Senolytic therapy in mild Alzheimer's disease: a phase 1 feasibility trial

May combine two claims.

The senescence stress response allows damaged cells to survive by upregulating senescent cell anti-apoptotic pathways and causes inflammation through the senescence-associated secretory phenotype.

“The senescence stress response allows damaged cells to survive by upregulating senescent cell anti-apoptotic pathways (SCAPs)10 and causes inflammation through their senescence-associated secretory phenotype (SASP)11,12.”

• cites [10] Zhu, Y. I. et al. The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs. Aging Cell 14, 644–658 (2015). sourceSupported
• cites [11] Kritsilis, M. et al. Ageing, cellular senescence and neurodegenerative disease. Int. J. Mol. Sci. 19, 2937 (2018). sourceSupported
• cites [12] Sharma, V., Gilhotra, R., Dhingra, D. & Gilhotra, N. Possible underlying influence of p38MAPK and NF-κB in the diminished anti-anxiety effect of diazepam in stressed mice. J. Pharmacol. Sci. 116, 257–263 (2011). sourceCould not verify

  The Introduction and Discussion address immobilization stress, anxiety, p38MAPK, NF-κB, and nitric oxide signaling in mice, not cellular senescence. Searches for senescent-cell anti-apoptotic pathways and the senescence-associated secretory phenotype found no passage supporting either mechanism; the citation placed after SCAPs is therefore not substantiated by our copy. (LLM, conf=0.76)

  Experimental — accuracy not yet measured

Probably not a substantial claim: may not pass S3 (load-bearing).

SASP factors can spread in a paracrine manner and propagate the senescent phenotype to neighboring cells.

“The SASP comprises cytokines, chemokines, growth factors and extracellular matrix remodeling molecules, which can spread in a paracrine manner and propagate the senescent phenotype to neighboring cells9,13.”

• cites [9] Kirkland, J. L. & Tchkonia, T. Cellular senescence: a translational perspective. EBioMedicine 21, 21–28 (2017). sourcePartly supported

  The Abstract (page unavailable) describes the SASP as secreted cytokines, chemokines, and extracellular matrix-damaging molecules, supporting the sentence’s description of SASP factors. Neither it nor the retrieved Section 3 passages says those factors spread senescence to neighboring cells in a paracrine manner. (LLM, conf=0.83)

  Experimental — accuracy not yet measured
• cites [13] Acosta, J. C. et al. A complex secretory program orchestrated by the inflammasome controls paracrine senescence. Nat. Cell Biol. 15, 978–990 (2013). sourceSupported

May combine two claims.

Other teams confirmed the association between tau and senescence in PS19 mice and effective senescent cell clearance by dasatinib plus quercetin in the Tg(APP/PS1) mouse model.

“Other research teams confirmed the association between tau and senescence in PS19 tau transgenic mice8 and the effective clearance of senescent cells using D + Q in the Tg(APP/PS1) Aβ-producing mouse model19.”

• cites [8] Bussian, T. J. et al. Clearance of senescent glial cells prevents tau-dependent pathology and cognitive decline. Nature 562, 578–582 (2018). sourceSupported
• cites [19] Zhang, P. et al. Senolytic therapy alleviates Aβ-associated oligodendrocyte progenitor cell senescence and cognitive deficits in an Alzheimer’s disease model. Nat. Neurosci. 22, 719–728 (2019). sourceSupported

May combine two claims.

Combined dasatinib and quercetin selectively clear senescent cells in culture, animal models, and humans at specified doses.

“When combined, D + Q has been shown to selectively clear senescent cells in culture (100 nM D + 10 μM Q), in animal models (5 mg kg−1 D + 50 mg kg−1 Q) and humans (100 mg D + 1,000 mg Q) (refs. 9,10,21,25).”

• cites [9] Kirkland, J. L. & Tchkonia, T. Cellular senescence: a translational perspective. EBioMedicine 21, 21–28 (2017). sourcePartly supported

  Section 5 reports that D + Q cleared senescent cells in preclinical mouse studies and retained senolytic effects in vitro. The cited copy does not give the stated culture or animal doses. Section 7 says clinical trials would need to establish whether senolytics reduce senescent-cell numbers in humans; it does not report human clearance at 100 mg D + 1,000 mg Q. Page numbers are unavailable in the indexed copy. (LLM, conf=0.91)

  Experimental — accuracy not yet measured
• cites [10] Zhu, Y. I. et al. The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs. Aging Cell 14, 644–658 (2015). sourcePartly supported

  The Results sections on in-vitro candidates and in-vivo treatment report selective effects in cultured cells at 100 nM dasatinib plus 10 μM quercetin, and reduced senescence markers in mice given 5 mg/kg plus 50 mg/kg. The Discussion (page unavailable) calls the work a first step toward clinical treatment and says further issues must be examined before senolytics are considered for use in humans. This paper does not establish senescent-cell clearance in humans at 100 mg plus 1,000 mg. (LLM, conf=0.93)

  Experimental — accuracy not yet measured
• cites [21] Tchkonia, T. & Kirkland, J. L. Aging, cell senescence, and chronic disease: emerging therapeutic strategies. JAMA 320, 1319–1320 (2018). sourceNot checked — no full text of the source
• cites [25] Ogrodnik, M. et al. Cellular senescence drives age-dependent hepatic steatosis. Nat. Commun. 8, 15691 (2017). sourcePartly supported

  The Results section says D+Q selectively ablates senescent cells in vitro and in vivo, and the Methods (Animals; page unavailable) specify 5 mg/kg dasatinib plus 50 mg/kg quercetin for db/db mice. The copy does not substantiate the stated culture concentrations or show senescent-cell clearance in humans at 100 mg plus 1,000 mg; its human observations concern senescence markers in NAFLD patients, not D+Q treatment. (LLM, conf=0.90)

  Experimental — accuracy not yet measured

May combine two claims.

In the rTg(tauP301L)4510 mouse model, biweekly dasatinib plus quercetin versus placebo reduced cortical neurofibrillary tangle accumulation by 35%, correlated with reduced cortical atrophy and restored cerebral blood flow.

“Using the rTg(tauP301L)4510 transgenic mouse model of tau pathogenesis, we found that biweekly administration of D + Q relative to placebo resulted in a 35% reduction in cortical NFT accumulation, which correlated with reduced cortical brain atrophy and restored aberrant cerebral blood flow6.”

• cites [6] Musi, N. et al. Tau protein aggregation is associated with cellular senescence in the brain. Aging Cell 17, e12840 (2018). sourceSupported

May combine two claims.

Transcriptomic data from postmortem Alzheimer's disease brain tissue and mouse models show senescent cell signatures responsive to dasatinib plus quercetin, associated with neurofibrillary tangle-bearing neurons.

“Transcriptomic data from postmortem human AD brain tissue and AD mouse models revealed senescent cell signatures predicted to be responsive to D + Q therapy (that is, SCAPs), which were specifically associated with neurofibrillary tangle (NFT)-bearing neurons6,7.”

• cites [6] Musi, N. et al. Tau protein aggregation is associated with cellular senescence in the brain. Aging Cell 17, e12840 (2018). sourcePartly supported

  The Results sections on postmortem AD neurons and tau transgenic mice report senescence-like transcriptomic profiles associated with NFTs. The senolytic-treatment Results section reports that dasatinib plus quercetin reduced NFT-containing neurons and an associated senescence gene array in mice. The paper does not say that the transcriptomic signatures themselves predicted responsiveness to that therapy in both human tissue and mouse models. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites [7] Dehkordi, S. K. et al. Profiling senescent cells in human brains reveals neurons with CDKN2D/p19 and tau neuropathology. Nat. Aging 1, 1107–1116 (2021). sourcePartly supported

  The Abstract (page unavailable) reports senescence signatures in transcriptomic data from postmortem human brains and their overlap with neurofibrillary tangle-bearing excitatory neurons. The Methods, “Eigengene analysis” (page unavailable), describes analysis of human RNA-sequencing data; the gene sets included findings from mouse models, but this paper does not report analyzing transcriptomic data from AD mouse models or predicting responsiveness to dasatinib plus quercetin. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

May combine two claims.

The trial was open-label, proof-of-concept, phase I, and single-site.

“As previously described29, the open-label, proof-of-concept, Phase I, single-site pilot study protocol included the completion of 11 study visits over a period of 20–24 weeks (Fig. 1).”

• cites [29] Gonzales, M. M. et al. Senolytic therapy to modulate the progression of Alzheimer’s disease (SToMP-AD): a pilot clinical trial. J. Prev. Alzheimers Dis. 9, 22–29 (2022). sourcePartly supported

  Methods > Study Design (page unavailable) describes this as an open-label pilot and an initial proof-of-concept for a larger phase II trial; it also says all visits will occur at one site. It does not identify SToMP-AD as a phase I trial. The Discussion’s references to phase I trials concern other studies. (LLM, conf=0.85)

  Experimental — accuracy not yet measured

May combine two claims.

Senescent cells accumulate slowly, and periodic clearance is sufficient for health benefits, so continuous treatment is not necessary.

“Senescent cells accumulate slowly, and preclinical studies demonstrate that continuous treatment is not necessary. Instead, periodic clearance of senescent cells is sufficient to exert health benefits (reviewed26).”

• cites [26] Kirkland, J. L. & Tchkonia, T. Senolytic drugs: from discovery to translation. J. Intern. Med. 288, 518–536 (2020). sourceSupported

May combine two claims.

Senolytic treatment uses intermittent dosing because its mechanism is to induce senescent cell death.

“Senolytic treatment follows an intermittent dosing strategy that reflects its mechanism of action, inducing senescent cell death10.”

• cites [10] Zhu, Y. I. et al. The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs. Aging Cell 14, 644–658 (2015). sourceSupported

May combine two claims.

Dasatinib and quercetin were selected because they are among the best-characterized senolytics, target multiple senescent cell anti-apoptotic pathways, and are repurposed, which expedites clinical testing.

“In our study, we selected the combination of D and Q as they are among the best-characterized senolytic agents, target multiple SCAP pathways and are repurposed9,21, expediting clinical testing.”

• cites [9] Kirkland, J. L. & Tchkonia, T. Cellular senescence: a translational perspective. EBioMedicine 21, 21–28 (2017). sourcePartly supported

  Table 1 (Search Strategy and Selection Criteria; page unavailable) lists multiple SCAP pathways targeted by D + Q, and section 5 reports that the drugs were combined because they target different senescent cell types. The review discusses substantial preclinical work on D + Q, consistent with their being well characterized, but the retrieved passages do not say that repurposing these agents expedites clinical testing. (LLM, conf=0.84)

  Experimental — accuracy not yet measured
• cites [21] Tchkonia, T. & Kirkland, J. L. Aging, cell senescence, and chronic disease: emerging therapeutic strategies. JAMA 320, 1319–1320 (2018). sourceNot checked — no full text of the source

May combine two claims.

Intermittent dosing was used because senescent cells across organs, including the brain, typically accumulate over weeks, so drugs need not be continuously present to be effective.

“The intermittent dosing regimen was implemented because senescent cells across organ systems, including the brain, typically accumulate over a period of weeks, suggesting that drugs do not continually need to be present to be effective6,10.”

• cites [6] Musi, N. et al. Tau protein aggregation is associated with cellular senescence in the brain. Aging Cell 17, e12840 (2018). sourcePartly supported

  The Methods (DQ administration; page unavailable) describe intermittent dosing in mice, and the Results (Senolytic treatment reduced NFT burden and neurodegeneration; page unavailable) report that it reduced NFT-containing cortical neurons. The paper does not say senescent cells typically accumulate over weeks across organs, or give that as the reason for intermittent dosing. Its finding supports effectiveness without continuous dosing in this mouse brain model, not a general rule across organ systems. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites [10] Zhu, Y. I. et al. The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs. Aging Cell 14, 644–658 (2015). sourcePartly supported

  The Discussion reports that a single senolytic treatment had effects lasting many weeks after the drugs were gone, supporting the suggestion that continuous drug presence is unnecessary. It does not say that senescent cells across organs, including the brain, typically accumulate over weeks or give that as the reason for intermittent dosing. Page numbers are unavailable in our copy. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

May combine two claims.

Postmortem AD brain tissue has senescent astrocytes, and mouse models show they are cleared with senolytic treatment.

“Furthermore, prior research conducted on postmortem brain tissue from individuals with AD has identified senescent astrocytes16, and mouse models have demonstrated that they are cleared with senolytic treatment8,17.”

• cites [16] Bhat, R. et al. Astrocyte senescence as a component of Alzheimer’s disease. PLoS ONE 7, e45069 (2012). sourceSupported
• cites [8] Bussian, T. J. et al. Clearance of senescent glial cells prevents tau-dependent pathology and cognitive decline. Nature 562, 578–582 (2018). sourcePartly supported

  The citation to this paper is attached to the mouse-model claim, not the preceding claim about postmortem AD tissue. In the main text (Fig. 1; page unavailable), the authors identify senescent astrocytes in PS19 mice and report their clearance with AP in a genetic model. Their senolytic ABT263 experiment (Fig. 4; page unavailable) shows reduced senescence-associated gene expression, but does not directly show that senescent astrocytes were cleared by the drug. (LLM, conf=0.82)

  Experimental — accuracy not yet measured
• cites [17] Chinta, S. J. et al. Cellular senescence is induced by the environmental neurotoxin paraquat and contributes to neuropathology linked to Parkinson’s disease. Cell Rep. 22, 930–940 (2018). sourceSupported

Probably not a substantial claim: may not pass S3 (load-bearing).

A prior retrospective study in adults with CML and normal baseline glucose and lipid levels suggested dasatinib may cause mild increases in glucose, triglycerides, and LDL cholesterol.

“A prior retrospective study conducted in adults with CML and normal baseline glucose and lipid levels suggested that D may cause mild increases in glucose, triglycerides and low-density lipoprotein–cholesterol levels46.”

• cites [46] Yu, L., Liu, J., Huang, X. & Jiang, Q. Adverse effects of dasatinib on glucose–lipid metabolism in patients with chronic myeloid leukaemia in the chronic phase. Sci. Rep. 9, 17601 (2019). sourceSupported

Probably not a substantial claim: may not pass S3 (load-bearing).

Dasatinib has been associated with changes in glucose regulation, including both hyperglycemia and hypoglycemia.

“D has been associated with changes in glucose regulation with reports of both hyperglycemia and hypoglycemia emerging45,46.”

• cites [45] Lundholm, M. D. & Charnogursky, G. A. Dasatinib-induced hypoglycemia in a patient with acute lymphoblastic leukemia. Clin. Case Rep. 8, 1238–1240 (2020). sourcePartly supported

  The Discussion and Case Presentation link dasatinib treatment to hypoglycemia. The Case Presentation also reports hyperglycemia, but it occurred after dasatinib was discontinued and the patient started imatinib; it does not support a report of dasatinib-associated hyperglycemia. Page numbers are unavailable in our copy. (LLM, conf=0.90)

  Experimental — accuracy not yet measured
• cites [46] Yu, L., Liu, J., Huang, X. & Jiang, Q. Adverse effects of dasatinib on glucose–lipid metabolism in patients with chronic myeloid leukaemia in the chronic phase. Sci. Rep. 9, 17601 (2019). sourcePartly supported

  The Results and Discussion report that dasatinib was associated with a higher onset of hyperglycaemia. The Discussion also reports studies in which dasatinib lowered blood glucose or ameliorated hyperglycaemia, but it does not report hypoglycaemia; lowering elevated glucose is not the same as causing low blood glucose. (LLM, conf=0.87)

  Experimental — accuracy not yet measured

Probably not a substantial claim: may not pass S3 (load-bearing).

Dasatinib reaches peak plasma concentrations within two hours after administration in humans.

“In plasma, D has been shown to reach peak concentrations within 2 h of administration36”

• cites [36] Porkka, K. et al. Dasatinib crosses the blood-brain barrier and is an efficient therapy for central nervous system Philadelphia chromosome-positive leukemia. Blood 112, 1005–1012 (2008). sourceCould not verify

  The ‘Dasatinib concentrations in CSF’ section describes patient samples collected about three hours after dosing, but does not establish when plasma concentrations peaked. The plasma pharmacokinetic measurements described elsewhere are from mice. A search for human peak plasma concentration or time to peak found no supporting passage in our copy. (LLM, conf=0.72)

  Experimental — accuracy not yet measured

Probably not a substantial claim: may not pass S3 (load-bearing).

Prior studies report that biomarkers of cellular senescence vary across cell types and inducers.

“Prior studies have reported that biomarkers of cellular senescence vary across cell types and inducers53,54.”

• cites [53] Tuttle, C. S. L. et al. Cellular senescence and chronological age in various human tissues: a systematic review and meta-analysis. Aging Cell 19, e13083 (2020). sourcePartly supported

  The Discussion (page unavailable) reports that the magnitude of senescence differed by tissue or cell type and by the marker used. The Introduction (page unavailable) suggests that different triggers of senescence may explain variation in cells expressing markers, but it does not establish that biomarkers vary across inducers. (LLM, conf=0.84)

  Experimental — accuracy not yet measured
• cites [54] Wiley, C. D. et al. Analysis of individual cells identifies cell-to-cell variability following induction of cellular senescence. Aging Cell 16, 1043–1050 (2017). sourcePartly supported

  The Discussion (page not provided) says that non-genotoxic senescence inducers can produce distinct SASP and gene-expression profiles, supporting variation by inducer. The paper studies variability among individual human fibroblasts, not differences in biomarkers across cell types; that part of the claim is not supported by our copy. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

CSF GFAP is presumed to reflect reactive astrogliosis and shows elevations early in neurodegenerative disease.

“CSF GFAP is presumed to reflect reactive astrogliosis48 and demonstrates elevations early in the neurodegenerative disease process49.”

• cites [48] Lamers, K. J. B. et al. Protein S-100B, neuron-specific enolase (NSE), myelin basic protein (MBP) and glial fibrillary acidic protein (GFAP) in cerebrospinal fluid (CSF) and blood of neurological patients. Brain Res. Bull. 61, 261–264 (2003). sourceNot checked — no full text of the source
• cites [49] Benedet, A. L. et al. Differences between plasma and cerebrospinal fluid glial fibrillary acidic protein levels across the Alzheimer disease continuum. JAMA Neurol. 78, 1471–1483 (2021). sourcePartly supported

  The Results (Plasma GFAP Levels Throughout the AD Continuum) show elevated CSF GFAP in the preclinical AD A+T+ group, supporting an elevation before symptomatic disease. But CSF GFAP was not significantly elevated in the earlier A+T– or low-Aβ groups. The cited finding is specific to AD, not neurodegenerative disease generally; the separate claim about reactive astrogliosis is attached to citation 48. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

May combine two claims.

In preclinical studies, dasatinib prevented intracranial tumor growth, stabilized and regressed CNS disease, indicating CNS action.

“In preclinical studies, D prevented intracranial tumor growth, stabilized and regressed CNS disease indicating its action in the CNS36, suggesting a CNS treatment effect.”

• cites [36] Porkka, K. et al. Dasatinib crosses the blood-brain barrier and is an efficient therapy for central nervous system Philadelphia chromosome-positive leukemia. Blood 112, 1005–1012 (2008). sourceSupported

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Twenty-one participants were screened by phone, eight did not meet eligibility criteria, thirteen completed in-person screening, seven were screen failures, one withdrew before enrollment, and five enrolled.

“A total of 21 participants were screened over the phone, eight of whom did not meet the eligibility criteria (Fig. 2). Thirteen participants completed the in-person screening visit, and of those, seven were screen failures and one withdrew prior to enrollment.”

May combine two claims.

In cerebrospinal fluid, TARC, IL-17A, I-TAC, eotaxin-2, eotaxin, and MIP-1α decreased and IL-6 increased from baseline to post-treatment.

“In CSF, thymus- and activation-regulated chemokine (TARC), IL-17A, I-TAC, eotaxin-2, eotaxin and MIP-1α levels decreased and IL-6 levels increased from baseline to post-treatment (Extended Data Table 3).”

May combine two claims.

The treatment was well-tolerated, with no early discontinuation.

“The treatment was well-tolerated, with no early discontinuation.”

• Also stated in: § Discussion · plain

  “In addition, the intervention was well-tolerated with no premature discontinuation and only three AEs occurring following treatment initiation.”

May combine two claims.

Total cholesterol increased statistically but not clinically from baseline to post-treatment.

“There was a statistically, but not clinically, significant increase in total cholesterol from baseline to post-treatment (baseline: 169.2 ± 35.5 mg dl−1; post-treatment: 179.4 ± 40.0 mg dl−1, t(4) = 2.904, P = 0.044, 95% CI: 0.45–19.95).”

May combine two claims.

Baseline to post-treatment changes in MoCA and CDR sum of boxes were not significant.

“Baseline to post-treatment changes in the prespecified secondary cognitive outcomes, MoCA and CDR sum of boxes (SOB), were not significant (Extended Data Table 1).”

May combine two claims.

There were no significant changes in body mass index, systolic blood pressure, or diastolic blood pressure.

“There were no significant changes in body mass index (BMI; baseline: 23.0 ± 4.3 kg m−2; post-treatment: 22.7 ± 4.2 kg m−2, t(4) = −1.12, P = 0.32, 95% CI: −0.77 to 0.33), systolic blood pressure (baseline: 114.4 ± 11.8 mmHg; post-treatment: 120.4 ± 16.7 mmHg, t(4) = 0.56, P = 0.61, 95% CI: −23.96 to 35.96) or diastolic blood pressure (baseline: 63.8 ± 14.3 mmHg; post-treatment: 67.4 ± 9.2 mmHg, t(”

May combine two claims.

Using an unadjusted P<0.05 cutoff, plasma levels of IL-17E, IL-21, IL-23, IL-17A/F, IL-17D, IL-10, VEGF, IL-31, MCP-2, MIP-1β, and MIP-1α decreased from baseline to post-treatment, while YKL-40 increased.

“Applying the unadjusted P < 0.05 cut-off, plasma levels of IL-17E, IL-21, IL-23, IL-17A/F, IL-17D, IL-10, vascular endothelial growth factor (VEGF), IL-31, MCP-2, macrophage inflammatory protein (MIP)-1β and MIP-1α decreased from baseline to post-treatment, whereas YKL-40 levels increased.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Educational attainment was two participants with high school diplomas, one with some college, and two with college degrees or higher.

“Regarding the highest level of educational attainment, two participants (40%) had high school diplomas, one (20%) had some college and two participants (40%) had college degrees or higher.”

May combine two claims.

Six adverse events occurred; three after intervention, including two mild events (diarrhea and emesis, urinary tract infection) and one moderate event (hypoglycemia).

“A total of six adverse events (AEs) occurred during the course of the study, of which three (two mild: diarrhea and emesis, urinary tract infection; one moderate: hypoglycemia) occurred following the start of the intervention.”

May combine two claims.

Before the intervention, there was one moderate adverse event (fall resulting in hematoma) and two mild adverse events (hematuria and diarrhea).

“Before the start of the intervention, there was one moderate-severity AE (fall resulting in hematoma) and two mild AEs (hematuria and diarrhea).”

May combine two claims.

At baseline, three participants had no detectable plasma quercetin and two had concentrations of 1.09 and 1.73 ng/ml.

“In plasma at baseline, three participants had no detectable Q levels and the other two had concentrations of 1.09 and 1.73 ng ml−1 (LOQ = 1.0 ng ml−1).”

May combine two claims.

No statistically significant treatment changes were observed in cerebrospinal fluid total tau, pTau181, Aβ40, or Aβ42.

“No statistically significant treatment changes were observed; however, there was a trend (t(4) = 2.34, P = 0.0795, 95% confidence interval (CI): −170.6 to 14.6) toward higher Aβ42 levels post-treatment (Fig. 4a–f).”

May combine two claims.

After treatment, dasatinib was detected in cerebrospinal fluid in four of five participants, with levels from 0.281 to 0.536 ng/ml, and the fifth had no detectable levels.

“In CSF, post-treatment D levels were slightly above the limit of quantitation (LOQ = 0.2 ng ml−1) in four of five participants, ranging from 0.281 to 0.536 ng ml−1, and the fifth had no detectable levels.”

May combine two claims.

The five enrolled participants were aged 70-82 years (median 76), 40% female, 80% non-Hispanic White, and 20% Hispanic.

“Five participants (aged 70–82 years, median 76; 40% female, based on self-report; 80% non-Hispanic White, 20% Hispanic) enrolled in the intervention between March 6, 2020, and April 19, 2021.”

May combine two claims.

Paired t-tests of baseline versus post-treatment MRIs showed no significant differences in total brain volume, gray matter or white matter density, or right or left hippocampal volume.

“Paired t-tests of baseline versus post-treatment MRIs revealed no significant differences in total brain volume, gray matter or white matter density or right or left hippocampal volume, indicative of stable brain morphology over the 3-month assessment period (Extended Data Table 2).”

May combine two claims.

The two mild post-intervention adverse events were deemed unlikely related to the study, and the moderate hypoglycemia was deemed possibly related to the intervention.

“The two mild AEs were deemed unlikely related to the study, and the one moderate AE, hypoglycemia, was deemed possibly related to the intervention.”

May combine two claims.

In this study, CSF analyses showed baseline to post-treatment decreases in adaptive immunity markers (TARC, IL-17A, I-TAC, eotaxin, eotaxin-2) and chemokines (MIP-1α); plasma showed similar decreases in adaptive immunity markers (IL-23, IL-21, IL-17, IL-31, VEGF) and chemokines (MIP-1α, MIP-1β).

“CSF analyses indicated baseline to post-treatment decreases in adaptive immunity markers (such as TARC, IL-17A, I-TAC, eotaxin and eotaxin-2) and chemokines (such as MIP-1α). A similar pattern was observed in plasma whereby treatment was associated with a decrease in adaptive immunity markers (such as IL-23, IL-21, IL-17, IL-31 and VEGF 47) and chemokines (such as MIP-1α and MIP-1β).”

May combine two claims.

In this study, quercetin was consistently detected in plasma but not detectable in CSF.

“In our study, Q was consistently measured in plasma across participants. However, unlike D, Q was not detectable in CSF within our sample.”

May combine two claims.

In this study, treatment was well-tolerated with excellent adherence to the study drug regimen.

“In our study, the treatment was well-tolerated with excellent adherence to the study drug regime.”

May combine two claims.

Clinical safety laboratories were generally stable from baseline to post-treatment; one statistically significant change was an increase in total cholesterol, but levels remained normative.

“Clinical safety laboratories were generally stable from baseline to post-treatment. Only one statistically significant change emerged, which was an increase in total cholesterol levels. However, cholesterol levels remained in the normative range.”

May combine two claims.

The Lumipulse assay, but not the Simoa assay, showed a trend toward increased post-treatment Aβ42 levels.

“The results from the Lumipulse assay, but not from the Simoa® assay, showed a trend toward increased post-treatment Aβ42 levels.”

May combine two claims.

In this trial, no changes were observed in total tau, pTau-181, or pTau-231.

“In this trial, we did not observe changes in total tau, pTau-181 or pTau-231”

May combine two claims.

In this study, there were no substantial changes in total brain volume, hippocampal volume, or gray or white matter density from baseline to post-treatment.

“Regarding neuroimaging outcomes, there were no substantial changes in total brain volume, hippocampal volume or gray matter or white matter density from baseline to post-treatment.”

May combine two claims.

In this study, CSF dasatinib concentrations were in a similar range to a prior ALL study, but detectable in 80% (4/5) of participants.

“In our study, we observed a similar range of D concentrations in CSF. However, the detectable levels were more readily observed in our population, occurring in 80% (4/5 individuals) of participants.”

May combine two claims.

In this study, IL-6 in CSF was significantly elevated after treatment; plasma IL-6 modestly increased but did not reach statistical significance.

“The analyses revealed a statistically significant elevation of IL-6 in CSF after treatment. Plasma levels modestly increased but did not reach statistical significance.”

May combine two claims.

In this study, six adverse events occurred, three after treatment initiation; two were mild and common; one participant had hypoglycemia.

“Throughout the study, a total of six AEs occurred, of which three emerged after treatment initiation. Two of these AEs were mild and highly common in the study population. Hypoglycemia was observed in one participant.”

May combine two claims.

Most people with Alzheimer's disease have multiple etiological contributors, so targets beyond amyloid beta and tau may be needed for maximum treatment benefit.

“The majority of individuals with AD present with multiple etiological contributors to dementia5, suggesting that therapeutic targets beyond Aβ and tau neuropathology may be important for maximum treatment benefits.”

• cites [5] Korczyn, A. D. Mixed dementia—the most common cause of dementia. Ann. N. Y. Acad. Sci. 977, 129–134 (2002). sourceNot checked — no full text of the source

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

All participants provided written informed consent, with legal representation for those lacking capacity.

“All participants provided written informed consent with appropriate legal representation for individuals lacking the capacity to consent.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Dasatinib plus quercetin were administered under Investigational New Drug 143945-0006.

“D + Q were administered under Investigational New Drug (IND) 143945–0006 (to N.M.).”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

The study was conducted in adherence with Good Clinical Practice, and the protocol was approved by the institutional review board.

“The study was conducted in adherence with the Guideline for Good Clinical Practice, and the protocol was approved by the UT Health San Antonio Institutional Review Board (IRB).”

Classified as probably not a substantial claim.

Biomarker data provided mechanistic insights into senolytic effects that need confirmation in fully powered placebo-controlled studies.

“Biomarker data provided mechanistic insights of senolytic effects that need to be confirmed in fully powered, placebo-controlled studies.”

• AssumptionRests on an assumption: Changes in cerebrospinal fluid biomarkers over the open-label period reflect senolytic treatment effects rather than natural variation or disease progression.
• AssumptionRests on an assumption: The measured senescence-associated secretory phenotype cytokines and chemokines are valid markers of senolytic target engagement in Alzheimer’s disease.

May combine two claims.

The trial outcomes support the safety, tolerability, and feasibility of dasatinib plus quercetin in patients with Alzheimer's disease.

“In summary, CNS penetrance of D was observed with outcomes supporting safety, tolerability and feasibility in patients with AD.”

May combine two claims.

This study was underpowered and of insufficient duration to comprehensively evaluate neuroimaging outcomes.

“While our study was underpowered and of insufficient duration to provide a comprehensive evaluation of neuroimaging outcomes”

May combine two claims.

In rats given 213 mg/day quercetin, brain homogenate levels reached 41.1 ± 11.11 pmol/g and plateaued after 1 week.

“For example, in a preclinical study of rats that ingested 213 mg of Q per day, Q was detectable in brain homogenates (41.1 ± 11.11 pmol g−1), using HPLC–tandem mass spectrometry, plateauing after 1 week of administration42.”

• cites [42] Ishisaka, A. et al. Accumulation of orally administered quercetin in brain tissue and its antioxidative effects in rats. Free Radic. Biol. Med. 51, 1329–1336 (2011). sourceNot checked — no full text of the source

May combine two claims.

None of the cytokine/chemokine markers would have withstood multiple comparisons correction, and the preliminary findings require replication in studies designed to assess this endpoint.

“It is important to highlight that none of the markers would have withstood multiple comparisons correction, and the preliminary findings require further replication in studies designed to assess this endpoint.”

May combine two claims.

This vanguard study supports safety and tolerability of D and Q in older adults with AD.

“We conclude that our vanguard study supports safety and tolerability of D and Q in older adults with AD.”

May combine two claims.

Extrapolating from sheep data, the assay timepoint in this study should have detected quercetin in CSF, but the expected level would be tenfold below the assay detection limit.

“If we extrapolate these results to our study, we assayed Q at a timepoint where it should have been detected in CSF, but the level would fall tenfold below the detection limits of our assay.”

• cites [44] Wiczkowski, W. et al. Quercetin and isorhamnetin aglycones are the main metabolites of dietary quercetin in cerebrospinal fluid. Mol. Nutr. Food Res. 59, 1088–1094 (2015). sourceNot checked — no full text of the source

• AssumptionRests on an assumption: Sheep CSF pharmacokinetic data for quercetin can be extrapolated to humans in this study.

May combine two claims.

In sheep given 22.19 mg intragastric quercetin, CSF quercetin was detectable within 1 h, peaked at 5.5 h with Cmax 0.30 ± 0.1 nmol/L, about 100-fold lower than plasma.

“In a sheep model, intragastric Q was administered at a dose of 22.19 mg; continuous monitoring of CSF through an implanted brain ventricle cannula demonstrated detectable Q within 1 h of dosing. The highest levels were observed at 5.5 h, Cmax = 0.30 ± 0.1 nmol l−1 (~100-fold less than that detected in matching plasma)44.”

• cites [44] Wiczkowski, W. et al. Quercetin and isorhamnetin aglycones are the main metabolites of dietary quercetin in cerebrospinal fluid. Mol. Nutr. Food Res. 59, 1088–1094 (2015). sourceNot checked — no full text of the source

May combine two claims.

In animal models, oral quercetin produces detectable brain levels and favorable outcomes including reduced oxidative stress, suggesting a CNS therapeutic effect.

“In animal model research, oral administration of Q has resulted in detectable brain levels40 resulting in favorable outcomes including reduced oxidative stress in the brain41,42, suggesting a therapeutic effect in the CNS.”

• cites [40] Wróbel-Biedrawa, D. et al. A flavonoid on the brain: Quercetin as a potential therapeutic agent in central nervous system disorders. Life (Basel) 12, 591 (2022).Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

• cites [41] Sun, S. W. et al. Quercetin attenuates spontaneous behavior and spatial memory impairment in d-galactose-treated mice by increasing brain antioxidant capacity. Nutr. Res. 27, 169–175 (2007). sourceNot checked — no full text of the source
• cites [42] Ishisaka, A. et al. Accumulation of orally administered quercetin in brain tissue and its antioxidative effects in rats. Free Radic. Biol. Med. 51, 1329–1336 (2011). sourceNot checked — no full text of the source

The quote only partly states this claim.

This study was not powered to assess tau outcomes.

“however, the study was not powered to assess these outcomes.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

The increases in GFAP and IL-6 may reflect clearance of senescent astrocytes or an acute inflammatory response to treatment.

“The increases observed in GFAP and IL-6 may reflect the clearance of senescent astrocytes or possibly an acute inflammatory response to treatment.”

May combine two claims.

In culture, quercetin permeates primary brain microvessel endothelial cells and primary astroglia, suggesting blood-brain barrier penetrance.

“In culture, Q has been shown to permeate primary brain microvessel endothelial cells and primary astroglia cells43, suggesting blood–brain barrier penetrance.”

• cites [43] Ren, S. C. et al. Quercetin permeability across blood–brain barrier and its effect on the viability of U251 cells. Sichuan Da Xue Xue Bao Yi Xue Ban 41, 751–754 (2010).Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

May combine two claims.

Quercetin is rapidly metabolized in human intestinal mucosa and liver and has low bioavailability.

“Given that Q is rapidly metabolized in the human intestinal mucosa and liver and it has low bioavailability40”

• cites [40] Wróbel-Biedrawa, D. et al. A flavonoid on the brain: Quercetin as a potential therapeutic agent in central nervous system disorders. Life (Basel) 12, 591 (2022).Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

May combine two claims.

This trial was not designed to evaluate efficacy and had a small sample size and short duration.

“The null findings are not surprising as our trial was not designed to evaluate the efficacy and included small sample size and short duration of treatment.”

Classified as probably not a substantial claim.

If the increased Aβ42 trend is replicated in well-powered efficacy studies, it would potentially suggest beneficial disease modification with senolytic treatment.

“if our findings are replicated in well-powered studies designed to assess efficacy, they would potentially suggest beneficial disease modification with senolytic treatment.”

• cites [51] Andreasen, N. et al. Cerebrospinal fluid β-amyloid(1-42) in Alzheimer disease: differences between early- and late-onset Alzheimer disease and stability during the course of disease. Arch. Neurol. 56, 673–680 (1999). sourceNot checked — no full text of the source

May combine two claims.

This study was designed to evaluate CNS penetrance of D and Q and was not powered to assess target engagement, cognition, or disease modification.

“First, our study was designed to evaluate the CNS penetrance of D and Q. Therefore, it was not powered to assess outcomes related to target engagement, cognition or disease modification.”

May combine two claims.

The short trial duration and lack of a placebo group restrict interpretation of outcomes.

“The short trial duration and lack of a placebo group place further restrictions on interpreting these outcomes.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

The treatment-induced changes in IL-6 may reflect senescent cell apoptosis, either through direct release from lysed senescent cells or through an immune response to clear cellular debris.

“The treatment-induced changes in IL-6 may reflect senescent cell apoptosis whereby IL-6 was directly released from senescent cells upon their lysis; alternatively, apoptosis may have initiated an immune response to clear the cellular debris.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Change in IL-6 was a prespecified secondary outcome.

“Change in IL-6 was a prespecified secondary outcome.”

May combine two claims.

In-clinic administrations on the first day of each cycle enabled careful safety monitoring and likely supported the 100% adherence rate.

“Our study design of in-clinic administrations on the first day of each drug cycle enabled us to carefully monitor participant safety and was likely supportive of our 100% study drug adherence rate.”

Classified as probably not a substantial claim.

The low CSF to plasma ratio of D and absence of Q in CSF may support Phase Ib studies aimed at increasing Q bioavailability and D levels in the CNS.

“The low CSF to plasma ratio of D and absence of Q in CSF may support Phase Ib studies aimed at increasing Q bioavailability (for example, reviewed40) and D levels in the CNS”

• cites [40] Wróbel-Biedrawa, D. et al. A flavonoid on the brain: Quercetin as a potential therapeutic agent in central nervous system disorders. Life (Basel) 12, 591 (2022).Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

May combine two claims.

This study was not powered to examine target engagement; it was designed to collect exploratory data on baseline to post-treatment changes in markers of cellular senescence and SASP in CSF and blood.

“Our study was not powered to examine target engagement, but instead designed to collect exploratory data on baseline to post-treatment changes in markers of cellular senescence and SASP both in CSF and blood.”

Classified as probably not a substantial claim.

The prespecified cognitive outcomes were baseline to post-treatment changes on the MoCA and CDR SOB.

“The prespecified cognitive outcomes of interest were baseline to post-treatment changes on the MoCA31 and CDR SOB30.”

• cites [31] Nasreddine, Z. S. et al. The Montreal Cognitive Assessment, MoCA: a brief screening tool for mild cognitive impairment. J. Am. Geriatr. Soc. 53, 695–699 (2005). sourceNot checked — no full text of the source
• cites [30] Morris, J. C. Clinical dementia rating: a reliable and valid diagnostic and staging measure for dementia of the Alzheimer type. Int. Psychogeriatr. 9, 173–176 (1997). sourceNot checked — no full text of the source

Probably not a substantial claim: may not pass S3 (load-bearing).

Adherence was assessed by total doses completed, counted by clinic administrations, home diary records, and pill bottle review.

“Adherence was assessed by the total number of doses completed, counted by administrations in clinic, home diary records and pill bottle review.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Given the exploratory nature of the pilot study, P values were not corrected for multiple comparisons unless otherwise noted.

“Given the exploratory nature of the pilot study, P values were not corrected for multiple comparisons unless otherwise noted in the text.”

Probably not a substantial claim: may not pass S3 (load-bearing).

The study was monitored by an independent data and safety monitoring board that reviewed safety data annually.

“The study was monitored by an independent data and safety monitoring board, which reviewed the safety data on an annual basis.”