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n=272 early AD (amyloid+ by PET); donanemab 700mg then 1400mg Q4W vs placebo; primary: iADRS at 76 weeks; amyloid PET centiloid; APOE4 stratified.","translation_scope":"human"},{"caveats":["comparator or baseline missing or unclear"],"clinical_trial":false,"comparator_status":"missing_or_unclear","exposure_or_efficacy":"unknown","finding_id":"vf_dc28e2c8084e9f8d","human_data":true,"id":"vcnd_4d943fe9f38dbb52","in_vitro":false,"in_vivo":true,"method":"manual state transition","model_system":"","species":"Homo sapiens","text":"Biogen aducanumab ENGAGE+EMERGE Phase III, halted March 2019, re-analyzed Oct 2019.","translation_scope":"human"},{"caveats":["comparator or baseline missing or unclear"],"clinical_trial":false,"comparator_status":"missing_or_unclear","exposure_or_efficacy":"efficacy","finding_id":"vf_ce83dfe6fbe4c01d","human_data":false,"id":"vcnd_5118aee75d3e7f5f","in_vitro":false,"in_vivo":false,"method":"manual state transition","model_system":"","text":"Candidate gap for maintainer review; 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Alzheimer's research & therapy 2019. doi:10.1186/s13195-019-0520-1|section:curator_source","measurement_or_claim":"Further analyses of the safety of verubecestat in the phase 3 EPOCH trial of mild-to-moderate Alzheimer's disease.","source_id":"vs_f5db239be60a7f74","supports_or_challenges":"supports"},{"caveats":[],"condition_refs":["vcnd_9287360689f469a5"],"evidence_type":"observational","extraction_method":"manual_curation","finding_id":"vf_b299e3ad7965e4d7","human_verified":false,"id":"vea_23692fba50a25a46","locator":"source:Cascade-densification deposit: Solanezumab EXPEDITION3 failure (Honig 2018) → broader anti-Aβ MAb scope refinement|section:curator_source","measurement_or_claim":"A4 Study (NCT02008357) preclinical solanezumab arm halted 2020 after EXPEDITION3 + multi-cohort futility analysis; preclinical AD as solanezumab indication ruled out alongside mild-AD.","source_id":"vs_c06a1be73809d6e0","supports_or_challenges":"supports"},{"caveats":[],"condition_refs":["vcnd_7ff7ecd9a14030d7"],"evidence_type":"theoretical","extraction_method":"manual_curation","finding_id":"vf_f105dd8fd726a462","human_verified":false,"id":"vea_24d1704bc7813d35","locator":"source:anti-amyloid frontier gap review|section:curator_source","measurement_or_claim":"Can APOE4-specific risk models prospectively identify patients whose ARIA risk outweighs expected anti-amyloid benefit?","source_id":"vs_1a872267d915e2ad","supports_or_challenges":"supports"},{"caveats":[],"condition_refs":["vcnd_cac2a88451e79c1c"],"evidence_type":"experimental","extraction_method":"manual_curation","finding_id":"vf_c0ab26a1a6a29290","human_verified":false,"id":"vea_2a4ef9dbad836272","locator":"source:.  . doi:10.1001/jamaneurol.2016.5076|section:curator_source","measurement_or_claim":"Gantenerumab subcutaneous dosing reduces brain amyloid in prodromal AD in a dose-dependent manner; a Phase II extension study demonstrated near-complete amyloid clearance at higher doses, informing the dose selection for the Phase III trials.","source_id":"vs_9fe1d1f2b8ba33b2","supports_or_challenges":"supports"},{"caveats":[],"condition_refs":["vcnd_8377b45829323351"],"evidence_type":"observational","extraction_method":"manual_curation","finding_id":"vf_4d8aa40cc734ab93","human_verified":false,"id":"vea_2b91c3cd1e9de1e9","locator":"source:FDA approval materials, CMS coverage decisions, and sponsor discontinuation notices|section:curator_source","measurement_or_claim":"Aducanumab approval did not establish a stable clinical translation pathway for anti-amyloid therapy because the program was discontinued after contested evidence and restricted uptake.","source_id":"vs_18c998c2035325a6","supports_or_challenges":"supports"},{"caveats":[],"condition_refs":["vcnd_34e817144a3d7be4"],"evidence_type":"theoretical","extraction_method":"manual_curation","finding_id":"vf_213d7b9c875676dc","human_verified":false,"id":"vea_2cc5e5b97c57e6a5","locator":"source:anti-amyloid frontier gap review|section:curator_source","measurement_or_claim":"What trial design can distinguish amyloid lowering that is causally upstream of cognitive benefit from amyloid lowering that is an insufficient biomarker response?","source_id":"vs_1a872267d915e2ad","supports_or_challenges":"supports"},{"caveats":[],"condition_refs":["vcnd_2700b6a10df26a24"],"evidence_type":"experimental","extraction_method":"manual_curation","finding_id":"vf_dfadec272ade726c","human_verified":false,"id":"vea_2edc3dae6958404c","locator":"source:Nitrini R; Studart-Neto A. Arquivos de neuro-psiquiatria 2025. doi:10.1055/s-0045-1808082|section:curator_source","measurement_or_claim":"Monoclonal antibodies against beta-amyloid protein (lecanemab and donanemab) should not be used in the treatment of Alzheimer's disease. — Two antiamyloid monoclonal antibodies (mAbs), lecanemab and donanemab, were recently launched for treatment of Alzheimer's disease (AD). These mAbs remove amyloid protein from...","source_id":"vs_e8252084e5df4d3c","supports_or_challenges":"supports"},{"caveats":[],"condition_refs":["vcnd_c1facc84ca2f1079"],"evidence_type":"experimental","extraction_method":"manual_curation","finding_id":"vf_08887f653748dc78","human_verified":false,"id":"vea_303f2cf9bbb3aa80","locator":"source:CLARITY-AD OLE (NCT05269731, Eisai / Biogen, Phase III): Provides durability and long-term ARIA safety data that regulators required for full approval.|section:curator_source","measurement_or_claim":"CLARITY-AD OLE (NCT05269731): NCT05269731 flagged as uncertain — possible alternate NCT. Enrolling CLARITY-AD participants; interim safety data presented 2024.","source_id":"vs_d431889aa3de34d0","supports_or_challenges":"supports"},{"caveats":[],"condition_refs":["vcnd_d621c94e17146764"],"evidence_type":"experimental","extraction_method":"manual_curation","finding_id":"vf_9a4c5010e77212f3","human_verified":false,"id":"vea_31d1a110eb132105","locator":"source:TRAILBLAZER-ALZ Phase II (NCT03367403, Eli Lilly, Phase II): Established proof-of-concept for donanemab and introduced tau-based patient stratification.|section:curator_source","measurement_or_claim":"TRAILBLAZER-ALZ Phase II (NCT03367403): Significant slowing of iADRS decline (−6.86 vs −10.06); rapid and near-complete amyloid clearance confirmed.","source_id":"vs_389ee6e7b8c090d0","supports_or_challenges":"supports"},{"caveats":[],"condition_refs":["vcnd_849dfa936f70a9ea"],"evidence_type":"experimental","extraction_method":"manual_curation","finding_id":"vf_bef33326792f5c60","human_verified":false,"id":"vea_34c582677bb7c1e0","locator":"source:TRAILBLAZER-ALZ 3 (NCT05026866, Eli Lilly, Phase III): Extends donanemab's established amyloid-clearing efficacy into a fully preclinical prevention paradigm.|section:curator_source","measurement_or_claim":"TRAILBLAZER-ALZ 3 (NCT05026866): Tau PET and amyloid PET dual-enrichment; donanemab dosing until amyloid clearance confirmed.","source_id":"vs_91a1d63b8dc17741","supports_or_challenges":"supports"},{"caveats":[],"condition_refs":["vcnd_30b6fbe7f6e7401f"],"evidence_type":"observational","extraction_method":"manual_curation","finding_id":"vf_a74a1efa53aa4ed8","human_verified":false,"id":"vea_35b5a12f0cb3aec2","locator":"source:US9447085B2 — Iminothiadiazine dioxides containing a thioamide, amidine, or amide oxime group as BACE inhibitors, compositions, and their use (assignee: Merck Sharp and Dohme LLC) — Represents Merck's commercial IP position on the BACE1 inhibitor scaffold that dominated AD drug development 2012–2018; Phase 3 failure of verubecestat established that BACE inhibition at symptomatic stage is insufficient, reorienting the field toward earlier intervention and combination strategies.|section:curator_source","measurement_or_claim":"Merck patent on iminothiadiazine dioxide scaffold BACE inhibitors encompassing the verubecestat (MK-8931) compound class; covers C2-ring-substituted variants of the thiadiazinane core used in the EPOCH and APECS Phase 3 trials.","source_id":"vs_5588c5efb07284af","supports_or_challenges":"supports"},{"caveats":[],"condition_refs":["vcnd_bb3884917eee7e51"],"evidence_type":"experimental","extraction_method":"manual_curation","finding_id":"vf_3d75299a343a2fc8","human_verified":false,"id":"vea_3aec718b610e49a1","locator":"source:Atabecestat clinical development records|section:curator_source","measurement_or_claim":"Atabecestat development was halted after liver toxicity signals, separating BACE1 target engagement from acceptable translational safety.","source_id":"vs_b498ebbc9a941199","supports_or_challenges":"supports"},{"caveats":[],"condition_refs":["vcnd_1b212eb6a809dbfa"],"evidence_type":"observational","extraction_method":"manual_curation","finding_id":"vf_5b5191d116e8c25a","human_verified":false,"id":"vea_3b292ab0308695b0","locator":"source:Cascade-densification deposit: Verubecestat APECS cognitive worsening → BACE inhibitor class shutdown|section:curator_source","measurement_or_claim":"Atabecestat Phase II/III development halted in 2018 after liver toxicity AND cognitive worsening signal in J&J's EARLY trial; class concern about BACE inhibitor cognitive harm propagated from verubecestat APECS findings.","source_id":"vs_30819ebd2ee9adad","supports_or_challenges":"supports"},{"caveats":[],"condition_refs":["vcnd_800ac78e6db4214b"],"evidence_type":"experimental","extraction_method":"manual_curation","finding_id":"vf_672632084731817f","human_verified":false,"id":"vea_3b98df0e63962a08","locator":"source:Jeong SY; Suh CH; Lim JS; Shim WH; Heo H; Choi Y. Neurology 2025. doi:10.1212/wnl.0000000000213483|section:curator_source","measurement_or_claim":"Incidence of Amyloid-Related Imaging Abnormalities in Phase III Clinical Trials of Anti-Amyloid-β Immunotherapy: An Updated Meta-Analysis.","source_id":"vs_1cf66fc2dc6287e3","supports_or_challenges":"supports"},{"caveats":[],"condition_refs":["vcnd_733b765ec45ee2ac"],"evidence_type":"experimental","extraction_method":"manual_curation","finding_id":"vf_3d380bcccbe5850e","human_verified":false,"id":"vea_3c01d09d72c7d5b1","locator":"source:Michael Egan; James Kost; Pierre N. Tariot; Paul Aisen; Jeffrey L. Cummings; Bruno Vellas; Cyrille Sur; Yuki Mukai. New England Journal of Medicine 2018. doi:10.1056/NEJMoa1706441|section:curator_source","measurement_or_claim":"Verubecestat (BACE1 inhibitor) Phase III EPOCH trial in mild-moderate AD halted for futility; cognitive worsening signal observed. Production-side amyloid intervention failed alongside MAb clearance approaches, narrowing therapeutic-window viability of the amyloid hypothesis.","source_id":"vs_e1be38b966c19185","supports_or_challenges":"supports"},{"caveats":[],"condition_refs":["vcnd_333bbbe7c0ec6245"],"evidence_type":"experimental","extraction_method":"manual_curation","finding_id":"vf_2b10fee64b9970af","human_verified":false,"id":"vea_3c6336156bc30f3f","locator":"source:.  . doi:10.1056/NEJMoa2305611|section:curator_source","measurement_or_claim":"Subcutaneous lecanemab maintenance dosing in CLARITY-AD open-label extension maintains amyloid clearance achieved during IV dosing phase; participants who cleared amyloid remain Aβ-negative at 18-month follow-up, suggesting potential for extended dosing intervals once clearance is achieved.","source_id":"vs_57a4abdabe4fac61","supports_or_challenges":"supports"},{"caveats":[],"condition_refs":["vcnd_88829c1128ee020e"],"evidence_type":"experimental","extraction_method":"manual_curation","finding_id":"vf_3bbf2c4761c9867f","human_verified":false,"id":"vea_3d2e3da79fdb9634","locator":"source:Lu M; Kim MJ; Collins EC; Shcherbinin S; Ellinwood AK; Yokoi Y. JAMA neurology 2025. doi:10.1001/jamaneurol.2025.3869|section:curator_source","measurement_or_claim":"Posttreatment Amyloid Levels and Clinical Outcomes Following Donanemab for Early Symptomatic Alzheimer Disease: A Secondary Analysis of the TRAILBLAZER-ALZ 2 Randomized Clinical Trial. — ImportanceAccumulation of amyloid plaque drives pathogenesis of Alzheimer disease (AD). Reduction of amyloid via...","source_id":"vs_6a5177b0b4a78497","supports_or_challenges":"supports"},{"caveats":[],"condition_refs":["vcnd_6c6b8a1e43bdecaf"],"evidence_type":"experimental","extraction_method":"manual_curation","finding_id":"vf_994f2bcb18f2aeeb","human_verified":false,"id":"vea_3dadd95dbdd6421f","locator":"source:Wang H; Nery ESM; Ardayfio P; Khanna R; Svaldi DO; Shcherbinin S. The journal of prevention of Alzheimer's disease 2025. doi:10.1016/j.tjpad.2025.100266|section:curator_source","measurement_or_claim":"The effect of modified donanemab titration on amyloid-related imaging abnormalities with edema/effusions and amyloid reduction: 18-month results from TRAILBLAZER-ALZ 6. — The TRAILBLAZER-ALZ 6 study (NCT05738486) evaluated the effect of different donanemab dosing regimens on amyloid-related imaging abnormalities...","source_id":"vs_d939535cea32a181","supports_or_challenges":"supports"},{"caveats":[],"condition_refs":["vcnd_0004a61484e0065f"],"evidence_type":"experimental","extraction_method":"manual_curation","finding_id":"vf_c7f8be49ea6547d8","human_verified":false,"id":"vea_413c78fe9dd802a5","locator":"source:Boosting brain uptake of a therapeutic antibody by reducing its affinity for a transcytosis target.|section:curator_source","measurement_or_claim":"High-affinity anti-TfR antibodies remain associated with the blood-brain barrier vasculature, whereas lower-affinity variants are released into the brain parenchyma.","source_id":"vs_aae94d67e282b304","supports_or_challenges":"supports"},{"caveats":[],"condition_refs":["vcnd_351f2ae67480f1a7"],"evidence_type":"experimental","extraction_method":"manual_curation","finding_id":"vf_59f9854299f25567","human_verified":false,"id":"vea_4255a926af43fcba","locator":"source:Vrillon A; Götze K; Dumurgier J; Cognat E; Hourrègue C; Munoz-Musat E. Journal of neurology 2026. doi:10.1007/s00415-026-13760-x|section:curator_source","measurement_or_claim":"Eligibility for lecanemab treatment in a French memory clinic setting.","source_id":"vs_50fe8b88b9408779","supports_or_challenges":"supports"},{"caveats":[],"condition_refs":["vcnd_aaa5d39c48c4d7fa"],"evidence_type":"experimental","extraction_method":"manual_curation","finding_id":"vf_47cdd5e5bf246fe0","human_verified":false,"id":"vea_426fc7a5b90e2ed0","locator":"source:TRAILBLAZER-ALZ 6 (NCT05738486, Eli Lilly, Phase III): Regulatory and commercial requirement to validate SC route before label expansion; mirrors lecanemab SC strategy.|section:curator_source","measurement_or_claim":"TRAILBLAZER-ALZ 6 (NCT05738486): Monthly SC dosing design; co-primary ARIA safety and amyloid clearance endpoints.","source_id":"vs_a4d8b24c38035ba8","supports_or_challenges":"supports"},{"caveats":[],"condition_refs":["vcnd_704243c183a13cfb"],"evidence_type":"experimental","extraction_method":"manual_curation","finding_id":"vf_f112dd973caf9328","human_verified":false,"id":"vea_430e060b4815ecfb","locator":"source:Høilund-Carlsen PF; Alavi A; Costa T; Neve RL; Revheim ME; Barrio JR. Journal of Alzheimer's disease : JAD 2026. doi:10.1177/13872877261417548|section:curator_source","measurement_or_claim":"Serious doubts about amyloid-β (Aβ) biomarkers and anti-Aβ immunotherapy. — Reports highlight new Alzheimer's disease treatments using anti-amyloid-β immunotherapy, but we see major concerns. The trials supporting lecanemab and donanemab approvals have methodological flaws, and the benefits may be smaller than the...","source_id":"vs_c327eb65aafda056","supports_or_challenges":"supports"},{"caveats":[],"condition_refs":["vcnd_36a21a22c912703b"],"evidence_type":"experimental","extraction_method":"manual_curation","finding_id":"vf_901cc5b7f2eaef25","human_verified":false,"id":"vea_43733452bd0614e5","locator":"source:Agosta F; Cecchetti G; Spinelli EG; Ghirelli A; Rugarli G; Filippi M. Current opinion in neurology 2025. doi:10.1097/wco.0000000000001388|section:curator_source","measurement_or_claim":"MRI protocols and sequences for amyloid-related imaging abnormalities monitoring in Alzheimer's disease patients treated with monoclonal antibodies. — Purpose of reviewThis review provides an updated overview of amyloid-related imaging abnormalities (ARIA) associated with antiamyloid monoclonal antibodies (mAbs) in...","source_id":"vs_ece1a2aea207a729","supports_or_challenges":"supports"},{"caveats":[],"condition_refs":["vcnd_19866d66b43b5a37"],"evidence_type":"experimental","extraction_method":"manual_curation","finding_id":"vf_ee9deb4e3c016569","human_verified":false,"id":"vea_46dcecbeb150deb0","locator":"source:Bjørnholm KD; Butler PM; Francis AE; Varma C; Spooner ET; Grenon MB. Alzheimer's & dementia : the journal of the Alzheimer's Association 2026. doi:10.1002/alz.71350|section:curator_source","measurement_or_claim":"Anti-amyloid antibody equilibrium binding to Aβ aggregates from human Alzheimer's disease brain.","source_id":"vs_abbcc662adf0b1c2","supports_or_challenges":"supports"},{"caveats":[],"condition_refs":["vcnd_e4372f3631fc5834"],"evidence_type":"experimental","extraction_method":"manual_curation","finding_id":"vf_ef2db88a81a37fcf","human_verified":false,"id":"vea_471c7a275602b5c4","locator":"source:Doroudinia A; York B; Colletti PM. Journal of nuclear medicine technology 2026. doi:10.2967/jnmt.125.271678|section:curator_source","measurement_or_claim":"Quantitative Amyloid Brain Imaging: A Literature Review of the Centiloid Scale in Alzheimer Disease Evaluation. — Amyloid PET has become a pivotal imaging biomarker for Alzheimer disease (AD), enabling in vivo detection and quantification of β-amyloid deposition. However, variability in quantitative measurements...","source_id":"vs_c70e81c4d3517c18","supports_or_challenges":"supports"},{"caveats":[],"condition_refs":["vcnd_d3d66940f82d0653"],"evidence_type":"experimental","extraction_method":"manual_curation","finding_id":"vf_15e91a7cbffb3d34","human_verified":false,"id":"vea_474779ee428931cd","locator":"source:Iwata A. Geriatrics & gerontology international 2024. doi:10.1111/ggi.14945|section:curator_source","measurement_or_claim":"How will the emergence of lecanemab change dementia treatment? — The introduction of lecanemab has dramatically changed the field of dementia medicine. Lecanemab, defined as an anti-amyloid-β (Aβ) drug, comprises an antibody against Aβ, a protein structure believed to cause Alzheimer's disease. This drug represents...","source_id":"vs_191b9e4760eb40a4","supports_or_challenges":"supports"},{"caveats":[],"condition_refs":["vcnd_47ff76faf2fbc0be"],"evidence_type":"observational","extraction_method":"manual_curation","finding_id":"vf_e075a3729ff31c8a","human_verified":false,"id":"vea_489e29f3597cc627","locator":"source:Cascade-densification deposit: Bapineuzumab Phase III ARIA-E in APOE4 → APOE4-stratified eligibility adoption|section:curator_source","measurement_or_claim":"CLARITY-AD lecanemab eligibility required APOE genotyping with specific dosing protocols for APOE4 homozygotes after early ARIA-E rates exceeded 25% in that subgroup; bapineuzumab APOE4 ARIA-E precedent informed design.","source_id":"vs_afe1fae94e7b014e","supports_or_challenges":"supports"},{"caveats":[],"condition_refs":["vcnd_79dbc57978086db9"],"evidence_type":"meta_analysis","extraction_method":"manual_curation","finding_id":"vf_4abaa170d4f846a4","human_verified":false,"id":"vea_4a92bd4668e28962","locator":"source:Terao I; Kodama W. Journal of psychopharmacology (Oxford, England) 2025. doi:10.1177/02698811251340901|section:curator_source","measurement_or_claim":"Comparative efficacy, tolerability, and acceptability of aducanumab, lecanemab, and donanemab with repetitive transcranial magnetic stimulation on cognitive function in mild cognitive impairment and Alzheimer's disease: A systematic review and network meta-analysis.","source_id":"vs_22e5f27a956e1576","supports_or_challenges":"supports"},{"caveats":[],"condition_refs":["vcnd_5118aee75d3e7f5f"],"evidence_type":"theoretical","extraction_method":"manual_curation","finding_id":"vf_ce83dfe6fbe4c01d","human_verified":false,"id":"vea_4bda5dca4e28f8af","locator":"source:anti-amyloid frontier gap review|section:curator_source","measurement_or_claim":"How should anti-amyloid trial results be interpreted when amyloid PET changes substantially but CDR-SB or iADRS changes remain near clinical meaningfulness thresholds?","source_id":"vs_1a872267d915e2ad","supports_or_challenges":"supports"},{"caveats":[],"condition_refs":["vcnd_6175a59d0bc43dd6"],"evidence_type":"experimental","extraction_method":"manual_curation","finding_id":"vf_de9cbca0f1e77165","human_verified":false,"id":"vea_4e8eaf8a60119f10","locator":"source:Khalafi M; Hojjati SH; Wang XH; Zhou L; Nordvig AS; Li Y. AJNR. American journal of neuroradiology 2025. doi:10.3174/ajnr.a8743|section:curator_source","measurement_or_claim":"Concordance between Centiloid Quantification and Visual Interpretation of Amyloid PET Scans across the Alzheimer Disease Continuum.","source_id":"vs_3029e6a2c07fae8e","supports_or_challenges":"supports"},{"caveats":[],"condition_refs":["vcnd_6bba0883096eb236"],"evidence_type":"experimental","extraction_method":"manual_curation","finding_id":"vf_49c7ced6d7804989","human_verified":false,"id":"vea_4eb7c5c78dbc8c28","locator":"source:Kim B; Yuk M; Park M; Ryu H; Park J; Yu H.  2025. doi:10.1093/brain/awaf244|section:curator_source","measurement_or_claim":"CRISPR editing of miR-33 restores ApoE lipidation and amyloid-β metabolism in ApoE4 sporadic Alzheimer's disease. — Sporadic Alzheimer's disease (sAD) is marked by dysregulated lipid metabolism, prominently involving apolipoprotein E (ApoE). MicroRNA-33 (miR-33) has emerged as a key regulator of lipid homeostasis,...","source_id":"vs_a3e0518df609331b","supports_or_challenges":"supports"},{"caveats":[],"condition_refs":["vcnd_733d06fb0a1596f4"],"evidence_type":"experimental","extraction_method":"manual_curation","finding_id":"vf_e2554d6d7ec32686","human_verified":false,"id":"vea_4ecb0853eb02c20b","locator":"source:John R. Sims; Jennifer A. Zimmer; Cynthia Evans; Ming‐Chi Lu; Paul Ardayfio; JonDavid Sparks; Alette M. Wessels; Sergey Shcherbinin. JAMA 2023. doi:10.1001/jama.2023.13239|section:curator_source","measurement_or_claim":"Donanemab (anti-pyroglutamate-Aβ MAb) shows positive primary endpoint in early symptomatic AD with low/medium tau PET burden. Tau PET stratification meaningfully modifies treatment effect — high-tau subgroup shows attenuated benefit. ARIA-E rate ~24%; APOE4-dose-dependent.","source_id":"vs_203b1035da52d780","supports_or_challenges":"supports"},{"caveats":[],"condition_refs":["vcnd_3d21a6866784ca5f"],"evidence_type":"experimental","extraction_method":"manual_curation","finding_id":"vf_a7e84efcebc68fb7","human_verified":false,"id":"vea_5130ea64916c8a1a","locator":"source:.  . doi:10.1056/NEJMoa2301247|section:curator_source","measurement_or_claim":"Donanemab in TRAILBLAZER-ALZ 4 demonstrates that early tau burden (low/medium tau PET) selects for greater clinical benefit; donanemab-treated participants with low/medium tau showed 35% slower iADRS decline vs. placebo at 18 months, underscoring importance of biomarker-based patient selection.","source_id":"vs_5fdb514dc142a638","supports_or_challenges":"supports"},{"caveats":[],"condition_refs":["vcnd_4d943fe9f38dbb52"],"evidence_type":"observational","extraction_method":"manual_curation","finding_id":"vf_dc28e2c8084e9f8d","human_verified":false,"id":"vea_51f3ded8e60b8f95","locator":"source:Cascade-densification deposit: Aducanumab Phase Ib (Sevigny 2016) → ENGAGE/EMERGE controversy + scope flags|section:curator_source","measurement_or_claim":"Aducanumab ENGAGE (NCT02477800) and EMERGE (NCT02484547) Phase III trials halted for futility March 2019; subsequent post-hoc re-analysis showed EMERGE high-dose arm numerically positive while ENGAGE remained null. 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Sperling; Nick C. Fox; Kaj Blennow; William E. Klunk; Murray A. Raskind; Marwan N. Sabbagh; Lawrence S. Honig. New England Journal of Medicine 2014. doi:10.1056/NEJMoa1304839|section:curator_source","measurement_or_claim":"Bapineuzumab (anti-Aβ monoclonal) failed primary endpoints in two Phase III trials in mild-moderate Alzheimer's. ARIA-E vasogenic edema rate was elevated in APOE4 carriers, foreshadowing the BBB-permeability / APOE4 axis later articulated by Montagne 2020.","source_id":"vs_6be7e4023729a088","supports_or_challenges":"supports"},{"caveats":[],"condition_refs":["vcnd_99345c862d48984d"],"evidence_type":"experimental","extraction_method":"manual_curation","finding_id":"vf_b5b25525daef5712","human_verified":false,"id":"vea_977caf2a0b05e905","locator":"source:Rachelle S. Doody; Ronald G. Thomas; Martin R. Farlow; Takeshi Iwatsubo; Bruno Vellas; Steven Joffe; Karl Kieburtz; Rema Raman. 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Hoffmann-La Roche AG and MorphoSys AG) — Core IP for gantenerumab (trontinemab backbone), the anti-Aβ component now reformatted with Brain Shuttle TfR module as trontinemab; dual-epitope binding to aggregated Aβ fibrils is the distinguishing SAR claim.|section:curator_source","measurement_or_claim":"Foundational composition patent for gantenerumab, a fully human IgG1 anti-Aβ antibody generated via MorphoSys HuCAL technology; binds dual N-terminal (AEFRHDSGY) and central (VHHQKLVFFAEDVG) Aβ epitopes on aggregated fibrillar forms.","source_id":"vs_8465a1e64c0370ef","supports_or_challenges":"supports"},{"caveats":[],"condition_refs":["vcnd_f6980cbf052b1a2b"],"evidence_type":"experimental","extraction_method":"manual_curation","finding_id":"vf_c28fc03e98c273ae","human_verified":false,"id":"vea_9eb74f9ffe52853e","locator":"source:Rosenberg A; Solomon A; Bonnard A; Daniilidou M; Hagman G; Hall A. 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Annals of clinical and translational neurology 2024. doi:10.1002/acn3.52042|section:curator_source","measurement_or_claim":"Amyloid-related imaging abnormalities (ARIA): diagnosis, management, and care in the setting of amyloid-modifying therapy. — Amyloid-related imaging abnormalities, were originally described by dementia care experts. The wider use of aducanumab and now lecanemab warrant broader understanding by the health care...","source_id":"vs_2181685f6ce07dfb","supports_or_challenges":"supports"},{"caveats":[],"condition_refs":["vcnd_3ea5db8edcefe5e1"],"evidence_type":"experimental","extraction_method":"manual_curation","finding_id":"vf_b49cc3f708a871f2","human_verified":false,"id":"vea_afaaa296191714af","locator":"source:Shichijo F. No shinkei geka. Neurological surgery 2025. doi:10.11477/mf.030126030530051000|section:curator_source","measurement_or_claim":"[Precautions for Neurosurgeons in Administering Anti-Amyloid β Antibody Therapy]. — In Japan, anti-amyloid β (Aβ) monoclonal antibodies, including lecanemab and donanemab, have recently been approved as disease-modifying therapies for early-stage Alzheimer's disease (AD). These drugs, developed based on the amyloid...","source_id":"vs_cc69c503930863a2","supports_or_challenges":"supports"},{"caveats":[],"condition_refs":["vcnd_8997d30489400625"],"evidence_type":"observational","extraction_method":"manual_curation","finding_id":"vf_a9203e156f10cb62","human_verified":false,"id":"vea_affb9927e1b48673","locator":"source:Roche-Denali Trontinemab (RG6102) Phase Ib, NCT04374253. Brain Shuttle TfR-bispecific gantenerumab fragment.|section:curator_source","measurement_or_claim":"Roche-Denali Brain Shuttle gantenerumab (Trontinemab / RG6102, NCT04374253) program scope reflects BBB-transcytosis-as-delivery-target architecture; following Montagne 2020 APOE4-stratified BBB evidence, program decision-making prioritizes APOE4-stratified PK/PD readouts and BBB-permeability biomarker integration.","source_id":"vs_ac582167140d7603","supports_or_challenges":"supports"},{"caveats":[],"condition_refs":["vcnd_e2424f28eb14f25e"],"evidence_type":"experimental","extraction_method":"manual_curation","finding_id":"vf_00dd3d0421cb98d6","human_verified":false,"id":"vea_b702383d25a71087","locator":"source:Miles LA; Masters CL. 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First clearly positive Phase III for amyloid-cascade-as-drug-target — confidence updates upward in early-stage AD...","source_id":"vs_c19d53ffa8238145","supports_or_challenges":"supports"},{"caveats":[],"condition_refs":["vcnd_48cab7813e54a66b"],"evidence_type":"theoretical","extraction_method":"manual_curation","finding_id":"vf_492d3cfa2c3df2cd","human_verified":false,"id":"vea_c107b084c11cb303","locator":"source:anti-amyloid frontier gap review|section:curator_source","measurement_or_claim":"Which non-APP BACE1 substrates explain cognitive worsening or toxicity in failed BACE inhibitor trials?","source_id":"vs_1a872267d915e2ad","supports_or_challenges":"supports"},{"caveats":[],"condition_refs":["vcnd_99fa26083c64ad24"],"evidence_type":"observational","extraction_method":"manual_curation","finding_id":"vf_421b336a4bf3e428","human_verified":false,"id":"vea_c191d3133216b2b6","locator":"source:Cascade-densification deposit: Bapineuzumab Phase III ARIA-E in APOE4 → APOE4-stratified eligibility adoption|section:curator_source","measurement_or_claim":"FDA labeling for lecanemab (Leqembi) and donanemab (Kisunla) requires APOE genotyping prior to initiation due to APOE4-dose-dependent ARIA-E risk; regulatory framework anchored in earlier MAb-class evidence including bapineuzumab.","source_id":"vs_afe1fae94e7b014e","supports_or_challenges":"supports"},{"caveats":[],"condition_refs":["vcnd_e2df489fc98b8d15"],"evidence_type":"experimental","extraction_method":"manual_curation","finding_id":"vf_624f7ed44a262689","human_verified":false,"id":"vea_c400d281899b0727","locator":"source:Avgerinos KI; Manolopoulos A; Ferrucci L; Kapogiannis D. Scientific reports 2024. doi:10.1038/s41598-024-75204-8|section:curator_source","measurement_or_claim":"Critical assessment of anti-amyloid-β monoclonal antibodies effects in Alzheimer's disease: a systematic review and meta-analysis highlighting target engagement and clinical meaningfulness. — Despite most monoclonal antibodies against Aβ in Alzheimer's failed to demonstrate efficacy, the newest antibodies showed...","source_id":"vs_02133590db99aeac","supports_or_challenges":"supports"},{"caveats":[],"condition_refs":["vcnd_9cb56ccb519b26af"],"evidence_type":"experimental","extraction_method":"manual_curation","finding_id":"vf_aa236af8df84fd0d","human_verified":false,"id":"vea_cbeaecdbcd1f63fe","locator":"source:Yang Yu; Jasvinder K. Atwal; Yin Zhang; Raymond K. Tong; Kristin R. Wildsmith; Christine Tan; Nga Bien‐Ly; Maria Hersom. 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CPT: pharmacometrics & systems pharmacology 2025. doi:10.1002/psp4.70038|section:curator_source","measurement_or_claim":"Use of Model-Based Meta-Analysis to Inform the Design of Early Clinical Trials of Anti-Amyloid Beta Therapies in Alzheimer's Disease. — To inform an efficient development of new investigational anti-amyloid beta (anti-Aβ) monoclonal antibodies (mAbs), a modeling-and-simulation-based strategy was proposed. 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