![]() ![]() All PET data were acquired on a Siemens ECAT HR + (3D mode 63 image planes 15.2 cm axial field of view 5.6 mm transaxial resolution 2.4 mm slice interval). PiB and FTP PET were prepared and acquired according to previously published protocols. Bilateral HV measures derived from FS were adjusted for intracranial volume (ICV) by regressing out the contribution of ICV on HV, using previously published parameters. ![]() FS outputs were quality-checked and manually edited where necessary to ensure accurate segmentation and surface identification. Images were processed with FreeSurfer (FS) version 6.0 ( ) to identify white and pial surfaces, standard regions-of-interest (ROI) from the Desikan atlas for PET sampling, and hippocampal volumes (HV). T1-weighted structural MRI data were acquired using a Siemens 3 Tesla Tim Trio (Siemens, Erlangen, Germany repetition time = 2300 ms echo time = 2.95 ms flip angle = 9° voxel size = 1.05 × 1.05 × 1.2 mm). Imaging data from the patient was compared with data from other, typical PSEN1 E280 carriers as well as older (> 65 years/old) sporadic AD patients described in a previous report. Structural MRI, 11C-Pittsburgh Compound B (PiB) and 18F-Flortaucipir (FTP) PET data were acquired at Massachusetts General Hospital, as previously described. Clinical ratings and neuropsychological tests were performed according to standard protocols as previously described. All subjects provided informed written consent. This study was approved by the institutional review boards of the University of Antioquia, Massachusetts General Hospital, and the Schepens Eye Research Institute of Massachusetts Eye and Ear. In this study we aim to describe these longitudinal in vivo and postmortem findings, including an atypical regional distribution of tau pathology evident in both imaging and postmortem assessments, and gene expression profiles of neurons and neuroglia that correspond to regional vulnerability and protection against tau. Since the original report, the availability of follow-up in vivo imaging and postmortem data has enabled us to further evaluate in greater detail the mechanisms of protection in this patient. In vitro experiments from that report suggested that the APOE3ch variant may have protective effects by reducing ApoE binding to heparan sulfate proteoglycans and lipoprotein receptors involved in tau uptake and spread compared to other APOE variants. At the time of first examination, she was found to carry two copies of the rare APOE3 Christchurch variant ( APOE3ch) and had severely elevated brain Aβ with limited tau pathology and neurodegeneration, as measured by in vivo PET imaging. We previously reported a PSEN1 E280A mutation carrier from the world’s largest known autosomal dominant Alzheimer’s disease (ADAD) kindred who was spared from Alzheimer’s symptoms until her seventies, nearly three decades after the typical age of clinical onset among mutation carriers in this kindred. APOE’s possible role in Alzheimer’s pathophysiology include cellular mechanisms involving neuronal and glial functions, together with direct effects in amyloid-β (Aβ) aggregation and deposition. Apolipoprotein E ( APOE) haplotype variants such as APOE4 have been associated with increased risk of sporadic Alzheimer’s disease. Nevertheless, some cases belonging to a large kindred carrying the presenilin-1 ( PSEN1) E280A mutation have shown delayed onset, suggesting possible mechanisms of disease modulation. 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.įamilial Alzheimer’s disease is characterized by its high pathological severity and early disease onset. The occipital cortex, the only cortical region showing cerebral amyloid angiopathy (CAA), exhibited a distinctive chronic inflammatory microglial profile and lower APOE expression. 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. ![]() 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. ![]() 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. ![]()
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