Long‐term neuropathological effects of amyloid‐β immunization revealed by spatial transcriptomics

Abstract

AbstractBackgroundModern Alzheimer’s disease (AD) therapeutics include immunization against amyloid‐β (Aβ). Intriguingly, neuropathological examination of the first active Aβ vaccination trial (Elan Pharmaceuticals’ AN1792) showed some patients with evidence of Aβ clearance 15 years post‐vaccination. Yet, these patients progressed to severe dementia before death, possibly due to ongoing tau propagation. The AN1792 trial was halted when some participants developed aseptic meningoencephalitis driven by auto‐aggressive T cells. Imaging features of meningoencephalitis experienced by AN1792 subjects are pathologically reminiscent of amyloid‐related imaging abnormalities (ARIA) that currently hamper clinical trials and the therapeutic use of passive Aβ immunotherapy for AD.MethodHere, we utilized spatial transcriptomics to sequence RNA from formalin‐fixed paraffin‐embedded (FFPE) cortical brain sections from a unique neuropathological cohort of 14 immunized AD cases and a placebo‐control from AN1792. Additional controls included 6 naïve (unimmunized) AD cases and 3 non‐neurological disease controls.ResultWe reveal a cytotoxic and migratory phenotype of infiltrating T cells in the meninges of AD patients immunized against Aβ. Specifically, brain infiltrating T cells express cytotoxic genes (e.g. GZMA), activation genes (e.g. CD74 and B2M), and migratory genes (e.g. ITGAL and VCAM1). Additionally, we discovered genetic signatures that distinguish cortical areas cleared of Aβ in immunized AN1792 subjects.ConclusionWe show that active Aβ immunotherapy induces long‐term adaptive immune effects in the AD cortex.