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Understanding the transition between these different stages is a major challenge, especially in view of the recent development of disease modifying therapy.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>This is an observational study, CSF levels of Tau, pTau181, pTau217, A\u03b238\/40\/42, sAPP\u03b1\/\u03b2, BACE1 and neurogranin were measured in the BALTAZAR cohort of cognitively impaired patients and in the Alzheimer's Disease Neuroimaging Initiative (ADNI). Biomarkers levels were related to the AT(N) framework. (A) and (T) were defined in BALTAZAR with CSF A\u03b242\/40 ratio and pTau217 respectively, and in ADNI with amyloid and tau PET. (N) was defined using total CSF tau in both cohorts.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>As expected, CSF A\u03b242 decreased progressively with the AD continuum going from the A-T-N- to the A\u2009+\u2009T\u2009+\u2009N\u2009+\u2009profile. On the other hand, Tau and pTau181 increased progressively with the disease. The final transition from A\u2009+\u2009T\u2009+\u2009N- to A\u2009+\u2009T\u2009+\u2009N\u2009+\u2009led to a sharp increase in A\u03b238, A\u03b242 and sAPP levels. Synaptic CSF biomarkers BACE1 and neurogranin, were lowest in the initial A\u2009+\u2009T-N- stage and increased with T\u2009+\u2009and N\u2009+\u2009. CSF pTau181 and total tau were closely related in both cohorts.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p>The early transition to an A\u2009+\u2009phenotype (A\u2009+\u2009T-N-) primarily impacts synaptic function. The appearance of T\u2009+\u2009and then N\u2009+\u2009is associated with a significant and progressive increase in pathological Alzheimer's disease biomarkers. Our main finding is that CSF pTau181 is an indicator of N\u2009+\u2009rather than T\u2009+\u2009, and that N\u2009+\u2009is associated with elevated levels of BACE1 protein and beta-amyloid peptides. This increase may potentially fuel the amyloid cascade in a positive feedback loop. Overall, our data provide further insights into understanding the interconnected pathological processes of amyloid, tau, and neurodegeneration underlying Alzheimer's disease.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s13024-024-00755-3","type":"journal-article","created":{"date-parts":[[2024,10,8]],"date-time":"2024-10-08T06:04:57Z","timestamp":1728367497000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Clarifying the association of CSF A\u03b2, tau, BACE1, and neurogranin with AT(N) stages in Alzheimer disease"],"prefix":"10.1186","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6117-562X","authenticated-orcid":false,"given":"Sylvain","family":"Lehmann","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susanna","family":"Schraen-Maschke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luc","family":"Bu\u00e9e","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean-S\u00e9bastien","family":"Vidal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Constance","family":"Delaby","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christophe","family":"Hirtz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fr\u00e9d\u00e9ric","family":"Blanc","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claire","family":"Paquet","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bernadette","family":"Allinquant","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"St\u00e9phanie","family":"Bombois","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Audrey","family":"Gabelle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olivier","family":"Hanon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"for the Alzheimer\u2019s Disease Neuroimaging Initiative (ADNI)","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,10,8]]},"reference":[{"key":"755_CR1","doi-asserted-by":"publisher","first-page":"535","DOI":"10.1016\/j.jalz.2018.02.018","volume":"14","author":"CR Jack","year":"2018","unstructured":"Jack CR, Bennett DA, Blennow K, Carrillo MC, Dunn B, Haeberlein SB, Holtzman DM, Jagust W, Jessen F, Karlawish J, et al. 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