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

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.

• Autores: Aguillón Niño, David Fernando; Quiroz Gaviria, Yakeel Tatiana; Baena, Ana; Sepulveda Falla, Diego Alonso; Lopera Restrepo, Francisco Javier; Almeida, María Camila; Boassa, Daniela; Acosta Uribe, Juliana; Vila Castelar, Clara; Ramírez Gómez, Liliana; Sánchez, Justin S.; Villalba Moreno, Nelson David; Littau, Jessica Lisa; Villegas Lanau, Carlos Andrés; Beach, Thomas G.; White 3rd, Charles L.; Ellisman, Mark; Krasemann, Susanne; Glatzel, Markus; Johnson, Keith A.; Sperling, Reisa A.; Reiman, Eric M.; Arboleda Velásquez, Joseph Fitzgerald; Kosik, Kenneth S.
• Tipo de recurso: Article of investigation
• Fecha de publicación: 2022
• Institución: Universidad de Antioquia
• Repositorio: Repositorio UdeA
• Idioma: eng
• OAI Identifier: oai:bibliotecadigital.udea.edu.co:10495/42134
• Acceso en línea: https://hdl.handle.net/10495/42134
• Palabra clave: Alzheimer Disease; Enfermedad de Alzheimer; Amyloid beta-Peptides; Péptidos beta-Amiloides; Apolipoprotein E3; Apolipoproteína E3; Brain; Éncefalo; Homozygote; Homocigoto; Positron-Emission Tomography; Tomografía de Emisión de Positrones; tau Proteins; Proteínas tau; https://id.nlm.nih.gov/mesh/D000544; https://id.nlm.nih.gov/mesh/D016229; https://id.nlm.nih.gov/mesh/D053318; https://id.nlm.nih.gov/mesh/D001921; https://id.nlm.nih.gov/mesh/D006720; https://id.nlm.nih.gov/mesh/D049268; https://id.nlm.nih.gov/mesh/D016875
• Rights: openAccess
• License: http://creativecommons.org/licenses/by/2.5/co/