2025
Prognostic value of plasma biomarkers for informing clinical trial design in mild-to-moderate Alzheimer’s disease
Qiu Y, Jacobs D, Messer K, Salmon D, Wellington C, Stukas S, Revta C, Brewer J, Léger G, Askew B, Donahue L, Kaplita S, Coric V, Qureshi I, Feldman H. Prognostic value of plasma biomarkers for informing clinical trial design in mild-to-moderate Alzheimer’s disease. Alzheimer's Research & Therapy 2025, 17: 97. PMID: 40317057, PMCID: PMC12046789, DOI: 10.1186/s13195-025-01745-3.Peer-Reviewed Original ResearchConceptsMild to moderate ADADAS-cog11CDR-SBBaseline plasma NfLAlzheimer's diseasePlasma biomarkersMild-to-moderate Alzheimer's diseasePrognostic valueClinical trialsBaseline NfLPlasma NfLPlacebo-controlled trialCortical volumeConcentrations of plasma biomarkersMethodsPost hoc analysisDesign of clinical trialsClinical outcome dataIncreased ventricular volumeTrial participantsVolumetric MRIBaseline concentrationsEarly disease stagesClinical trial designTrial entry criteriaAD trialsUse of lecanemab and donanemab in the Canadian healthcare system: Evidence, challenges, and areas for future research
Smith E, Phillips N, Feldman H, Borrie M, Ganesh A, Henri-Bhargava A, Desmarais P, Frank A, Badhwar A, Barlow L, Bartha R, Best S, Bethell J, Bhangu J, Black S, Bocti C, Bronskill S, Burhan A, Calon F, Camicioli R, Campbell B, Collins D, Dadar M, DeMarco M, Ducharme S, Duchesne S, Einstein G, Fisk J, Gawryluk J, Grossman L, Ismail Z, Itzhak I, Joshi M, Harrison A, Kröger E, Kumar S, Laforce R, Lanctot K, Lau M, Lee L, Masellis M, Massoud F, Mitchell S, Montero-Odasso M, Barnett K, Nygaard H, Pasternak S, Peters J, Rajah M, Robillard J, Rockwood K, Rosa-Neto P, Seitz D, Soucy J, Trenaman S, Wellington C, Zadem A, Chertkow H, Investigators C. Use of lecanemab and donanemab in the Canadian healthcare system: Evidence, challenges, and areas for future research. The Journal Of Prevention Of Alzheimer's Disease 2025, 12: 100068. PMID: 39893139, PMCID: PMC12184013, DOI: 10.1016/j.tjpad.2025.100068.Peer-Reviewed Original ResearchConceptsCanadian healthcare systemStatistically significant group differencesAlzheimer's diseaseMild cognitive impairmentMild dementiaHealthcare systemStage of mild cognitive impairmentQuality evidenceSignificant group differencesMonoclonal antibody therapyTrial publicationsCerebrospinal fluid analysisCognitive impairmentCanadian ConsortiumGroup differencesPositron emission tomographyAntibody therapyImaging abnormalitiesTreatment populationClinical trialsIndividual patientsReview evidenceClinical relevanceTherapyAmyloid-related imaging abnormalities
2024
Varoglutamstat: Inhibiting Glutaminyl Cyclase as a Novel Target of Therapy in Early Alzheimer’s Disease
Feldman H, Messer K, Qiu Y, Sabbagh M, Galasko D, Turner R, Lopez O, Smith A, Durant J, Lupo J, Revta C, Balasubramanian A, Kuehn-Wache K, Wassmann T, Schell-Mader S, Jacobs D, Salmon D, Léger G, DeMarco M, Weber F. Varoglutamstat: Inhibiting Glutaminyl Cyclase as a Novel Target of Therapy in Early Alzheimer’s Disease. Advances In Alzheimer's Disease 2024 DOI: 10.3233/aiad240007.Peer-Reviewed Original ResearchGlutaminyl cyclasePost-translationallyAlzheimer's diseasePhase 2bEarly phase clinical trialsAmyloid-bCytokine monocyte chemoattractant protein-1Monocyte chemoattractant protein-1Highest tolerated doseLonger-term safetyPhase clinical trialsWeeks of treatmentFirst-in-classTarget of therapyUnique dual mechanismChemoattractant protein-1Interim futility analysisClinical efficacyDisease cascadeProtein 1Electroencephalogram changesOptimal doseClinical trialsAnalysis of cognitive functionHigh dosesPost hoc analysis of ADAMANT, a phase 2 clinical trial of active tau immunotherapy with AADvac1 in patients with Alzheimer’s disease, positive for plasma p-tau217
Kovacech B, Cullen N, Novak P, Hanes J, Kontsekova E, Katina S, Parrak V, Fresser M, Vanbrabant J, Feldman H, Winblad B, Stoops E, Vanmechelen E, Zilka N. Post hoc analysis of ADAMANT, a phase 2 clinical trial of active tau immunotherapy with AADvac1 in patients with Alzheimer’s disease, positive for plasma p-tau217. Alzheimer's Research & Therapy 2024, 16: 254. PMID: 39580468, PMCID: PMC11585249, DOI: 10.1186/s13195-024-01620-7.Peer-Reviewed Original ResearchConceptsClinical Dementia Rating-Sum of BoxesPhase 2 clinical trialGlial fibrillary acidic proteinPost hoc analysisAlzheimer's diseaseAlzheimer's Disease Cooperative Study ActivitiesPlasma p-tau217Clinical Dementia Rating-SumClinical trialsWhole-brain volumeSpread of tau pathologyPlasma biomarkers of neurodegenerationPlasma P-tau217 levelsMicrotubule-binding regionSubgroup of participantsADAMS participantsTau pathologyAD-related neuropathological changesCognitive declineFibrillary acidic proteinActive immunotherapyDouble-blindPlacebo-controlledVolumetric MRITau immunotherapyVaroglutamstat: Inhibiting Glutaminyl Cyclase as a Novel Target of Therapy in Early Alzheimer’s Disease
Feldman H, Messer K, Qiu Y, Sabbagh M, Galasko D, Turner R, Lopez O, Smith A, Durant J, Lupo J, Revta C, Balasubramanian A, Kuehn-Wache K, Wassmann T, Schell-Mader S, Jacobs D, Salmon D, Léger G, DeMarco M, Weber F, Group F. Varoglutamstat: Inhibiting Glutaminyl Cyclase as a Novel Target of Therapy in Early Alzheimer’s Disease. Journal Of Alzheimer’s Disease 2024, 101: s79-s93. PMID: 39422941, PMCID: PMC11494639, DOI: 10.3233/jad-231126.Peer-Reviewed Original ResearchConceptsGlutaminyl cyclasePost-translationallyAlzheimer's diseasePhase 2bEarly phase clinical trialsAmyloid-bCytokine monocyte chemoattractant protein-1Monocyte chemoattractant protein-1Highest tolerated doseLonger-term safetyPhase clinical trialsWeeks of treatmentFirst-in-classTarget of therapyUnique dual mechanismChemoattractant protein-1Interim futility analysisClinical efficacyDisease cascadeProtein 1Electroencephalogram changesOptimal doseClinical trialsAnalysis of cognitive functionHigh dosesA framework for translating tauopathy therapeutics: Drug discovery to clinical trials
Feldman H, Cummings J, Boxer A, Staffaroni A, Knopman D, Rizzo S, Territo P, Arnold S, Ballard C, Beher D, Boeve B, Dacks P, Diaz K, Ewen C, Fiske B, Gonzalez M, Harris G, Hoffman B, Martinez T, McDade E, Nisenbaum L, Palma J, Quintana M, Rabinovici G, Rohrer J, Rosen H, Troyer M, Kim D, Tanzi R, Zetterberg H, Ziogas N, May P, Rommel A. A framework for translating tauopathy therapeutics: Drug discovery to clinical trials. Alzheimer's & Dementia 2024, 20: 8129-8152. PMID: 39316411, PMCID: PMC11567863, DOI: 10.1002/alz.14250.Peer-Reviewed Original ResearchPrimary tauopathiesClinically heterogeneous neurodegenerative diseasesTau protein aggregationHeterogeneous neurodegenerative diseaseSurrogate disease biomarkersTauopathiesProtein aggregationDefinition of rare diseasesAlzheimer's diseaseNeurodegenerative diseasesClinical trialsEarly-phase clinical trialsEarly-phase trialsDisease biomarkersFrontotemporal degenerationDrug developmentProgressive supranuclear palsyDiscovery to clinical trialsSelection of targetsTherapeuticsPharmacodynamic biomarkersA multicenter, randomized, double-blind, placebo-controlled ascending dose study to evaluate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamic (PD) effects of Posiphen in subjects with early Alzheimer’s Disease
Galasko D, Farlow M, Lucey B, Honig L, Elbert D, Bateman R, Momper J, Thomas R, Rissman R, Pa J, Aslanyan V, Balasubramanian A, West T, Maccecchini M, Feldman H. A multicenter, randomized, double-blind, placebo-controlled ascending dose study to evaluate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamic (PD) effects of Posiphen in subjects with early Alzheimer’s Disease. Alzheimer's Research & Therapy 2024, 16: 151. PMID: 38970127, PMCID: PMC11225352, DOI: 10.1186/s13195-024-01490-z.Peer-Reviewed Original ResearchConceptsOrally administered small moleculeFractional synthesis rateAscending dose studyDose-dependent loweringIRB-approved protocolEarly ADMini-Mental State ExamDose-dependent effectAlzheimer's diseaseBlood patchDouble-blindWell-toleratedCatheter placementPreclinical modelsLumbar punctureDose studyIntravenous infusionMild cognitive impairmentEvaluate safetyPlacebo participantsCognitive measuresStable isotope labeling kineticsActive drugClinical trialsADAS-Cog12Protocol for a seamless phase 2A-phase 2B randomized double-blind placebo-controlled trial to evaluate the safety and efficacy of benfotiamine in patients with early Alzheimer’s disease (BenfoTeam)
Feldman H, Luchsinger J, Léger G, Taylor C, Jacobs D, Salmon D, Edland S, Messer K, Revta C, Flowers S, Jones K, Koulman A, Yarasheski K, Verghese P, Venkatesh V, Zetterberg H, Durant J, Lupo J, Gibson G, Group F. Protocol for a seamless phase 2A-phase 2B randomized double-blind placebo-controlled trial to evaluate the safety and efficacy of benfotiamine in patients with early Alzheimer’s disease (BenfoTeam). PLOS ONE 2024, 19: e0302998. PMID: 38809849, PMCID: PMC11135745, DOI: 10.1371/journal.pone.0302998.Peer-Reviewed Original ResearchConceptsPhase 2bPhase 2aRandomized double-blind placebo-controlled trialDouble-blind placebo-controlled trialCo-primary efficacy endpointsTolerability eventsBest-tolerated dosePlacebo-controlled trialWell-tolerated dosesAlzheimer's diseaseLonger-term safetyEfficacy of drug deliveryWeeks of treatmentTargeted therapeutic approachesErythrocyte transketolase activityGroups of participantsDouble-blindPlacebo armEfficacy endpointSecondary endpointsOral treatmentPharmacokinetic measurementsClinical trialsTherapeutic approachesBlood markers
2023
CAN‐THUMBS UP: Recruitment in the Virtual Era
Nygaard H, Slack P, Feldman H, Chertkow H, Belleville S, Montero‐Odasso M, Anderson N, Bennett D, Borrie M, Chan S, Jarrett P, Lee A, Lupo J, Matthews G, McGibbon C, Revta C, Robillard J, Shadyab A, Shajan S. CAN‐THUMBS UP: Recruitment in the Virtual Era. Alzheimer's & Dementia 2023, 19 DOI: 10.1002/alz.075155.Peer-Reviewed Original ResearchMajority of participantsUp StudyModifiable lifestyle risk factorsLifestyle risk factorsHealth support programInteractive educational interventionComprehensive recruitment strategyConclusions RecruitmentDementia literacyClinical trialsRisk factorsSpecialty clinicClinical cohortBasic demographic informationFuture recruitment effortsClinical sitesMedical clinicsSpecific target populationCohortTraditional recruitment methodsDiverse Canadian populationEducational interventionTarget cohortCanadian populationDemographic informationPrognostic value of plasma biomarkers in a clinical trial of mild‐to‐moderate Alzheimer’s Disease
Qiu Y, Messer K, Jacobs D, Salmon D, Kaplita S, Wellington C, Stukas S, Askew B, Brewer J, Brody M, Donahue L, Drake J, Grossman K, Hendrix S, Jicha G, Leger G, Porsteinsson A, Shadyab A, Taylor C, Thomas R, van Dyck C, Zhang J, Coric V, Qureshi I, Feldman H, Group A. Prognostic value of plasma biomarkers in a clinical trial of mild‐to‐moderate Alzheimer’s Disease. Alzheimer's & Dementia 2023, 19 DOI: 10.1002/alz.076047.Peer-Reviewed Original ResearchModerate Alzheimer's diseaseAlzheimer's Disease Cooperative StudyPlasma NfLPlasma biomarkersCDR-SBADAS-cog11Baseline NfLAlzheimer's diseaseMRI outcomesClinical trialsTrial designBaseline biomarker measurementsBaseline plasma biomarkersPlacebo-controlled RCTsClinical trial designOnly significant associationGlobal functionClinical declineClinical outcomesP-tauTotal tauTreatment armsPrognostic valueSignificant treatment effectBiomarker changes
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