Cerebellar subregional structural changes across the Alzheimer's disease continuum: a longitudinal analysis of...

Although traditionally viewed as relatively spared in Alzheimer's disease (Ad), the cerebellum is increasingly recognized for its contribution to cognitive and behavioural dysfunction. However, longitudinal data delineating subregional cerebellar involvement across the Ad continuum remain limited. In this study, we investigated longitudinal cerebellar atrophy and its clinical correlates in 259 older adults classified via amyloid PET into four biomarker-defined groups: cognitively normal controls, preclinical Ad, Ad-related mild cognitive impairment and Ad dementia. Structural MRI data were analysed using the Spatially Unbiased Infratentorial Template (SUIT), and longitudinal changes in 28 cerebellar subregions were assessed via generalized estimating equations, controlling for demographic and biological covariates. Across longitudinal analyses, cerebellar structural alterations in preclinical Ad were closely associated with both cognitive and behavioural measure changes. Reductions in lobule VI and Crus I/II were correlated with episodic memory decline, emphasizing the cerebellum's contributions to early cognitive deterioration. The same regions were involved in associations with apathy and behavioural dysregulation, suggesting the cerebellar contribution to emerging neuropsychiatric symptoms through disruption of motivational and executive circuits. In addition, stage-dependent cortico-cerebellar coupling was noted, with coordinated volume loss between cerebellar lobule VI and temporo-orbitofrontal cortices in the preclinical stage, but selective posterior cerebellar-posterior cingulate synchrony in dementia, indicating progressive network reorganization and eventual decoupling along the disease continuum. This study provides the first biomarker-defined longitudinal mapping of cerebellar subregional atrophy in Ad. The findings demonstrate that cerebellar degeneration is not confined to advanced stages but emerges early and dynamically interacts with cortical networks, influencing both cognitive decline and neuropsychiatric symptoms. The distinct atrophy patterns and cortico-cerebellar decoupling underscore the cerebellum's potential as a disease-stage-specific biomarker and therapeutic target in Ad.