Medial Temporal Lobe Atrophy in Down Syndrome Along the Alzheimer’s Disease Continuum
The medial temporal lobe (MTL) is one of the first regions affected by tau pathology, making structural changes in these areas promising biomarkers for identifying early signs of Alzheimer’s disease (AD). However, little is known about the integrity of these regions in individuals with Down syndrome (DS) – a population that almost universally develops AD – offering a unique opportunity to investigate early structural changes related to the disease.
This study, published in Brain, provides a comprehensive characterization of the sequential involvement of MTL structures in DS across the AD continuum.
What did we do in this study?
Using T1-weigthed MRI scans, we assessed MTL integrity in 259 DS adults and 138 cognitively unimpaired euploid controls. We examined the association between regional MTL volumes/cortical thickness and AD clinical stages, estimated year to symptom onset (EYO), and cerebrospinal fluid (CSF) AD biomarkers. We also evaluated the ability of these brain measures to distinguish between clinical stages of AD.
Key findings
- There was a progressive loss of volume and cortical thickness in MTL with advancing AD stage in DS, with all subregions showing significant decline by the dementia stage.
- The entorhinal cortex and posterior hippocampus were the first regions to show signs of atrophy, starting approximately 13-15 years before the EYO of clinical symptoms (around age 53).
- We observed non-linear structural changes, with some MTL structures initially showing an increase in cortical thickness before subsequent thinning.
- The posterior hippocampus demonstrated high discriminatory power – comparable to CSF biomarkers – in differentiating asymptomatic individuals from those in the prodromal or dementia stages of AD.
Why is this important?
The structural changes observed in the MTL of individuals with DS resemble those reported in sporadic and other genetically determined forms of AD, supporting the translational value of these findings. The topographical sequence in which MTL areas are affected mirrors the known pattern of tau buildup, highlighting the strong link between tau pathology and neurodegeneration. The non-linear trajectories across MTL subregions suggest that disease progression may involve different biological mechanisms, such as neuroinflammatory. Notably, we showed that these structural changes begin approximately 15 years before the estimated onset of clinical symptoms. Together, these results highlight that structural MRI can detect early MTL changes in DS. Longitudinal studies are now required to establish whether these changes can be used to monitor disease progression in the context of clinical trials targeting AD in individuals with DS.
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