- Plasma phosphorylated tau-217 is elevated in tuberous sclerosis complex at younger ages, showing age-related trajectories comparable to Alzheimer disease.
- Findings indicate amyloid-independent tauopathy in TSC, supporting shared downstream neurodegenerative pathways with Alzheimer disease.
- Plasma ptau-217 could serve as a minimally invasive biomarker to stratify TAND severity and guide mTOR-targeted therapeutic strategies.
medRxiv [Preprint]. 2026 Sep 11:2026.09.09.26362677. doi: 10.64898/2026.09.09.26362677.
ABSTRACT
BACKGROUND: Tuberous sclerosis complex (TSC) is a rare autosomal dominant neurodevelopmental disorder caused by loss-of-function mutations in TSC1 or TSC2 , 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’s disease (AD). Prior neuropathological studies have shown accumulation of AD-type mixed 3R/4R tau isoforms in adults with TSC that is amyloid-independent.
METHODS: 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.
RESULTS: 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 2 ptau-217 concentrations were significantly lower in the CU cohort relative to TSC (β = -0.21, SE = 0.05, p < 0.0001) but were not significantly different between the TSC and AD cohorts (β = 0.17, SE = 0.09, p < 0.071). The comparison of slopes analysis (ANCOVA) supported that the slopes for the regression of log 2 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).
CONCLUSIONS: 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.
PMID:42818507 | PMC:PMC13622798 | DOI:10.64898/2026.09.09.26362677
Share Evidence Blueprint
Save to Google Notes
Search Google Scholar
Save as PDF
⭐ My Revision List
