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Designing both observational longitudinal cohorts and clinical trials with novel mAbs in mind is imperative. These studies should capture mAb type, dosing, duration, degree of amyloid clearance, and downstream effects on neurodegeneration to interpret outcomes. Observational cohorts can compare treated and untreated populations, track biomarker trajectories, assess co\u2010pathologies, and evaluate social determinants of health. Future trials must address variability in treatment response, identify resistant subgroups, and include long\u2010term follow\u2010up to assess durability and post\u2010treatment effects. Combination therapy trials should be stage specific, pairing novel agents with mAbs and incorporating broader stratification beyond traditional biomarkers to reflect clinical and pathological heterogeneity. Integrating biological and clinical outcomes, with digital biomarkers and responder\u2010enrichment strategies will enable more precise, mechanism\u2010driven, and individualized therapeutic approaches in AD.<\/jats:p>","DOI":"10.1002\/alz.71829","type":"journal-article","created":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T04:42:24Z","timestamp":1789620144000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Operationalizing Alzheimer's disease trials in the era of targeted therapies"],"prefix":"10.1002","volume":"22","author":[{"given":"Jagan A.","family":"Pillai","sequence":"first","affiliation":[{"name":"Center for Brain Health Cleveland Clinic Neurological Institute  Cleveland Ohio USA"},{"name":"Cleveland Clinic Lerner College of Medicine at Case Western Reserve University  Cleveland Ohio USA"},{"name":"Cleveland Alzheimer's Disease Research Center  Cleveland Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suvarna","family":"Alladi","sequence":"additional","affiliation":[{"name":"Department of Neurology National Institute of Mental Health and Neurosciences (NIMHANS)  Bengaluru India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian S.","family":"Appleby","sequence":"additional","affiliation":[{"name":"Cleveland Alzheimer's Disease Research Center  Cleveland Ohio USA"},{"name":"Departments of Neurology, Psychiatry, and Pathology Case Western Reserve University School of Medicine\/University Hospitals Cleveland Medical Center  Cleveland Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jared Robert","family":"Brosch","sequence":"additional","affiliation":[{"name":"Department of Neurology Indiana University School of Medicine  Indianapolis Indiana USA"},{"name":"Indiana Alzheimer Disease Research Center  Indianapolis Indiana USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristian Steen","family":"Frederiksen","sequence":"additional","affiliation":[{"name":"Department of Clinical Medicine University of Copenhagen  Copenhagen Denmark"},{"name":"Danish Dementia Research Centre Rigshospitalet  Copenhagen Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Douglas","family":"Galasko","sequence":"additional","affiliation":[{"name":"Department of Neurosciences University of California San Diego  San Diego California USA"},{"name":"Shiley\u2010Marcos Alzheimer's Disease Research Center  San Diego California USA"},{"name":"VA San Diego Healthcare System  San Diego California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oscar L.","family":"Lopez","sequence":"additional","affiliation":[{"name":"Department of Neurology Division of Cognitive &amp; 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