Amyloid-Independent Elevation of Plasma phosphorylated tau-217 Tracks Neurodegenerative Risk in Tuberous Sclerosis Complex: Implications for mTOR-Targeted Intervention
Open accessAbstract
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.
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Written from the paper’s full text.
TL;DR
Plasma ptau-217 is elevated in tuberous sclerosis complex (TSC) at younger ages and follows an age-related trajectory similar to Alzheimer’s disease (AD), despite TSC tauopathy being described as amyloid-independent. The authors propose plasma ptau-217 as a minimally invasive biomarker for neurodegenerative risk and mTOR-targeted intervention in TSC.
Key findings
- In 63 TSC, 25 AD, and 116 cognitively unimpaired (CU) participants, log2 ptau-217 was significantly lower in CU than TSC (β = -0.21, SE = 0.05, p < 0.0001) but not significantly different between TSC and AD (β = 0.17, SE = 0.09, p = 0.071).
- Age was significantly associated with log2 ptau-217 (β = 0.04, SE = 0.008, p < 0.0001); sex was not (β = -0.07, SE = 0.07, p = 0.32).
- Slopes of log2 ptau-217 versus age did not differ significantly for TSC vs CU (TSC slope = 0.030, SE = 0.008; CU slope = 0.019, SE = 0.006; p = 0.26) or TSC vs AD (TSC slope = 0.030, SE = 0.01; AD slope = 0.06, SE = 0.03; p = 0.099).
- Propensity-score matched analyses preserved the CU vs TSC difference (β = -0.23, SE = 0.05, p < 0.0001) and the null TSC vs AD comparison (β = 0.18, SE = 0.12, p = 0.14).
Methods
- Retrospective comparison of plasma ptau-217 in 63 genetically confirmed TSC patients (140 blood samples; earliest sample per patient used), 25 AD patients, and 116 CU patients with CSF negative for AD biomarkers. TSC samples came from the TSC Alliance Biosample Repository; AD/CU samples came from the Duke-UNC ADRC.
- Plasma ptau-217 was measured with Quanterix SIMOA HD-X: TSC samples at Duke Molecular Genomics Core using the Quanterix ptau-217 Advantage PLUS kit; AD/CU samples at NCRAD using the Alzpath ptau-217 kit. Values were log2 transformed.
- Main analyses used multivariable linear regression with cohort, age, and sex; ANCOVA comparison of slopes; and 1:1 propensity-score matching (greedy nearest neighbor, caliper 0.25, SMD < 0.20) to balance age and sex. Statistical significance was two-sided p < 0.05; analyses used JMP 19.0.1.
Limitations
- The paper states that chronic kidney disease (CKD) may influence plasma tau concentrations and could contribute to higher baseline ptau-217 in TSC; CKD status was requested but not obtained. It also notes that soluble amyloid could still be present, though prior CSF Aβ42 in TSC was comparable to controls, and that underweight status, anemia, and non-AD tauopathies such as FTD with MAPT variants can affect p-tau levels.
- The paper notes future directions include collecting neuropsychologic testing to determine whether ptau-217 relates to cognitive decline and TAND severity; the current study does not report those cognitive/TAND outcome associations.
- Evident from the text: the study is cross-sectional, uses different ptau-217 assays/kits for TSC versus AD/CU cohorts, and relies on prior neuropathology for the amyloid-independent framing rather than current amyloid measurement in these participants.
Model-written summary. Check it against the paper before relying on it.
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Cites
Statistics
Claims the paper makes
36 of 45 cited sources checked · 13 supported · 1 flagged · accuracy not yet measured
- Premisecitation
Cerebrospinal fluid Aβ42 levels in TSC patients are comparable to those of healthy controls.
“Cerebrospinal fluid analysis of Aβ42levels in TSC patients were found to be comparable to those of healthy controls making soluble forms of amyloid less likely (9).”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [9] 2020, Association of Cognitive and Behavioral Features between Adults with Tuberous Sclerosis and Frontotemporal Dementia, JAMA Neurol source
- Premisecitation
Neurons with heightened mTOR activity, particularly hippocampal CA1 neurons, are selectively predisposed to tau accumulation and degeneration.
“Experimental data further indicate that neurons with heightened mTOR activityparticularly hippocampal CA1 neurons, a region highly vulnerable in AD-are selectively predisposed to tau accumulation and degeneration, implicating mTOR dysregulation as a central upstream driver (14,15).”
Quote in the paperSubstantial claim2 of 2 sources checked- cites [14] source
The CA1 results (page not available in our copy) report increased phos-mTOR, greater tau burden than CA3, and reduced neuronal density in severe AD. The Discussion links CA1 mTOR activation to selective vulnerability, but the experiments do not establish that heightened mTOR activity predisposes neurons to tau accumulation or causes their degeneration; rapamycin did not reduce TSC1-knockdown-related cell death. (LLM, conf=0.86)
Experimental — accuracy not yet measured - cites [15] 2023, Microtubule Cytoskeletal Network Alterations in a Transgenic Model of Tuberous Sclerosis Complex: Relevance to Autism Spectrum Disorders, Int J Mol Sci source
The Discussion reports increased tau levels and phosphorylation in the hippocampus of mice with elevated mTOR signalling, supporting an mTOR–tau link. It does not identify CA1 neurons as selectively predisposed or show that those neurons degenerate; the reported findings concern brain regions and cytoskeletal changes, not selective neuronal degeneration. (LLM, conf=0.87)
Experimental — accuracy not yet measured
- Premisecitation
Flortaucipir is well established to exhibit off-target binding.
“This radioligand is well established to exhibit off-target binding (9, 12, 13).”
Quote in the paperNot a substantial claim2 of 3 sources checked- cites [9] 2020, Association of Cognitive and Behavioral Features between Adults with Tuberous Sclerosis and Frontotemporal Dementia, JAMA Neurol source
- cites [12] source
- cites [13] 2023, Tuberous sclerosis complex is associated with a novel human tauopathy, Acta Neuropathol source
The Introduction mentions focal uptake on flortaucipir PET imaging, and the Discussion mentions a study of AV1451 (flortaucipir) staining. Neither passage addresses off-target binding. Searches for off-target binding and nonspecific tracer uptake found no passage in our copy that establishes the claim. (LLM, conf=0.73)
Experimental — accuracy not yet measured
- Premisecitation
Beginning in mid-to-late adulthood, a subset of individuals with TSC demonstrate cognitive decline that clinically overlaps with Alzheimer's disease dementia.
“Notably, beginning in mid-to-late adulthood, a subset of individuals with TSC demonstrate cognitive decline that clinically overlaps with Alzheimer's disease (AD) dementia (8-10).”
Quote in the paperSubstantial claim2 of 3 sources checked- cites [8] source
The Abstract reports that many patients with TSC experience objectively measured memory and executive-function impairment beginning in their late 40s. The Introduction links significant memory loss to a hypothesis that TSC may resemble the tauopathy seen in AD, but describes the reported clinical overlap as being with frontotemporal dementia; it does not establish clinical overlap with AD dementia. (LLM, conf=0.84)
Experimental — accuracy not yet measured - cites [9] 2020, Association of Cognitive and Behavioral Features between Adults with Tuberous Sclerosis and Frontotemporal Dementia, JAMA Neurol source
The Results (Clinical Phenotyping; page unavailable) describe cognitive difficulties in adults with TSC, and the Discussion reports clinical overlap with frontotemporal dementia (FTD). The paper does not report clinical overlap with Alzheimer’s disease dementia, and it says that whether TSC predisposes to a neurodegenerative disorder requires further study. Its findings therefore support the adult cognitive-symptom portion of the claim, but not the specified Alzheimer’s overlap or an established onset of decline in mid-to-late adulthood. (LLM, conf=0.88)
Experimental — accuracy not yet measured - cites [10] source
- Premisecitation
In CU, amyloid-negative AD populations, correlations between plasma ptau-217 and age are typically modest or absent (correlation coefficients ranging from 0.48 to -0.02).
“In CU, amyloid-negative AD populations, correlations between plasma ptau-217 and age are typically modest or absent (correlation coefficients ranging from 0.48 to -0.02), consistent with limited age-driven change (16,23,24).”
Quote in the paperSubstantial claim3 of 3 sources checked- cites [16] 2024, Diagnostic Accuracy of a Plasma Phosphorylated Tau 217 Immunoassay for Alzheimer Disease Pathology, JAMA Neurol source
The Results sections on longitudinal changes and comparison with other plasma biomarkers (page unavailable) discuss changes by amyloid/tau status and the addition of age to prediction models, but do not report correlations between age and plasma p-tau217 in cognitively unimpaired, amyloid-negative participants. Searches for the stated coefficients (0.48 and −0.02) and for age-related change found no passage establishing the claimed range or limited age-driven change. (LLM, conf=0.75)
Experimental — accuracy not yet measured - cites [23] source
The Results section (‘Longitudinal plasma p-tau217 in different diagnostic groups’; page unavailable) reports that plasma p-tau217 remained stable over time in amyloid-negative cognitively unimpaired participants, consistent with limited longitudinal change. It does not report correlations between p-tau217 and age or the claimed coefficients of 0.48 to −0.02; longitudinal stability is not itself an age-correlation estimate. (LLM, conf=0.78)
Experimental — accuracy not yet measured - cites [24] 2024, Longitudinal plasma phosphorylated-tau217 and other related biomarkers in a non-demented Alzheimer’s risk- enhanced sample, Alzheimer’s Dement source
The Discussion (Aim 1: amyloid-negative CU controls) reports a modest but significant age-related increase in plasma p-tau217, supporting limited age-driven change in this group. The Results (Aim 1) likewise report significant age terms, but give regression estimates rather than the claimed correlation-coefficient range of 0.48 to −0.02; this paper does not support describing its observed association as absent. (LLM, conf=0.86)
Experimental — accuracy not yet measured
- Premisecitation
Neuroimaging studies using tau-specific positron emission tomography radiotracers have demonstrated accumulation of flortaucipir (AV1451) in patients with TSC.
“Neuroimaging studies using tau-specific positron emission tomography radiotracers have demonstrated accumulation of flortaucipir (AV1451) in patients with TSC, a tracer with high affinity for phosphorylated tau 181 (ptau-181) linked to AD.”
Quote in the paperSubstantial claim2 of 3 sources checked - Premisecitation
Neuropathological studies in adults with TSC showed sparse neurofibrillary tangles that stain with both AV1451 and GT-38 in the absence of insoluble amyloid-β deposition.
“Subsequently, complementary neuropathological studies in adults with TSC showed sparse neurofibrillary tangles that stain with both AV1451 and GT-38.GT-38 is an antibody that detects mixed 3R/4R isoforms of tau seen in AD, in the absence of insoluble amyloid-β deposition (8).”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [8] source
- Findingown data
The slopes for regression of log2 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).
“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).”
- Also stated in: § Results · plain
“log 2 ptau-217 versus age are not significantly different for the TSC and CU cohorts (CU slope = 0.019, SE = 0.006; TSC slope = 0.030, SE = 0.008; p = 0.26), nor for the TSC and AD cohorts (AD slope = 0.06, SE = 0.03; TSC slope = 0.030, SE = 0.01; p = 0.099).”
Quote in the paperNot a substantial claim - Also stated in: § Results · plain
- Findingown data
In the study sample, log2 plasma ptau-217 concentrations were not significantly different between the TSC and AD cohorts (β = 0.17, SE = 0.09, p = 0.071, reference TSC).
“Multivariable linear regression showed that the log 2 ptau-217 concentrations were not significantly different between the TSC and AD cohorts (β = 0.17, SE = 0.09, p = 0.071, reference is TSC).”
- Also stated in: § Abstract · plain
“but were not significantly different between the TSC and AD cohorts (β = 0.17, SE = 0.09, p < 0.071).”
Quote in the paperSubstantial claim - Also stated in: § Abstract · plain
- Findingown data
In propensity score matched analysis, the association between log2 ptau-217 and cohort (TSC versus CU) remained significant (β = -0.23, SE = 0.05, p < 0.0001).
“(TSC versus CU) remained significant (β = -0.23,SE = 0.05, p < 0.0001).”
Quote in the paperSubstantial claim - Findingown data
In propensity score matched analysis, the association between log2 ptau-217 and cohort (TSC versus AD) remained not significant (β = 0.18, SE = 0.12, p = 0.14).
“For the propensity score matched analysis, the association between log 2 ptau-217 and cohort (TSC versus AD) remained not significant (β = 0.18, SE = 0.12, p = 0.14).”
Quote in the paperSubstantial claim - Findingown data
The slopes for regression of log2 ptau-217 versus age are not significantly different for the TSC and AD cohorts (TSC slope = 0.030, SE = 0.01; AD slope = 0.06, SE = 0.03; p = 0.099).
“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).”
- Also stated in: § Results · plain
“log 2 ptau-217 versus age are not significantly different for the TSC and CU cohorts (CU slope = 0.019, SE = 0.006; TSC slope = 0.030, SE = 0.008; p = 0.26), nor for the TSC and AD cohorts (AD slope = 0.06, SE = 0.03; TSC slope = 0.030, SE = 0.01; p = 0.099).”
Quote in the paperSubstantial claim - Also stated in: § Results · plain
- Findingown data
In males, slopes for log2 ptau-217 versus age were not significantly different between TSC and CU (CU slope=0.024, SE=0.01; TSC slope=0.035, SE=0.02; p=0.56).
“or for males (TSC versus CU: CU slope = 0.024, SE = 0.01; TSC slope = 0.035, SE = 0.02; p = 0.56; TSC versus AD: AD slope = 0.07, SE = 0.03; TSC slope = 0.04, SE = 0.02; p = 0.24).”
Quote in the paperNot a substantial claim - Findingown data
In the study sample, log2 plasma ptau-217 concentrations were significantly lower in the CU cohort than in the TSC cohort (β = -0.21, SE = 0.05, p < 0.0001, reference TSC).
“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).”
Quote in the paperSubstantial claim - Findingown data
In males, slopes for log2 ptau-217 versus age were not significantly different between TSC and AD (AD slope=0.07, SE=0.03; TSC slope=0.04, SE=0.02; p=0.24).
“or for males (TSC versus CU: CU slope = 0.024, SE = 0.01; TSC slope = 0.035, SE = 0.02; p = 0.56; TSC versus AD: AD slope = 0.07, SE = 0.03; TSC slope = 0.04, SE = 0.02; p = 0.24).”
Quote in the paperNot a substantial claim - Findingown data
Age was significantly associated with log2 ptau-217 concentrations (β = 0.04, SE = 0.008, p < 0.0001).
“Age was significantly associated with log 2 ptau-217 concentrations (β = 0.04, SE = 0.008, p < 0.0001); sex was not significantly associated with log 2 ptau-217 concentrations (β = -0.07,SE = 0.07, p = 0.32, reference is male).”
Quote in the paperNot a substantial claim - Findingown data
Individuals with TSC demonstrated higher plasma ptau-217 levels at younger ages compared to healthy controls.
“Notably, individuals with TSC demonstrated higher ptau-217 levels at younger ages compared to healthy controls, suggesting early emergence of AD-like tau changes.”
Quote in the paperSubstantial claim - Interpretationown data
The higher ptau-217 levels at younger ages in TSC suggest early emergence of AD-like tau changes.
“Notably, individuals with TSC demonstrated higher ptau-217 levels at younger ages compared to healthy controls, suggesting early emergence of AD-like tau changes.”
Quote in the paperSubstantial claim - Study design and conductown data
Propensity score matching based on age and sex reduced standardized mean difference from 1.2 to 0.09 (93% reduction) for TSC versus AD, supporting adequate balance.
“The propensity score matching based on age and sex shows a reduction in standardized mean difference from 1.2 to 0.09, a 93% reduction, supporting adequate balance for these variables.”
Quote in the paperSubstantial claim - Interpretationreasoning
Hyperactivation of the mTOR pathway is responsible for the accumulation of ptau-217.
“This also suggests that hyperactivation of the mTOR pathway is responsible for the accumulation of ptau-217.”
Quote in the paperNot a substantial claim - Interpretationown data
The age-associated increase observed in the TSC cohort suggests that ptau-217 may have comparable utility for identifying individuals with TSC at heightened risk for cognitive decline.
“The age-associated increase observed in our TSC cohort suggests that ptau-217 may have comparable utility for identifying individuals with TSC at heightened risk for cognitive decline.”
Quote in the paperSubstantial claim - Interpretationreasoning
These results support the potential utility of ptau-217 as a tool to guide new mTOR-targeted therapeutic strategies.
“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.”
Quote in the paperNot a substantial claim
- May combine two claims. 21
- Classified as probably not a substantial claim. 8
May combine two claims.
PremisecitationTSC is a distinct tauopathy characterized by AD-type mixed 3R/4R tau isoforms and absence of amyloid-β deposition.
“Prior neuropathological studies have shown accumulation of AD-type mixed 3R/4R tau isoforms in adults with TSC that is amyloid-independent.”
- Also stated in: § Background · boosted
“Collectively, these findings support the classification of TSC as a distinct tauopathy, characterized by widespread neurofibrillary tangle deposition across cortical, limbic, and subcortical regions.Although these tangles share key biochemical features with AD, including mixed 3R/4R tau isoforms, they display distinct post-translational modifications, regional distributions, and an amyloid-indepen”
Quote in the paperSubstantial claim2 of 2 sources checked- cites [8] source
- cites [13] 2023, Tuberous sclerosis complex is associated with a novel human tauopathy, Acta Neuropathol source
The Discussion says TSC tauopathy occurs without amyloid-beta deposition, supporting that part of the claim. But it distinguishes TSC tauopathy from AD: AD has a balanced 3R/4R pattern, whereas TSC tauopathy has more 3R than 4R tau. Calling its isoform pattern AD-type is therefore contrary to the paper. (LLM, conf=0.88)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measured
- Also stated in: § Background · boosted
May combine two claims.
PremisecitationElevated cerebrospinal fluid p-tau levels are observed in frontotemporal dementia associated with MAPT variants, and comparable cerebrospinal fluid p-tau levels have been reported in TSC and frontotemporal dementia cohorts.
“Elevated cerebrospinal fluid p-tau levels are also observed in frontotemporal dementia (FTD) associated with MAPT variants, and comparable CSF p-tau levels have been reported in TSC and FTD cohorts, suggesting that increased p-tau is not exclusively specific to AD pathology (9).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [9] 2020, Association of Cognitive and Behavioral Features between Adults with Tuberous Sclerosis and Frontotemporal Dementia, JAMA Neurol source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationCKD prevalence in TSC ranges from approximately 12-13% in pediatric populations to 20-40% in adults.
“CKD prevalence in TSC ranges from approximately 12-13% in pediatric populations to 20-40% in adults, underscoring the importance of accounting for renal function in future biomarker studies (30)(31)(32).”
Quote in the paperNot a substantial claim2 of 3 sources checked- cites [30] source
- cites [31] source
Table 5 and the kidney-complications section report CKD or kidney insufficiency in 12.3% (10/81) of children with available eGFR estimates, supporting the pediatric figure for this cohort. The paper does not report the claimed 20–40% adult CKD prevalence; its Discussion instead says the precise proportion of TSC patients with CKD remains unclear. Page numbers were not available in our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measured - cites [32] 2020, Renal Manifestations of Tuberous Sclerosis Complex : Key Findings From the Final Analysis of the TOSCA Study Focussing Mainly on Renal Angiomyolipomas, Front Neurol
Not checked in the free run.
May combine two claims.
PremisecitationPtau-217 is a sensitive and specific marker of early AD pathology.
“Ptau-217 is a sensitive and specific marker of early AD pathology, localizes to neurofibrillary tangles and neuropil threads, and correlates strongly with brain tau burden (16)(17)(18)(19)(20).”
- Also stated in: § Abstract · plain
“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.”
Quote in the paperSubstantial claim2 of 3 sources checked- cites [16] 2024, Diagnostic Accuracy of a Plasma Phosphorylated Tau 217 Immunoassay for Alzheimer Disease Pathology, JAMA Neurol source
- cites [17] source
The Results (Presence of brain p-tau217 in Cohort 2; page not available) report higher brain p-tau217 in high-likelihood AD than in PART or non-AD tauopathies, supporting an association with AD pathology. The Discussion (page not available) describes this association as only “somewhat selective” and notes that the intermediate-AD group did not differ significantly from other groups. The paper does not establish that p-tau217 is a sensitive and specific marker of early AD pathology. (LLM, conf=0.84)
Experimental — accuracy not yet measured - cites [18] 2023, Localization, induction, and cellular effects of tau phosphorylated at threonine 217, Alzheimer’s Dement source
- Also stated in: § Abstract · plain
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationIndividuals with TSC commonly experience a wide spectrum of cognitive, behavioral and psychiatric symptoms collectively known as Tuberous Sclerosis Complex Associated Neuropsychiatric Disorders (TAND).
“Individuals with TSC commonly experience a wide spectrum of cognitive, behavioral and psychiatric symptoms collectively known as Tuberous Sclerosis Complex Associated Neuropsychiatric Disorders (TAND) (5).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [5] source
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationPlasma ptau-217 has repeatedly demonstrated strong prognostic performance and generally outperforms other plasma biomarkers in predicting conversion from MCI to dementia.
“Plasma ptau-217 has repeatedly demonstrated strong prognostic performance and generally outperforms other plasma biomarkers in predicting conversion from MCI to dementia (20,24).”
Quote in the paperNot a substantial claim1 of 2 sources checked- cites [20] 2021, Comparison of Plasma Phosphorylated Tau Species with Amyloid and Tau Positron Emission Tomography, Neurodegeneration, Vascular Pathology, and Cognitive Outcomes, JAMA Neurol source
- cites [24] 2024, Longitudinal plasma phosphorylated-tau217 and other related biomarkers in a non-demented Alzheimer’s risk- enhanced sample, Alzheimer’s Dement source
The Discussion (Aim 3; page unavailable) reports that p-tau217 had the strongest associations with cognitive decline among the plasma biomarkers studied. The Methods (Statistical analyses; page unavailable) specify that this analysis began with cognitively unimpaired participants and examined cognitive trajectories, not conversion from MCI to dementia. The paper therefore supports the broader prognostic comparison but not the claimed MCI-to-dementia outcome. (LLM, conf=0.87)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationUnderweight status and anemia have been reported to influence plasma ptau-217 independent of amyloid status.
“Additional biological factors, including underweight status and anemia, have been reported to influence plasma ptau-217 independent of amyloid status (26).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [26] source
May combine two claims.
PremisecitationAmyloid positivity in AD patients is associated with substantially accelerated increases in ptau-217, with prospective longitudinal studies demonstrating a six-fold higher annual increase in plasma ptau-217 in amyloid-positive versus amyloid-negative individuals.
“In contrast, amyloid positivity in AD patients is associated with substantially accelerated increases in ptau-217, with prospective longitudinal studies demonstrating a six-fold higher annual increase in plasma ptau-217 in amyloid-positive versus amyloid-negative individuals (16,23,26).”
Quote in the paperNot a substantial claim3 of 3 sources checked- cites [16] 2024, Diagnostic Accuracy of a Plasma Phosphorylated Tau 217 Immunoassay for Alzheimer Disease Pathology, JAMA Neurol source
Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measured - cites [23] source
- cites [26] source
Split into 2 atoms — 0 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 1 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measured
May combine two claims.
PremisecitationPtau-217 localizes to neurofibrillary tangles and neuropil threads and correlates strongly with brain tau burden.
“Ptau-217 is a sensitive and specific marker of early AD pathology, localizes to neurofibrillary tangles and neuropil threads, and correlates strongly with brain tau burden (16)(17)(18)(19)(20).”
Quote in the paperSubstantial claim2 of 3 sources checked- cites [16] 2024, Diagnostic Accuracy of a Plasma Phosphorylated Tau 217 Immunoassay for Alzheimer Disease Pathology, JAMA Neurol source
The Results (Accuracy in Discriminating Abnormal Aβ and Tau Pathologies; page not provided) report that plasma p-tau217 predicts abnormal tau-PET signal and increases across tau-PET–defined Braak stages, supporting an association with brain tau burden. Our copy does not establish that p-tau217 localizes to neurofibrillary tangles or neuropil threads, and the reported passages do not quantify the correlation as strong. (LLM, conf=0.85)
Experimental — accuracy not yet measured - cites [17] source
- cites [18] 2023, Localization, induction, and cellular effects of tau phosphorylated at threonine 217, Alzheimer’s Dement source
Classified as probably not a substantial claim. May combine two claims.
PremisecitationPlasma ptau-217 changes are detectable in preclinical stages and predictive of progression to mild cognitive impairment and AD dementia in a dose-dependent relationship.
“These changes are detectable in preclinical stages and predictive of progression to mild cognitive impairment (MCI) and AD dementia in a dose-dependent relationship (16,23,27).”
Quote in the paperSubstantial claim3 of 3 sources checked- cites [16] 2024, Diagnostic Accuracy of a Plasma Phosphorylated Tau 217 Immunoassay for Alzheimer Disease Pathology, JAMA Neurol source
The Methods and Results (page numbers unavailable) include participants without cognitive impairment and show that plasma p-tau217 levels and rates of increase differ by amyloid and tau status. However, the longitudinal analysis examines biomarker changes, not whether p-tau217 predicts progression to MCI or AD dementia; its stepwise relationship is with pathology status, not clinical progression. (LLM, conf=0.88)
Experimental — accuracy not yet measured - cites [23] source
The Results (Longitudinal plasma p-tau217 in different diagnostic groups; page unavailable) show increasing p-tau217 in amyloid-β+ cognitively unimpaired participants and higher baseline levels in MCI patients who later developed Alzheimer’s disease dementia; a Cox analysis also links p-tau217 to dementia-conversion risk. The paper does not establish that p-tau217 predicts progression from the preclinical stage to MCI, or a dose-dependent relationship for progression through both MCI and dementia. (LLM, conf=0.86)
Experimental — accuracy not yet measured - cites [27] source
The Introduction reports that plasma p-tau217 predicts Aβ pathology in asymptomatic stages, supporting the preclinical-detection portion. The Discussion states that this study did not include plasma p-tau217 and that longitudinal studies are needed to assess whether its biomarkers predict cognitive impairment. It does not establish dose-dependent prediction of progression to MCI or AD dementia. Page numbers are unavailable in our copy. (LLM, conf=0.87)
Experimental — accuracy not yet measured
May combine two claims.
PremisecitationTSC is a rare autosomal dominant neurodevelopmental disorder caused by loss-of-function mutations in TSC1 or TSC2, resulting in chronic hyperactivation of the mTOR pathway.
“Tuberous sclerosis complex (TSC) is a rare autosomal dominant neurodevelopmental disorder caused by loss-of-function mutations in the TSC1 or TSC2 genes, which encode the proteins hamartin and tuberin (1).”
- Also stated in: § Abstract · plain
“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.”
Quote in the paperSubstantial claim1 of 2 sources checked- cites [1] source
The Introduction (page not provided) describes TSC as rare and identifies TSC1 and TSC2 as its two causative genes. Genetic diagnostic criteria (page not provided) describe pathogenic mutations that prevent protein synthesis or inactivate protein function. The cited passages do not establish the verbatim citing sentence’s autosomal-dominant classification or identify the proteins as hamartin and tuberin; the supplied paraphrase additionally mentions mTOR hyperactivation, which the retrieved passages do not address. (LLM, conf=0.84)
Experimental — accuracy not yet measured - cites [2] source
- Also stated in: § Abstract · plain
May combine two claims.
PremisecitationCerebrospinal fluid analyses in TSC participants demonstrated elevated ptau-181 and neurofilament light chain, consistent with ongoing neurodegeneration due to AD pathology.
“Cerebrospinal fluid analyses in TSC participants further demonstrated elevated ptau-181 and neurofilament light chain, consistent with ongoing neurodegeneration due to AD pathology (9).”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [9] 2020, Association of Cognitive and Behavioral Features between Adults with Tuberous Sclerosis and Frontotemporal Dementia, JAMA Neurol source
The Results (Cerebrospinal Fluid Biomarkers; page unavailable) report significantly higher CSF P-tau in participants with TSC than in healthy controls. They say the NfL comparison was underpowered to show a significant difference, while the Results (Investigational Tau-PET Imaging Biomarker; page unavailable) report negative amyloid PET scans in the three TSC participants tested. The paper does not establish ongoing neurodegeneration due to Alzheimer disease pathology. (LLM, conf=0.90)
Experimental — accuracy not yet measured
May combine two claims.
PremisecitationChronic kidney disease is associated with increased plasma p-tau levels independent of age or AD pathology, likely reflecting reduced peripheral clearance rather than increased central production, as cerebrospinal fluid tau does not show parallel elevations.
“CKD, which is common in TSC, has been associated with increased plasma p-tau levels independent of age or AD pathology, likely reflecting reduced peripheral clearance rather than increased central production, as cerebrospinal fluid tau does not show parallel elevations (26,28).”
Quote in the paperNot a substantial claim2 of 2 sources checked- cites [26] source
Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measured - cites [28] source
Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measured
May combine two claims.
Study design and conductcitationA power analysis from previous work based on cerebrospinal fluid ptau-181 levels in TSC indicated that 40 participants would be sufficient to detect group differences; the study included 63 individuals with TSC.
“A power analysis from our previous work based on cerebrospinal fluid ptau-181 levels in TSC indicated that 40 participants would be sufficient to detect group differences (9); our study included 63 individuals with TSC.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [9] 2020, Association of Cognitive and Behavioral Features between Adults with Tuberous Sclerosis and Frontotemporal Dementia, JAMA Neurol source
The Methods and Results describe measuring CSF phosphorylated tau181 in 7 participants with TSC, but do not report a power analysis or say that 40 participants would suffice to detect group differences. Searches for the power analysis and sample-size threshold found no supporting passage. The citing sentence presents its 63 participants as the citing study’s own sample, not as a figure attributed to this source. (LLM, conf=0.75)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing).
Findingown dataSex was not significantly associated with log2 ptau-217 concentrations (β = -0.07, SE = 0.07, p = 0.32, reference male).
“Age was significantly associated with log 2 ptau-217 concentrations (β = 0.04, SE = 0.008, p < 0.0001); sex was not significantly associated with log 2 ptau-217 concentrations (β = -0.07,SE = 0.07, p = 0.32, reference is male).”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationChronic mTOR hyperactivation exerts broad downstream effects relevant to neurodegeneration, including impaired autophagy, synaptic dysfunction, oxidative stress, neuroinflammation, and abnormal protein aggregation.
“Regarding the pathogenesis, chronic mTOR hyperactivation exerts broad downstream effects relevant to neurodegeneration, including impaired autophagy, synaptic dysfunction, oxidative stress, neuroinflammation, and abnormal protein aggregation (11).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [11] 2025, Dysregulated mTOR signaling in Alzheimer’s disease: Linking pathogenic mechanisms to emerging therapeutic strategies, J Alzheimer’s Dis
Not checked in the free run.
May combine two claims.
InterpretationreasoningThe increase in plasma ptau-217 and absence of amyloid plaque in TSC brain tissue suggests that ptau-217 accumulation may occur independently of amyloid deposition.
“The increase in plasma ptau-217 and absence of amyloid plaque in TSC brain tissue participants suggests that ptau-217 accumulation may occur independently of amyloid deposition.”
Quote in the paperSubstantial claimMay combine two claims.
Study design and conductown dataPost-matching covariates were balanced: mean age TSC 62.8 (SD 8.1) versus AD 63.3 (SD 8.5); sex was 57% female in both cohorts.
“Examination of the covariates post-matching confirmed strong balance with mean age for the TSC group at 62.8 years (SD = 8.1) versus 63.3 years (SD = 8.5) for the AD group; sex was balanced at 57% female for both cohorts.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S2 (checkable), S4 (based).
InterpretationreasoningIdentifying mTOR pathway biomarkers has the potential to discover new therapeutics such as FDA approved mTOR inhibitors for both TSC and AD patients.
“Identifying mTOR pathway biomarkers also has the potential to discover new therapeutics such as FDA approved mTOR inhibitors for both TSC and AD patients.”
Quote in the paperNot a substantial claimMay combine two claims.
Study design and conductown dataThe three cohorts were well matched for age, sex, and race, reducing potential demographic confounding.
“The three cohorts were well matched for age, sex, and race, reducing potential demographic confounding.”
Quote in the paperNot a substantial claimMay combine two claims.
Interpretationown dataThese results suggest a novel link between TSC and AD that substantiates shared downstream neurodegenerative pathways.
“These results suggest a novel link between TSC and AD that substantiates shared downstream neurodegenerative pathways.”
- Also stated in: § Conclusion · hedged
“These results support the hypothesis of partially overlapping neurodegenerative pathways and suggest that plasma ptau-217 may serve as a minimally invasive biomarker for TAND, neurodegenerative risk stratification, and AD-like prognostication in TSC.”
Quote in the paperSubstantial claim- Also stated in: § Conclusion · hedged
May combine two claims.
Interpretationown dataTSC may represent a genetically mediated tauopathy with downstream features overlapping those of an amyloid-independent AD pathology.
“Collectively, these findings suggest that TSC may represent a genetically mediated tauopathy with downstream features overlapping those of an amyloid-independent AD pathology.”
Quote in the paperSubstantial claimMay combine two claims.
Study design and conductown dataPropensity score matching based on age and sex reduced standardized mean difference from 0.27 to 0.15 (42% reduction) for TSC versus CU, supporting adequate balance.
“The propensity score matching based on age and sex shows a reduction in standardized mean difference from 0.27 to 0.15, a 42% reduction, supporting adequate balance for these variables.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductown dataResidual plots did not show systematic lack of fit by predicted Y values; leverage plots did not show systematic lack of fit by values of the covariates.
“Residual plots did not show systematic lack of fit by predicted Y values; leverage plots did not show systematic lack of fit by values of the covariates.”
- Also stated in: § Strengths of this study include the relatively large TSC sample and cohort matching. A power · hedged
“Moreover, the residual plots did not show a systemic lack of fit suggesting that our current statistical model is appropriate.”
Quote in the paperNot a substantial claim- Also stated in: § Strengths of this study include the relatively large TSC sample and cohort matching. A power · hedged
May combine two claims.
Interpretationown dataThese results support the potential utility of ptau-217 as a minimally invasive biomarker for TAND severity, neurodegenerative risk, and AD-like prognosis in TSC.
“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.”
- Also stated in: § Conclusion · hedged
“These results support the hypothesis of partially overlapping neurodegenerative pathways and suggest that plasma ptau-217 may serve as a minimally invasive biomarker for TAND, neurodegenerative risk stratification, and AD-like prognostication in TSC.”
Quote in the paperSubstantial claim- Rests on an assumption: Plasma ptau-217 levels in TSC reflect brain tau pathology and neurodegeneration and can serve as a biomarker for TAND severity and neurodegenerative risk.
- Also stated in: § Conclusion · hedged
May combine two claims.
Study design and conductown dataPost-matching covariates were balanced: mean age TSC 55.2 (SD 9.9) versus CU 53.6 (SD 9.8); sex was 60% female in both cohorts.
“Examination of the covariates post-matching confirmed strong balance with mean age for the TSC group at 55.2 years (SD = 9.9) versus 53.6 years (SD = 9.8) for the CU group; sex was balanced at 60% female for both cohorts.”
Quote in the paperSubstantial claim
The paper relies on this without support.
Plasma ptau-217 levels in TSC reflect brain tau pathology and neurodegeneration and can serve as a biomarker for TAND severity and neurodegenerative risk.
“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.”
“Ptau-217 is a sensitive and specific marker of early AD pathology, localizes to neurofibrillary tangles and neuropil threads, and correlates strongly with brain tau burden (16)(17)(18)(19)(20).”
The paper relies on this without support.
Plasma ptau-217 measurements obtained with the Quanterix Advantage PLUS kit in the TSC cohort and the Alzpath ptau-217 kit in the AD and CU cohorts are comparable.
“Plasma ptau-217 measurements used high precision Quanterix SIMOA ptau-217 Advantage PLUS Reagent kit (cat # 104570; lot # 504576; Quanterix Corp., Billerica, MA, USA).”
“In the AD and CU cohorts, plasma ptau-217 samples were run at the National Centralized Repository for Alzheimer's and Related Disease (NCRAD) at Indiana University as part of the Duke-UNC Alzheimer's Disease Research Center (ADRC) standard operating procedure.NCRAD also used the Quanterix HD-X platform to complete these results using the Alzpath ptau-217 kit.”
The paper relies on this without support.
The TSC cohort is representative of the broader TSC population.
“140 blood samples from 63 patients with TSC confirmed by genetic testing were obtained through the TSC Alliance Biosample Repository.”
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Genetic-confirmation claim conflicts with mutation counts
MajorThe text says all 63 TSC patients were confirmed by genetic testing, but Table 2 records only 14 with TSC1 and 29 with TSC2 mutations. Even if those groups do not overlap, they account for at most 43 of the 63 patients.
“140 blood samples from 63 patients with TSC confirmed by genetic testing were obtained through the TSC Alliance Biosample Repository.”
“| TSC1 | 14 (22.2) | 36 (57.1) | 13 (20.6) | | TSC2 | 29 (46.0) | 22 (34.9) | 12 (19.0) |”
Age differences contradict the claim that cohorts were well matched
MinorThe paper describes the three cohorts as well matched for age, but Table 1 reports mean ages of 53.1, 57.4, and 64.8 years, with significant differences in both comparisons against TSC.
“The three cohorts were well matched for age, sex, and race, reducing potential demographic confounding.”
“| Age (Mean, SD) | 57.4 (9.7) | 64.8 (8.5) 53.1 (9.9) | 0.006 <0.0001 | | |”
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Dysregulated mTOR signaling in Alzheimer’s disease: Linking pathogenic mechanisms to emerging therapeutic strategies
(2025) · J Alzheimer’s Dis
UnresolvedPlasma Biomarker Profile and Clinical Correlations in Adult Patients with Tuberous Sclerosis Complex
(2023) · Neurology
UnresolvedRenal Manifestations of Tuberous Sclerosis Complex : Key Findings From the Final Analysis of the TOSCA Study Focussing Mainly on Renal Angiomyolipomas
(2020) · Front Neurol
Unresolved
Flagged first, then by citations
3 of the 34 references couldn’t be matched to a known paper.
- Authors
- Baumel, J., Lutz, M., Ding, C., Capal, J., Ritter, D., Krueger, D., Salter, A., Werner, K., & Liu, A. J.
- Affiliations
- Duke University (US)
- Cincinnati Children's Hospital Medical Center (US)
- Corresponding author
- Liu, Andy J.
- Venue
- medRxiv
- Publisher
- openRxiv
- Published
- 2026-09-11
- PMC
- PMC13622798
- OpenAlex
- W7212360312
- Cited by
- 0
- References
- 34
- Type
- posted content
- Language
- en
- Open access
- green
- doi.org
- Locations
- medRxiv (acceptedVersion)
- PubMed (publishedVersion)
- PubMed Central (submittedVersion)
- Funders
- Ruth K. Broad Foundation (Ann. B. Bussell Award)
- Topics
- Health Sciences › Medicine › Physiology › Tuberous Sclerosis Complex Research
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- tuberous sclerosis complex, phosphorylated tau217, plasma biomarkers, Alzheimer's disease, mTOR signaling, TSC1, TSC2, neurodegeneration, cognitive impairment
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