Alzheimer disease neuropathology in a patient previously treated with aducanumab

Abstract

Amyloid beta (Aβ) plaque is a defining pathologic feature of Alzheimer disease (AD). Aducanumab, a monoclonal IgG1 that selectively binds aggregated species of Aβ, has been shown by amyloid positron emission tomography (Amyloid PET) to reduce Aβ plaques in patients with prodromal and mild AD. This is the first autopsy report of the AD neuropathology in a patient previously treated with aducanumab. The patient was an 84-year-old woman who was randomized to the placebo arm of the PRIME Phase 1b study (221AD103). The patient progressed to moderate dementia (MMSE = 14/30), beyond the targeted early AD treatment stage, before receiving aducanumab in the long-term extension (LTE). The patient then received 32 monthly doses of aducanumab, titrated up to 6 mg/kg, for a cumulative dose of 186 mg/kg. In the LTE, Amyloid PET scans demonstrated robust Aβ plaque reduction, from a composite standard uptake value ratio (SUVR) of 1.5 at screening to < 1.1 at 56 weeks post-aducanumab dosing. MRI examinations were negative for amyloid-related imaging abnormalities (ARIA). She passed away in hospice care 4 months after her last dose of aducanumab. The postmortem neuropathologic examination confirmed AD neuropathologic changes. Aβ and IBA1 immunohistochemistry assays demonstrated sparse residual Aβ plaque engaged by amoeboid reactive microglia. Phospho-Tau (pTau) immunohistochemistry demonstrated neocortical neurofibrillary degeneration (Braak stage V, NIA/AA Stage B3). However, the density of pTau neuropathology, including neuritic plaque pTau (NP-Tau), appeared lower in the PRIME LTE Patient compared to a reference cohort of untreated Braak stage V–VI, NIA/AA Stage B3 AD cases. Taken together, this case report is the first to provide Amyloid PET and neuropathologic evidence substantiating the impact of aducanumab to reduce Aβ plaque neuropathology in a patient with AD. Furthermore, this report underscores the critical importance of autopsy neuropathology studies to augment our understanding of aducanumab’s mechanism of action and impact on AD biomarkers.

Increase in Tau Pathology in P290SMaptKnock-In Mice Crossed withAppNL-G-FMice

“…In 3xTg-AD mice, anti-Aβ immunotherapy has been shown to reduce the amount of tau pathology ( Oddo et al, 2004 ). A recent report of an 84-year-old woman receiving the anti-Aβ antibody aducanumab for 32 months showed lower phospho-tau immunoreactivity when compared with untreated AD cases ( Plowey et al, 2022 ). Together, these findings suggest that assembled Aβ can promote, but not induce, the assembly of tau.…”

An anti-amyloid therapy works for Alzheimer’s disease: why has it taken so long and what is next?

“…These will perhaps be best informed by neuropathological investigations of those who have died after being treated after antibody treatment. 6 , 7 …”

Glymphatic system dysfunction in neurodegenerative diseases

“…The pathophysiology behind ARIA is incompletely understood but seems to correlate with coexisting high loads of CAA [23]. Both in mouse models and in humans, CAA seems to increase in response to Aβ immunotherapies that successfully clear parenchymal Aβ from the brain [24,25]. The observed increase in CAA is likely due to the separation of Aβ peptides from parenchymal plaques into the blood vessels and thus establishes a link between the phenomenon of ARIA and the newly discovered glymphatic system [26,27] which is a glial-dependent clearance pathway that is unique to the brain and was first described in 2012 [28].…”