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APOE ISOFORMS DIFFERENTIALLY MODULATE THE ASSOCIATIONS BETWEEN REGIONAL TAU DEPOSITION AND NEUROINFLAMMATION IN ALZHEIMER’S DISEASE
Abstract
Aims
Apolipoprotein E (APOE) has been recognised as the most important genetic risk factors for sporadic Alzheimer disease (AD), with three allelic variants: APOE ε2, APOE ε3 and APOE ε4 exist. Neuroinflammation is considered one of the hallmarks of AD, and it manifests as the presence of both reactive astrocytes and microglia. Mounting evidence suggests that APOE modulates the brain inflammatory responses in an isoform-dependent manner. The role of APOE ε4 in neuroinflammation was interrogated in previous studies. However, relevance of these mechanisms in relation to other AD pathologies, such as tau deposition, still warrants further investigation.
Methods
This was a cross-sectional study examining a total number of 162 subjects from the TRIAD cohort at McGill University Research Centre for Studies in Aging. Cerebral tau neurofibrillary tangles were assessed using positron emission tomography (PET) radiopharmaceuticals [18F]MK6240. Cerebrospinal fluid (CSF) neuroinflammation biomarkers including soluble triggering receptor expressed on myeloid cells 2 (sTREM2), YKL40 and glial fibrillary acidic protein (GFAP) were also measured. Voxelwise analyses were performed to evaluate the relationships between regional tau burden and neuroinflammation biomarkers.
Results
Voxelwise analyses revealed that subjects with different APOE variants showed different relationships between neuroinflammation biomarkers and tau burden. Noteworthy, in APOE ε4 carriers, a significant correlation between neuroinflammation biomarkers and tau burden was found in medial temporal regions. These associations were absent in APOE ε2 and ε3 subjects, suggested APOE exerts immunomodulatory effects in an isoform-dependent way.
Conclusions
APOE isoforms differentially modulate the associations between regional tau deposition and neuroinflammation.