{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T21:19:23Z","timestamp":1792790363223,"version":"4.5.0"},"posted":{"date-parts":[[2026,9,11]]},"group-title":"Neurology","reference-count":34,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T00:00:00Z","timestamp":1789084800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.medrxiv.org\/about\/FAQ#license"}],"funder":[{"award":["P30AG028716"],"award-info":[{"award-number":["P30AG028716"]}],"id":[{"id":"https:\/\/ror.org\/049v75w11","id-type":"ROR","asserted-by":"publisher"}]},{"award":["Biosample Seed Grant"],"award-info":[{"award-number":["Biosample Seed Grant"]}],"id":[{"id":"https:\/\/ror.org\/02gegq725","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Ruth K. Broad Foundation","award":["Ann. B. Bussell Award"],"award-info":[{"award-number":["Ann. B. Bussell Award"]}],"id":[{"id":"https:\/\/ror.org\/03atssj74","id-type":"ROR","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,9,11]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>\n                    Tuberous sclerosis complex (TSC) is a rare autosomal dominant neurodevelopmental disorder caused by loss-of-function mutations in\n                    <jats:italic>TSC1<\/jats:italic>\n                    or\n                    <jats:italic>TSC2<\/jats:italic>\n                    , resulting in chronic hyperactivation of the mechanistic target of rapamycin (mTOR) pathway. TSC patients experience a wide spectrum of cognitive, behavioral, and psychiatric features collectively termed Tuberous Sclerosis Complex Associated Neuropsychiatric Disorders (TAND). Moreover, these patients develop a clinical trajectory in adulthood with clinical and neuropathological features overlapping those of Alzheimer\u2019s disease (AD). Prior neuropathological studies have shown accumulation of AD-type mixed 3R\/4R tau isoforms in adults with TSC that is amyloid-independent.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>To further explore the biological convergence of TSC and AD, this study compared plasma levels of phosphorylated tau-217 (ptau-217), a sensitive and specific marker of early AD pathology, in 63 TSC, 25 AD, and 116 cognitively unimpaired (CU) patients.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>\n                    Findings revealed elevated levels of plasma ptau-217 in individuals with TSC at younger ages with a parallel age-related trajectory between TSC, AD, and CU cohorts. Multivariable linear regression showed that the log\n                    <jats:sub>2<\/jats:sub>\n                    ptau-217 concentrations were significantly lower in the CU cohort relative to TSC (\u03b2 = \u22120.21, SE = 0.05, p &lt; 0.0001) but were not significantly different between the TSC and AD cohorts (\u03b2 = 0.17, SE = 0.09, p &lt; 0.071). The comparison of slopes analysis (ANCOVA) supported that the slopes for the regression of log\n                    <jats:sub>2<\/jats:sub>\n                    ptau-217 versus age are not significantly different for the TSC and CU cohorts (TSC slope = 0.030, SE = 0.008; CU slope = 0.019, SE = 0.006; p = 0.26), nor for the TSC and AD cohorts (TSC slope = 0.030, SE = 0.01; AD slope = 0.06, SE = 0.03; p = 0.099).\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>These results suggest a novel link between TSC and AD that substantiates shared downstream neurodegenerative pathways. Furthermore, these results support the potential utility of ptau-217 as a minimally invasive biomarker for TAND severity, neurodegenerative risk, and AD-like prognosis in TSC and as a tool to guide new mTOR-targeted therapeutic strategies.<\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.09.09.26362677","type":"posted-content","created":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T05:15:23Z","timestamp":1789190123000},"source":"Crossref","is-referenced-by-count":0,"title":["Amyloid-Independent Elevation of Plasma phosphorylated tau-217 Tracks Neurodegenerative Risk in Tuberous Sclerosis Complex: Implications for mTOR-Targeted Intervention"],"prefix":"10.64898","author":[{"given":"Jocelyn","family":"Baumel","sequence":"first","affiliation":[{"name":"Department of Pediatrics, Division of Pediatric Neurology and Developmental Medicine, Duke University School of Medicine, 3000 Erwin Rd., Ste 100, Durham, NC 27705, 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Pediatrics, University of Cincinnati College of Medicine, 3230 Eden Ave., Cincinnati, OH 45267, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7723-3636","authenticated-orcid":false,"given":"David","family":"Ritter","sequence":"additional","affiliation":[{"name":"Department of Neurology, Cincinnati Children\u2019s Hospital Medical Center, 3333 Burnet Ave., Cincinnati, OH 45229, USA"},{"name":"Department of Pediatrics, University of Cincinnati College of Medicine, 3230 Eden Ave., Cincinnati, OH 45267, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7250-7391","authenticated-orcid":false,"given":"Darcy","family":"Krueger","sequence":"additional","affiliation":[{"name":"Department of Neurology, Cincinnati Children\u2019s Hospital Medical Center, 3333 Burnet Ave., Cincinnati, OH 45229, USA"},{"name":"Department of Pediatrics, University of Cincinnati College of Medicine, 3230 Eden Ave., 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