Autopsy Results from the ENGAGE Trial of Aducanumab: Lessons from Co‐pathology

Abstract

AbstractBackgroundAducanumab, a monoclonal antibody that clears amyloid aggregates, received FDA approval for early‐stage Alzheimer’s Disease (AD). Clinicopathologic studies from patients treated with aducanumab are as yet unavailable, and may inform clinical use. Therefore, we report the clinical course, PET, and autopsy results from two patients treated with aducanumab.MethodsPatients were seen at UCSF and enrolled in ENGAGE (NCT02477800). Florbetapir (FBP) PET was obtained, including the initial six‐month treatment interval. Additional data, including flortaucipir (FTP) PET, was available through UCSF ADRC. PET was analyzed locally, and neuropathological analyses were performed by the UCSF Neurodegenerative Disease Brain Bank.ResultsPatient 1: 77‐year‐old male (ApoE3/3) with vascular risk factors; onset age 63 with slowed processing, memory loss, and executive dysfunction. Fourteen doses aducanumab (6mg/kg) were administered in ENGAGE and 3 doses (1mg/kg) in EMBARK (NCT04241068). FBP demonstrated 8% reduction in amyloid centiloids (67.8→62.7). FTP encompassing four‐year interval from diagnosis to ENGAGE closure showed increase in metatemporal SUVR (1.175→1.273), with progression of cortical atrophy on MRI. He died of myocardial infarction (FBP‐to‐autopsy interval: 577d). Autopsy revealed intermediate ADNC (Thal 3, Braak 5, CERAD frequent), and substantial vascular pathology including chronic multifocal microinfarcts.Patient 2: 64‐year‐old female (ApoE4/4); onset age 55 with rapid forgetting, executive dysfunction, prominent anxiety, and dream enactment. Fourteen doses aducanumab (10mg/kg) were administered prior to early‐termination due to disease progression. FBP showed 38% reduction in amyloid centiloids (42.1→26.2). After discontinuation, she developed dysautonomia, parkinsonism, and paranoia, later dying in status epilepticus (FBP‐to‐autopsy interval: 1120d). Autopsy revealed high ADNC (Thal 5, Braak 6, CERAD frequent), extensive cortical Lewy bodies disease (LBD, Braak 6), moderate cerebral amyloid angiopathy, and amygdalar TDP‐43 (LATE‐NC Stage 1).ConclusionVascular disease and LBD, both common co‐pathologies in AD, likely contributed to the clinical phenomenology and course of these patients. In the first case, low‐dose aducanumab did not substantially reduce amyloid, and the patient later died from unrelated heart disease. In the second case, despite substantial amyloid clearance on high‐dose, co‐morbid LBD led to clinical progression and discontinuation. Additional autopsy studies are needed to clarify the neuropathological effects of aducanumab, and the role of AD co‐pathology.