Distinct tau neuropathology and cellular profiles of an APOE3 Christchurch homozygote protected against autosomal dominant Alzheimer’s dementia

Diego Sepulveda-Falla, Justin S. Sanchez, Maria Camila Almeida, Daniela Boassa, Juliana Acosta-Uribe, Clara Vila-Castelar, Liliana Ramirez-Gomez, Ana Baena, David Aguillon, Nelson David Villalba-Moreno, Jessica Lisa Littau, Andres Villegas, Thomas G. Beach, Charles L. White, Mark Ellisman, Susanne Krasemann, Markus Glatzel, Keith A. Johnson, Reisa A. Sperling, Eric M. ReimanJoseph F. Arboleda-Velasquez, Kenneth S. Kosik, Francisco Lopera, Yakeel T. Quiroz

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

We describe in vivo follow-up PET imaging and postmortem findings from an autosomal dominant Alzheimer’s disease (ADAD) PSEN1 E280A carrier who was also homozygous for the APOE3 Christchurch (APOE3ch) variant and was protected against Alzheimer’s symptoms for almost three decades beyond the expected age of onset. We identified a distinct anatomical pattern of tau pathology with atypical accumulation in vivo and unusual postmortem regional distribution characterized by sparing in the frontal cortex and severe pathology in the occipital cortex. The frontal cortex and the hippocampus, less affected than the occipital cortex by tau pathology, contained Related Orphan Receptor B (RORB) positive neurons, homeostatic astrocytes and higher APOE expression. The occipital cortex, the only cortical region showing cerebral amyloid angiopathy (CAA), exhibited a distinctive chronic inflammatory microglial profile and lower APOE expression. Thus, the Christchurch variant may impact the distribution of tau pathology, modulate age at onset, severity, progression, and clinical presentation of ADAD, suggesting possible therapeutic strategies.

Original languageEnglish (US)
Pages (from-to)589-601
Number of pages13
JournalActa Neuropathologica
Volume144
Issue number3
DOIs
StatePublished - Sep 2022

Keywords

  • Alzheimer’s disease
  • APOE
  • Dementia
  • PET
  • Tau
  • Transcriptomics

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

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