# Cerebellar subregional structural changes across the Alzheimer’s disease continuum: a longitudinal analysis of cognitive and behavioural correlates

## TL;DR

The cerebellum shows early structural changes in Alzheimer’s disease, linked to cognitive and behavioral decline, suggesting it could be a key biomarker and treatment target.

## Contribution

First biomarker-defined longitudinal mapping of cerebellar subregional atrophy across Alzheimer’s disease stages.

## Key findings

- Cerebellar atrophy in lobule VI and Crus I/II correlates with memory decline and behavioral symptoms in preclinical Alzheimer’s.
- Cortico-cerebellar coupling shifts from temporo-orbitofrontal regions in early stages to posterior cingulate in dementia.
- Cerebellar degeneration begins early and dynamically interacts with cortical networks, influencing cognitive and psychiatric symptoms.

## Abstract

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.

Um et al. report that cerebellar degeneration in Alzheimer’s disease begins early, with subregional atrophy in lobule VI and Crus I/II during the preclinical stage and widespread loss in dementia. These longitudinal findings reveal cortico-cerebellar interactions underlying cognitive and neuropsychiatric symptoms, suggesting the cerebellum as an early biomarker and therapeutic target.

Graphical Abstract