Regional Brain Metabolism across the Alzheimer's Disease Continuum in Down Syndrome

Objective The goal was to examine the effect of sociodemographic variables, Alzheimer's disease (AD) clinical stages and pathology on brain metabolism in Down syndrome (DS). Methods We included 71 euploid healthy controls (HC) and 105 adults with DS (67 asymptomatic, 12 prodromal, and 26 with dementia) from the Down‐Alzheimer Barcelona Neuroimaging Initiative. Participants underwent [18F]fluorodeoxyglucose positron emission tomography, 3 Tmagnetic resonance imaging, and lumbar puncture to measure cerebrospinal fluid (CSF) biomarkers (ratio beween amyloid β peptide 42 and 40, phosphorylated tau 181, and neurofilament light chain [NfL]). Voxel‐wise analyses in SPM12 examined the effects of age, sex, intellectual disability, Alzheimer's clinical stage, and CSF biomarkers on brain metabolism. Results In HC, brain metabolism decreased with age primarily in the frontal lobe. By contrast, a more distributed pattern of metabolic loss was observed in DS with age, predominating in temporoparietal regions. Compared to asymptomatic DS participants, those at the prodromal stage exhibited medial parietal hypometabolism, which later extended to other temporoparietal and frontal regions at the dementia stage. In asymptomatic individuals, we observed a widespread hypometabolism compared to HC, mainly in medial frontal and parietal regions. All CSF biomarkers were closely associated with hypometabolism in regions affected by the disease, with the strongest association observed for NfL in medial parietal structures. Interpretation The brain metabolic decline in DS with age reflects Alzheimer's pathological processes and involves temporoparietal regions in a similar pattern to that found in other forms of AD. Hypometabolism is more tightly related to CSF NfL levels than to core AD biomarkers. ANN NEUROL 2025