INTRODUCTION: Up to 90% of Down syndrome (DS) patients develop Alzheimer’s disease (AD). Sleep disturbance, affecting over 75% of DS patients, is implicated in AD pathogenesis. The thalamus, central to sleep and arousal, shows early vulnerability in DS-related AD.

METHODS: Structural 3T MRI scans from 253 DS participants (119 males, mean age 43.0±9.4y) and 36 controls (30 males, mean age 43.1±12.2y) from the ABC-DS study were analysed, alongside neurodegenerative plasma biomarker assays (pTau181, pTau217, NfL, Aβ40, Aβ42).

RESULTS: In DS, intracranial volume-adjusted thalamic volume declined with age (t = −2.589, p = 0.00987), approximating 2.5% loss per decade. This was linear, grey matter involution-independent, and heterogeneous across nuclei, correlating negatively with pTau and NfL. Controls exhibited no significant volumetric changes.

DISCUSSION: Anteromedial and posterior thalamic shrinkage in DS AD mirrors sporadic AD. Associations with neurodegenerative biomarkers support thalamic atrophy as a sensitive marker of DS-related AD progression.