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

In the paper

“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.”

What the sources say

• Supported

  Citation 10 is attached to the claim about senescent cell anti-apoptotic pathways, not the SASP inflammation claim cited to references 11 and 12. In Results (‘The senescent transcriptome and anti-apoptotic pathways’), the paper reports upregulation of anti-apoptotic gene sets in senescent cells; the Discussion says these pathways help ensure survival following stress and damage. (LLM, conf=0.93)

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

  Section 2 describes senescence as a response to cellular damage and says senescent cells remain viable. Section 3 describes resistance to apoptosis, including increased expression of anti-apoptotic proteins, while sections 3 and 5 describe SASP factors as pro-inflammatory. (LLM, conf=0.88)

  cites [11] Kritsilis, M. et al. Ageing, cellular senescence and neurodegenerative disease. Int. J. Mol. Sci. 19, 2937 (2018). source
• ?Could 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)

  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). sourceExperimental — accuracy not yet measured

In the paper

“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.”

What the sources say

• Partly 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)

  cites [9] Kirkland, J. L. & Tchkonia, T. Cellular senescence: a translational perspective. EBioMedicine 21, 21–28 (2017). sourceExperimental — accuracy not yet measured
• Supported

  The section “Paracrine senescence is a stable arrest mediated by secreted factors” (page not provided) reports that conditioned medium from senescent cells induced senescence in normal cells, and that nearby cells showed reduced proliferation. “Multiple components of the SASP mediate paracrine senescence” identifies secreted SASP factors involved in that effect. (LLM, conf=0.93)

  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). source

In the paper

“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.”

What the sources say

• Supported

  The citation to this paper is attached to the PS19 tau–senescence association, not the separate D + Q claim, which has its own citation. The main text reports increased senescence-marker expression in PS19 mice at sites of tau pathology; Extended Data Figure 1 also documents senescent-cell accumulation. Page numbers are not provided in our copy. (LLM, conf=0.93)

  cites [8] Bussian, T. J. et al. Clearance of senescent glial cells prevents tau-dependent pathology and cognitive decline. Nature 562, 578–582 (2018). source
• Supported

  The citation to this paper is attached to the D + Q finding in APP/PS1 mice, not the preceding PS19 tau finding. The Results report that D + Q reduced markers of Aβ-plaque-associated senescent cells in APP/PS1 mouse brains, and the Discussion states that it removed senescent cells from the plaque environment. (LLM, conf=0.94)

  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). source

In the paper

“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).”

What the sources say

• Partly 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)

  cites [9] Kirkland, J. L. & Tchkonia, T. Cellular senescence: a translational perspective. EBioMedicine 21, 21–28 (2017). sourceExperimental — accuracy not yet measured
• Partly 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)

  cites [10] Zhu, Y. I. et al. The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs. Aging Cell 14, 644–658 (2015). sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [21] Tchkonia, T. & Kirkland, J. L. Aging, cell senescence, and chronic disease: emerging therapeutic strategies. JAMA 320, 1319–1320 (2018). source
• Partly 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)

  cites [25] Ogrodnik, M. et al. Cellular senescence drives age-dependent hepatic steatosis. Nat. Commun. 8, 15691 (2017). sourceExperimental — accuracy not yet measured

In the paper

“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.”

What the sources say

• Supported

  The Results section reports that biweekly dasatinib plus quercetin reduced NFT-containing cortical neurons by 35% in tauNFT–Mapt0/0 mice. It also reports reduced cortical atrophy and improved aberrant cerebral blood flow, which was no longer statistically different from controls. The Methods identify the P301L tau-expressing rTg4510 line used in the study. (LLM, conf=0.91)

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

In the paper

“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.”

What the sources say

• Partly 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)

  cites [6] Musi, N. et al. Tau protein aggregation is associated with cellular senescence in the brain. Aging Cell 17, e12840 (2018). sourceExperimental — accuracy not yet measured
• Partly 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)

  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). sourceExperimental — accuracy not yet measured

In the paper

“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).”

What the sources say

• Partly 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)

  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). sourceExperimental — accuracy not yet measured

In the paper

“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).”

What the sources say

• Supported

  The Cellular senescence figure caption says a cell can take up to six weeks to become fully senescent and that cells can therefore be removed intermittently rather than through continuous treatment. The experimental-animal section reports that intermittent D + Q was as effective as continuous treatment and produced benefits for bone health in old mice. (LLM, conf=0.92)

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

In the paper

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

What the sources say

• Supported

  The Introduction says the drugs induce apoptosis preferentially in senescent cells. The Discussion links a single treatment’s lasting effects to a reduced senescent-cell burden rather than a need for continued dosing, and proposes intermittent short treatments. The paper presents this as a rationale and experimental approach, not an established clinical schedule. (LLM, conf=0.88)

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

In the paper

“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.”

What the sources say

• Partly 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)

  cites [9] Kirkland, J. L. & Tchkonia, T. Cellular senescence: a translational perspective. EBioMedicine 21, 21–28 (2017). sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [21] Tchkonia, T. & Kirkland, J. L. Aging, cell senescence, and chronic disease: emerging therapeutic strategies. JAMA 320, 1319–1320 (2018). source

In the paper

“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.”

What the sources say

• Partly 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)

  cites [6] Musi, N. et al. Tau protein aggregation is associated with cellular senescence in the brain. Aging Cell 17, e12840 (2018). sourceExperimental — accuracy not yet measured
• Partly 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)

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

In the paper

“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.”

What the sources say

• Supported

  The Discussion (page not provided) reports senescent astrocytes in postmortem brain tissue from patients with AD. The mouse-model and senolytic-treatment claim carries separate citations (8, 17), so it is not attributed to this source. (LLM, conf=0.93)

  cites [16] Bhat, R. et al. Astrocyte senescence as a component of Alzheimer’s disease. PLoS ONE 7, e45069 (2012). source
• Partly 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)

  cites [8] Bussian, T. J. et al. Clearance of senescent glial cells prevents tau-dependent pathology and cognitive decline. Nature 562, 578–582 (2018). sourceExperimental — accuracy not yet measured
• Supported

  The Results section, “Depleting Senescent Cells Abrogates PQ-Induced Neuropathology” (page unavailable), reports that systemic ganciclovir eliminated senescent cells and abrogated senescent astrocyte phenotypes in paraquat-treated p16-3MR mice. This supports the mouse-treatment portion attributed to this source; the postmortem AD-tissue finding is attached to a different citation. The mice in this study modeled paraquat-induced Parkinsonian pathology, not AD. (LLM, conf=0.88)

  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). source

In the paper

“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.”

What the sources say

• Supported

  The Discussion describes this as a retrospective study of CML patients with normal baseline glucose-lipid levels. The Results sections on hyperglycaemia, hypertriglyceridemia and hyper-LDL-cholesterolemia report increases during therapy in the dasatinib cohort; the Results also describe the metabolic abnormalities as mild or intermediate. Page numbers are unavailable in our copy. (LLM, conf=0.92)

  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). source

In the paper

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

What the sources say

• Partly 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)

  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). sourceExperimental — accuracy not yet measured
• Partly 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)

  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). sourceExperimental — accuracy not yet measured

In the paper

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

What the sources say

• ?Could 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)

  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). sourceExperimental — accuracy not yet measured

In the paper

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

What the sources say

• Partly 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)

  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). sourceExperimental — accuracy not yet measured
• Partly 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)

  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). sourceExperimental — accuracy not yet measured

In the paper

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

What the sources say

• ?Not checked — no full text of the sourcecites [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). source
• Partly 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)

  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). sourceExperimental — accuracy not yet measured

In the paper

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

What the sources say

• Supported

  Experiment 2 reports regression of CNS tumors followed by stasis while mice remained on dasatinib. Experiment 3 reports that intracranial tumors regressed to near-undetectable levels and remained so during treatment; measured brain drug concentrations support CNS action. The effects were observed during treatment, not after it stopped. (LLM, conf=0.92)

  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). source

In the paper

“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.”

In the paper

“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).”

In the paper

“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.”

In the paper

“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).”

In the paper

“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).”

In the paper

“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(”

In the paper

“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.”

In the paper

“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.”

In the paper

“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.”

In the paper

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

In the paper

“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).”

In the paper

“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).”

In the paper

“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.”

In the paper

“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.”

In the paper

“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).”

In the paper

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

In the paper

“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).”

In the paper

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

In the paper

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

In the paper

“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.”

In the paper

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

In the paper

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

In the paper

“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.”

In the paper

“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.”

In the paper

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

In the paper

“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.”

In the paper

“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.”

What the sources say

• ?Not checked — no full text of the sourcecites [5] Korczyn, A. D. Mixed dementia—the most common cause of dementia. Ann. N. Y. Acad. Sci. 977, 129–134 (2002). source

In the paper

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

In the paper

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

In the paper

“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).”

In the paper

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

In the paper

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

In the paper

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

In the paper

“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.”

What the sources say

• ?Not checked — no full text of the sourcecites [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). source

In the paper

“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.”

In the paper

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

In the paper

“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.”

What the sources say

• ?Not checked — no full text of the sourcecites [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). source

In the paper

“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.”

What the sources say

• ?Not checked — no full text of the sourcecites [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). source

In the paper

“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.”

What the sources say

• ?Not matched

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

  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 checked — no full text of the sourcecites [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). source
• ?Not checked — no full text of the sourcecites [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). source

In the paper

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

In the paper

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

In the paper

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

What the sources say

• ?Not matched

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

  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).

In the paper

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

What the sources say

• ?Not matched

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

  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).

In the paper

“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.”

In the paper

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

What the sources say

• ?Not checked — no full text of the sourcecites [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). source

In the paper

“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.”

In the paper

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

In the paper

“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.”

In the paper

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

In the paper

“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.”

In the paper

“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”

What the sources say

• ?Not matched

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

  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).

In the paper

“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.”

In the paper

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

What the sources say

• ?Not checked — no full text of the sourcecites [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). source
• ?Not checked — no full text of the sourcecites [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). source

In the paper

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

In the paper

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

In the paper

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