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

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.

Automated summary

This study presents PET imaging and postmortem findings of an ADAD PSEN1 E280A carrier with the APOE3 Christchurch (APOE3ch) variant, who remained symptom-free for nearly three decades past the expected age of onset. It revealed a unique anatomical pattern of tau pathology, with atypical accumulation in vivo and distinct regional distribution in the postmortem analysis. The frontal cortex and hippocampus, less affected by tau pathology, displayed specific cell types and higher APOE expression, while the occipital cortex, the only region with cerebral amyloid angiopathy (CAA), showed chronic inflammation and lower APOE expression. This suggests that the Christchurch variant may impact tau pathology distribution and modulate the clinical presentation of ADAD.