INTERPLAY BETWEEN NEUROINFLAMMATION, AMYLOID-BETA DEPOSITION AND NEURODEGENERATION IN DOWN SYNDROME

Down syndrome is a genetically determined form of Alzheimer’s disease (DS-AD) characterized by early, age-dependent neuropathology. However, no neuroimaging studies have investigated multimodal associations among neuroinflammation, amyloid-beta, and cortical atrophy. Elucidating these relationships is essential for defining the biological profiles of DS-AD, particularly its neuroinflammatory signatures, which remain underexplored and contribute to the continued exclusion of this population from AD clinical trials.
We aimed to map spatial relationships between amyloid-beta, neuroinflammation, and cortical atrophy in a DS-AD group at a predementia stage. Using multimodal imaging: 11C-PiB PET for amyloid-beta, 11C-PK11195 PET for neuroinflammation, and structural MRI for cortical atrophy, we studied 20 DS-AD individuals (19 preclinical/prodromal AD) (mean age: 35.55 ± 13.08) and 20 age- and sex-matched neurotypical controls. Voxel-wise regression analysis assessed cross-modal associations.
Results revealed significant associations between amyloid-beta and neuroinflammation in the frontal, parietal, and temporal cortices in DS-AD (p < 0.05, FDR corrected). Amyloid-beta related atrophy was widespread, mainly in temporoparietal regions of the posterior medial memory network (p < 0.005, FDR corrected), while neuroinflammation-atrophy associations were more restricted and localized to frontal and parietal cortices (p < 0.001).
Amyloid-beta deposition seems central to structural damage in posteromedial memory network regions, whereas neuroinflammation appears to play a dual role in the frontal lobe and relates to neurodegeneration in some select areas. The spatial patterns of neuroinflammation-atrophy and amyloid-beta associations recapitulate other forms of AD, supporting the relevance of DS-AD as a model for AD pathology and its potential inclusion in future AD-related clinical trials.