The Lancet. Neurology · 2025
Neuropathological changes and amyloid-related imaging abnormalities in Alzheimer's disease treated with aducanumab versus untreated: a retrospective case-control study.
Клиническое исследование III фазыСтатьяРандомизированное исследованиеНазвание и аннотация: Перевод в очереди
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Boon Baayla D C, Piura Yoav D, Moloney Christina M, Chalk Jessica L, Lincoln Sarah J, Rutledge Matthew H, Rothberg Darren M, Kouri Naomi, Hinkle Kelly M, Roemer Shanu F, Johnson Derek R, Burkett Brian J, Lowe Val J, Petersen Ronald C, Dickson Dennis W, Reichard R Ross, Nguyen Aivi T, Graff-Radford Jonathan, Knopman David S, Graff-Radford Neill R, Murray Melissa E
Аннотация
BACKGROUND: Understanding the neuropathological effects of amyloid β (Aβ)-targeting therapies and amyloid-related imaging abnormalities (ARIA) in Alzheimer's disease is critical for optimising treatment efficacy and patient outcomes. Comparing Aβ PET imaging with neuropathological assessments provides context for evaluating the extent of Aβ clearance and interpreting in-vivo biomarkers. We aimed to assess clinicopathological changes and ARIA-related effects in aducanumab-treated versus untreated Alzheimer's disease.
METHODS: This retrospective case-control study included five aducanumab-treated participants from clinical trials conducted at the Mayo Clinic (2016-21) who underwent autopsy (2020-23). Treated participants were matched by autosomal dominant Alzheimer's disease mutation or APOE genotype, age at cognitive symptom onset, and sex to 12 untreated participants from the Mayo Clinic Alzheimer's Disease Research Center and Mayo Clinic Study of Aging cohorts in the Mayo Clinic brain bank (Jacksonville, FL, USA). Cognitive, imaging, and neuropathological outcomes were compared using descriptive analyses and Mann-Whitney U tests.
FINDINGS: Aducanumab-treated participants comprised four males and one female, all carrying at least one APOE ∊4 allele, with two harbouring a PSEN1 mutation. Cumulative dosages of aducanumab ranged from 5 mg/kg to 241 mg/kg; all participants cognitively declined during treatment, and two exhibited ARIA. Reductions in [18F]florbetapir PET Centiloid values ranged from -6% to -81% compared with baseline. Treatment-to-death intervals ranged from 5 months to 41 months. Neuropathological analyses revealed clearance of Aβaa1-8 and Aβ42 localised to cortical layer I in treated participants, with no significant clearance in deeper cortical layers. Regions corresponding to ARIA on MRI showed microinfarcts with haemosiderin, complement activation, and CD68-positive vessel walls originating from Aβ-laden leptomeningeal and penetrating vessels.
INTERPRETATION: Disproportionate Aβ clearance and ARIA-associated neuropathology localised to superficial cortical layers suggest a distinctive pattern of target engagement by aducanumab. These findings inform understanding and monitoring of similar Aβ-targeting therapies.
FUNDING: Alzheimer Nederland, National Institute on Aging, and Alzheimer's Association.
METHODS: This retrospective case-control study included five aducanumab-treated participants from clinical trials conducted at the Mayo Clinic (2016-21) who underwent autopsy (2020-23). Treated participants were matched by autosomal dominant Alzheimer's disease mutation or APOE genotype, age at cognitive symptom onset, and sex to 12 untreated participants from the Mayo Clinic Alzheimer's Disease Research Center and Mayo Clinic Study of Aging cohorts in the Mayo Clinic brain bank (Jacksonville, FL, USA). Cognitive, imaging, and neuropathological outcomes were compared using descriptive analyses and Mann-Whitney U tests.
FINDINGS: Aducanumab-treated participants comprised four males and one female, all carrying at least one APOE ∊4 allele, with two harbouring a PSEN1 mutation. Cumulative dosages of aducanumab ranged from 5 mg/kg to 241 mg/kg; all participants cognitively declined during treatment, and two exhibited ARIA. Reductions in [18F]florbetapir PET Centiloid values ranged from -6% to -81% compared with baseline. Treatment-to-death intervals ranged from 5 months to 41 months. Neuropathological analyses revealed clearance of Aβaa1-8 and Aβ42 localised to cortical layer I in treated participants, with no significant clearance in deeper cortical layers. Regions corresponding to ARIA on MRI showed microinfarcts with haemosiderin, complement activation, and CD68-positive vessel walls originating from Aβ-laden leptomeningeal and penetrating vessels.
INTERPRETATION: Disproportionate Aβ clearance and ARIA-associated neuropathology localised to superficial cortical layers suggest a distinctive pattern of target engagement by aducanumab. These findings inform understanding and monitoring of similar Aβ-targeting therapies.
FUNDING: Alzheimer Nederland, National Institute on Aging, and Alzheimer's Association.