Regional cerebral hypometabolism and pathological heterogeneity in sporadic early onset alzheimer's disease: China Aging and Neurodegenerative Initiative (CANDI) study.

PURPOSE: Although EOAD patients constitute a minority of AD cases, they occupy pivotal familial and societal roles, frequently serving as primary household providers. The study aims to explore the underlying mechanism of sEOAD. METHODS: In our prospective clinical cohort study, we included 232 participants who underwent comprehensive structural MRI, multi-tracer PET imaging, and fluid biomarker assessments in addition to routine neurological, neuropsychological, and laboratory tests. This is a sub-study of the CANDI, which is a prospective observational cohort study on AD and related cognitive disorders. Patients were recruited between December 2018 and January 2024. It included 112 patients with sEOAD, 88 with late-onset AD, and 32 controls. All AD patients met the ATN diagnostic criteria. Patients with familial EOAD or non-AD dementia were excluded. Participants underwent biomarker assessment, structural MRI, and multi-tracer PET/CT(18F-FDG-PET,18F-AV45-PET, and 18F-AV1451-PET). PET imaging data of three different tracers were analyzed by SPM12 software implemented in MATLAB 2020b environment. SUVR values calculated from the different brain ROI regions based on multi-tracer-PET images. Voxel-wise group comparison, ROI-based group quantitative analysis, and mediation analysis were explored in imaging biomarkers and fluid biomarkers. RESULTS: In sEOAD, the cerebral hypometabolism pattern was observed in the bilateral angular, precuneus, and posterior cingulate gyri. This pattern was associated with higher levels of tau pathology, particularly in the bilateral angular and precuneus regions. CONCLUSION: Regional cerebral hypometabolism, rather than Aβ plaques, strongly correlates with tau pathology in sEOAD, suggesting that hypometabolism is closely associated with regional tau accumulation in sEOAD, which may precede tau aggregation and underpins disease mechanisms.