TY - JOUR
T1 - Distinct tau neuropathology and cellular profiles of an APOE3 Christchurch homozygote protected against autosomal dominant Alzheimer’s dementia
AU - Sepulveda-Falla, Diego
AU - Sanchez, Justin S.
AU - Almeida, Maria Camila
AU - Boassa, Daniela
AU - Acosta-Uribe, Juliana
AU - Vila-Castelar, Clara
AU - Ramirez-Gomez, Liliana
AU - Baena, Ana
AU - Aguillon, David
AU - Villalba-Moreno, Nelson David
AU - Littau, Jessica Lisa
AU - Villegas, Andres
AU - Beach, Thomas G.
AU - White, Charles L.
AU - Ellisman, Mark
AU - Krasemann, Susanne
AU - Glatzel, Markus
AU - Johnson, Keith A.
AU - Sperling, Reisa A.
AU - Reiman, Eric M.
AU - Arboleda-Velasquez, Joseph F.
AU - Kosik, Kenneth S.
AU - Lopera, Francisco
AU - Quiroz, Yakeel T.
N1 - Publisher Copyright:
© 2022, The Author(s).
PY - 2022/9
Y1 - 2022/9
N2 - 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.
AB - 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.
KW - APOE
KW - Alzheimer’s disease
KW - Dementia
KW - PET
KW - Tau
KW - Transcriptomics
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U2 - 10.1007/s00401-022-02467-8
DO - 10.1007/s00401-022-02467-8
M3 - Article
C2 - 35838824
AN - SCOPUS:85134310754
SN - 0001-6322
VL - 144
SP - 589
EP - 601
JO - Acta Neuropathologica
JF - Acta Neuropathologica
IS - 3
ER -