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To capitalize on the temporal order of tau biomarker-abnormality and capture the earliest changes of tau accumulation, we implemented an observational study design to examine longitudinal changes in tau-PET, cortical thickness and cognitive decline in amyloid-\u03b2-positive individuals with elevated CSF p-tau levels (P+) but subthreshold Tau-PET retention (T\u2212). To this end, individuals without dementia (i.e. cognitively unimpaired or mild cognitive impairment, n = 231) were selected from the BioFINDER-2 study. Amyloid-\u03b2-positive (A+) individuals were categorized into biomarker groups based on cut-offs for abnormal CSF p-tau217 and 18F-RO948 (Tau) PET, yielding groups of tau-concordant-negative (A+P\u2212T\u2212; n = 30), tau-discordant (i.e. A+P+T\u2212; n = 48) and tau-concordant-positive (A+P+T+; n = 18) individuals. In addition, 135 amyloid-\u03b2-negative, tau-negative, cognitively unimpaired individuals served as controls. Differences in annual change in regional tau-PET, cortical thickness and cognition between the groups were assessed using general linear models, adjusted for age, sex, clinical diagnosis and (for cognitive measures only) education. Mean follow-up time was \u223c2 years. Longitudinal increase in tau-PET was faster in the A+P+T\u2212 group than in the control and A+P\u2212T\u2212 groups across medial temporal and neocortical regions, with the highest accumulation rates in the medial temporal lobe. The A+P+T\u2212 group showed a slower rate of increase in tau-PET compared to the A+P+T+ group, primarily in neocortical regions. We did not detect differences in yearly change in cortical thickness or in cognitive decline between the A+P+T\u2212 and A+P\u2212T\u2212 groups. The A+P+T+ group, however, showed faster cognitive decline compared to all other groups. Altogether, these findings suggest that the A+P+T\u2212 biomarker profile in persons without dementia is associated with an isolated effect on increased tau-PET accumulation rates but not on cortical thinning and cognitive decline. While this suggests that the tau-discordant biomarker profile is not strongly associated with short-term clinical decline, this group does represent an interesting population for monitoring the effects of interventions with disease-modifying agents on tau accumulation in early Alzheimer\u2019s disease, and for examining the emergence of tau aggregates in Alzheimer\u2019s disease. Further, we suggest updating the AT(N) criteria for Alzheimer\u2019s disease biomarker classification to APT(N).<\/jats:p>","DOI":"10.1093\/brain\/awac329","type":"journal-article","created":{"date-parts":[[2022,9,8]],"date-time":"2022-09-08T13:29:47Z","timestamp":1662643787000},"page":"1580-1591","source":"Crossref","is-referenced-by-count":55,"title":["Phospho-tau with subthreshold tau-PET predicts increased tau accumulation rates in amyloid-positive individuals"],"prefix":"10.1093","volume":"146","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5802-6946","authenticated-orcid":false,"given":"Colin","family":"Groot","sequence":"first","affiliation":[{"name":"Clinical Memory Research Unit, Department of Clinical Sciences in Malm\u00f6, Lund University , 205 02 Malm\u00f6 , Sweden"},{"name":"Alzheimer Center, Amsterdam UMC Location Vumc , 1081 HV Amsterdam , The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7147-0112","authenticated-orcid":false,"given":"Ruben","family":"Smith","sequence":"additional","affiliation":[{"name":"Clinical Memory Research Unit, Department of Clinical Sciences in Malm\u00f6, Lund University , 205 02 Malm\u00f6 , Sweden"},{"name":"Department of Neurology, Sk\u00e5ne University Hospital, Lund University , 222 42 Lund , Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erik","family":"Stomrud","sequence":"additional","affiliation":[{"name":"Clinical Memory Research Unit, Department of Clinical Sciences in Malm\u00f6, Lund University , 205 02 Malm\u00f6 , Sweden"},{"name":"Memory Clinic, Sk\u00e5ne University Hospital , 222 42 Malm\u00f6 , Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexa Pichet","family":"Binette","sequence":"additional","affiliation":[{"name":"Clinical Memory Research Unit, Department of Clinical Sciences in Malm\u00f6, Lund University , 205 02 Malm\u00f6 , Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antoine","family":"Leuzy","sequence":"additional","affiliation":[{"name":"Clinical Memory Research Unit, Department of Clinical Sciences in Malm\u00f6, Lund University , 205 02 Malm\u00f6 , Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anika","family":"Wuestefeld","sequence":"additional","affiliation":[{"name":"Clinical Memory Research Unit, Department of Clinical Sciences in Malm\u00f6, Lund University , 205 02 Malm\u00f6 , Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura E M","family":"Wisse","sequence":"additional","affiliation":[{"name":"Department of Diagnostic Radiology, Lund University , 223 62 Lund , Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sebastian","family":"Palmqvist","sequence":"additional","affiliation":[{"name":"Clinical Memory Research Unit, Department of Clinical Sciences in Malm\u00f6, Lund University , 205 02 Malm\u00f6 , Sweden"},{"name":"Memory Clinic, Sk\u00e5ne University Hospital , 222 42 Malm\u00f6 , Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8885-7724","authenticated-orcid":false,"given":"Niklas","family":"Mattsson-Carlgren","sequence":"additional","affiliation":[{"name":"Clinical Memory Research Unit, Department of Clinical Sciences in Malm\u00f6, Lund University , 205 02 Malm\u00f6 , Sweden"},{"name":"Department of Neurology, Sk\u00e5ne University Hospital, Lund University , 222 42 Lund , Sweden"},{"name":"Wallenberg Center for Molecular Medicine, Lund University , 223 62 Lund , Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7729-1702","authenticated-orcid":false,"given":"Shorena","family":"Janelidze","sequence":"additional","affiliation":[{"name":"Clinical Memory Research Unit, Department of 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