Distinct brain regions are affected by neurodevelopmental or pre-dementia changes in Down syndrome

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ID: 320876
2026
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Abstract
Abstract Down syndrome, a condition characterized by triplication of chromosome 21, leading to a complex interplay between neurodevelopmental and dementia-related changes similar to the ones observed in Alzheimer’s disease. Here we aimed to understand this interplay by using imaging biomarkers for different cognitive profiles in Down syndrome, and by analysing early developmental differences versus age-related changes. We analysed voxel-based morphometric measures of grey matter volume from high-resolution T1-weighted MRI in 23 adults with Down syndrome (18-59 years, five female) in preclinical/prodromal stages of Alzheimer’s disease and 24 age- and sex-matched controls, along with cognitive assessments. Neuroanatomical group differences were assessed using two-sample t-tests. Age-related effects on brain integrity, and cognitive function were examined through voxel-wise regression analyses and correlation tests, respectively. Finally, structural correlates of episodic memory were explored across the whole brain at the voxel level within the Down syndrome group. Results revealed a neuroanatomic phenotype with both regional increases and decreases in grey matter volume compared to controls (false discovery rate, q ≤ 0.05). Based on regression analysis, we found the following patterns in regions that were differentially reduced in Down syndrome: same intercept and different age-related slope (defining specific age-related differences), different intercept (implying initial neurodevelopmental differences) and same slope (signalling no age-related differences). A notable example of the first was the left hippocampus and its subfields, and of the second was the orbitofrontal cortex. Follow-up whole brain analyses confirmed age-related changes in Down syndrome (false discovery rate, q ≤ 0.05) in the parietal and temporal cortices, extending into hippocampus, as compared to controls, independent of neurodevelopmental (non-age related) features, and most pronounced in the right hemisphere. Episodic and associative memory declined significantly with age (P = 0.016) in Down syndrome and correlated with shrinkage in regions vulnerable to Alzheimer’s disease (P < 0.01), including the precuneus and posterior cingulate cortex. Our findings suggest that individuals with Down syndrome undergo early brain atrophy that occurs independently of baseline neurodevelopmental changes, particularly in the hippocampus and temporoparietal regions. Notably the posterior cingulate cortex and precuneus showed an association with episodic memory loss, a pattern that is consistent with Alzheimer’s Disease. In sum we found a dichotomic distinction between brain regions affected by developmental or ageing changes in Down syndrome.
Reference Key
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Authors Lília Jorge, Joana Oliveira, Ricardo Martins, Tânia Lopes, Hugo Quental, Miguel Castelo‐Branco
Journal Brain communications
Year 2026
DOI
10.1093/braincomms/fcag269
URL
https://doi.org/10.1093/braincomms/fcag269
Keywords Keywords not found

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