 ,","place":["Germany"]},{"name":"Max Planck School of Cognition , Max Planck Institute for Human Cognitive and Brain Sciences, Leipzig 04103 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zeyu","family":"Zhu","sequence":"additional","affiliation":[{"name":"Institute for Stroke and Dementia Research (ISD), University Hospital LMU , Munich 81377 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amir","family":"Dehsarvi","sequence":"additional","affiliation":[{"name":"Institute for Stroke and Dementia Research (ISD), University Hospital LMU , Munich 81377 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2597-1992","authenticated-orcid":false,"given":"Davina","family":"Biel","sequence":"additional","affiliation":[{"name":"Institute for Stroke and Dementia Research (ISD), University Hospital LMU , Munich 81377 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Madleen","family":"Klonowski","sequence":"additional","affiliation":[{"name":"Institute for Stroke and Dementia Research (ISD), University Hospital LMU , Munich 81377 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9321-956X","authenticated-orcid":false,"given":"Lukas","family":"Frontzkowski","sequence":"additional","affiliation":[{"name":"Institute for Stroke and Dementia Research (ISD), University Hospital LMU , Munich 81377 ,","place":["Germany"]},{"name":"Department of Nuclear Medicine, University Hospital LMU , Munich 81377 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4331-8145","authenticated-orcid":false,"given":"Carla","family":"Palleis","sequence":"additional","affiliation":[{"name":"Department of Neurology, University Hospital LMU , Munich 81377 ,","place":["Germany"]},{"name":"Munich Cluster for Systems Neurology (SyNergy) , Institute for Stroke and Dementia Research (ISD), Munich 81377 ,","place":["Germany"]},{"name":"German Center for Neurodegenerative Diseases (DZNE) Munich , Institute for Stroke and Dementia Research (ISD), Munich 81377 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johannes","family":"Gn\u00f6rich","sequence":"additional","affiliation":[{"name":"Department of Nuclear Medicine, University Hospital LMU , Munich 81377 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0654-387X","authenticated-orcid":false,"given":"Martin","family":"Dichgans","sequence":"additional","affiliation":[{"name":"Institute for Stroke and Dementia Research (ISD), University Hospital LMU , Munich 81377 ,","place":["Germany"]},{"name":"Munich Cluster for Systems Neurology (SyNergy) , Institute for Stroke and Dementia Research (ISD), Munich 81377 ,","place":["Germany"]},{"name":"German Center for Neurodegenerative Diseases (DZNE) Munich , Institute for Stroke and Dementia Research (ISD), Munich 81377 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G\u00fcnter","family":"H\u00f6glinger","sequence":"additional","affiliation":[{"name":"Department of Neurology, University Hospital LMU , Munich 81377 ,","place":["Germany"]},{"name":"Munich Cluster for Systems Neurology (SyNergy) , Institute for Stroke and Dementia Research (ISD), Munich 81377 ,","place":["Germany"]},{"name":"German Center for Neurodegenerative Diseases (DZNE) Munich , Institute for Stroke and Dementia Research (ISD), Munich 81377 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9247-2843","authenticated-orcid":false,"given":"Matthias","family":"Brendel","sequence":"additional","affiliation":[{"name":"Department of Nuclear Medicine, University Hospital LMU , Munich 81377 ,","place":["Germany"]},{"name":"Munich Cluster for Systems Neurology (SyNergy) , Institute for Stroke and Dementia Research (ISD), Munich 81377 ,","place":["Germany"]},{"name":"German Center for Neurodegenerative Diseases (DZNE) Munich , Institute for Stroke and Dementia Research (ISD), Munich 81377 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9736-2283","authenticated-orcid":false,"given":"Nicolai","family":"Franzmeier","sequence":"additional","affiliation":[{"name":"Institute for Stroke and Dementia Research (ISD), University Hospital LMU , Munich 81377 ,","place":["Germany"]},{"name":"Munich Cluster for Systems Neurology (SyNergy) , Institute for Stroke and Dementia Research (ISD), Munich 81377 ,","place":["Germany"]},{"name":"The Sahlgrenska Academy, Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, University of Gothenburg , M\u00f6lndal and Gothenburg SE 413 90 ,","place":["Sweden"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2025,12,18]]},"reference":[{"key":"2026060310571187300_awaf463-B1","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1016\/j.jalz.2018.02.018","article-title":"NIA-AA Research framework: Toward a biological definition of Alzheimer\u2019s disease","volume":"14","author":"Jack","year":"2018","journal-title":"Alzheimers Dement"},{"key":"2026060310571187300_awaf463-B2","doi-asserted-by":"crossref","first-page":"2225","DOI":"10.1007\/s00259-021-05191-9","article-title":"Relationship between amyloid and tau levels and its impact on tau spreading","volume":"48","author":"Dor\u00e9","year":"2021","journal-title":"Eur J Nucl Med Mol Imaging"},{"key":"2026060310571187300_awaf463-B3","doi-asserted-by":"crossref","first-page":"550","DOI":"10.1093\/brain\/awx347","article-title":"Tau burden and the functional connectome in 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