The emerging role of the cerebellum in neurodegeneration linked to cognitive impairment

The cerebellum, traditionally associated with motor control, has recently gained attention for its involvement in cognition functions. Numerous neuroimaging and clinical research has unveiled the cerebellum's functional heterogeneity, with distinct cerebellar topographical regions exhibiting selective functional connectivity with distributed cortical networks that modulate diverse motor and non-motor processes.^1–4 These findings challenge the view of the cerebellum as a unitary structure, instead supporting a model wherein dissociable cortico-cerebellar circuits are topographically organized and functionally dedicated to specific cognitive domains. The recognition of the cerebellum's functional topology and connectivity architecture has catalyzed a shift in conceptualizing it as a versatile cognitive neural system, in addition to a structure for motor control. This evolved perspective has sparked intensive investigation into how cerebellar dysfunction contributes to the cognitive and behavioral deficits manifested in various neurological and neuropsychiatric conditions.

Accumulating evidence suggests cerebellar structure and function may be altered in Alzheimer's disease (AD). ⁵ Structural magnetic resonance imaging (MRI) studies have found progressive cerebellar gray matter atrophy across the different disease severity of AD, particularly in the posterior cerebellar lobe that is known to have a significant role in cognition.^6,7 Additionally, a functional MRI study discovered that AD patients have a disruption in cerebro-cerebellar limbic network connectivity. ⁸ In patients with amnestic mild cognitive impairment (aMCI), a prodromal state of AD, early cerebellar volume changes have also been identified by structure MRI. ⁹ However, we still do not know if there is functional connectivity disruption of cerebello-cortical network in aMCI, which will provide information if the cerebellar network is involved in this early stage.

To determine the cerebellar network changes in aMCI, Lin et al., ¹⁰ obtained the resting state functional MRI in 15 cognitively normal and 16 aMCI participants and used seed-based analyses to examine cerebello-cerebral functional connectivity in cognitive cerebellar lobules (VI, VII, Crus I/II) between aMCI patients and controls. They found that aMCI patients have weaker functional connectivity between left cerebellar Crus I - right supramarginal gyrus and left cerebellar Crus II - bilateral supramarginal gyrus, compared to controls. Participants with aMCI exhibited stronger cerebellar Vermis III - left parietal operculum functional connectivity. To test if cognitive impairment was associated with cerebello-cerebral functional connectivity changes, they performed clinico-imaging correlation and found that cognitive performance in aMCI patients, measured by Clinical Dementia Rating scale score sum-of-boxes (CDR-SB) scores, positively correlate with cerebellar lobule VI - bilateral precentral and cerebellar Vermis III - precuneus functional connectivity. In other words, aMCI patients with worse cognitive status had a stronger sub-circuit cerebello-cortical connectivity. In addition, they found better word recall is associated with stronger cerebellar lobule VIII - angular gyrus and cerebellar VIIb - cingulate gyrus functional connectivity. Moreover, a higher AD Assessment Scale-Cognitive subscale (ADAS-Cog) in orientation is related to stronger cerebellar lobule IX - bilateral putamen functional connectivity. Therefore, there are connectivity changes between the cognitive part of the cerebellum and widespread regions in the cerebral cortex and putamen in aMCI.

This study provides interesting insights into the dynamic cerebello-cortical interactions in the prodromal stage of AD (i.e., aMCI). First, these different cerebello-cortical circuits may have circuit-specific increases or decreases in functional connectivity, providing a contributory or compensatory role for cognitive performance. Second, each cerebellar lobule has distinct changes, corresponding to different parts of the cerebral cortex, which may play roles in specific cognitive functions. Third, some of the connectivity readouts correlate with cognitive performance in aMCI, suggesting greater recruitment of cerebello-cortical and cerebello-subcortical circuits may help preserve specific cognitive abilities in the early stages of AD neurodegeneration. Alternatively, the mal-adaptation of cerebello-cortical circuits may contribute to cognitive impairment.^11,12 Since the cerebellum is not the primary site for tau or amyloid pathology, these changes could be the consequences of neurodegeneration of the cerebral cortex but still contribute to the overall cognitive performance and/or to help maintain cognitive functioning in the face of emerging neuropathology. ¹³

It is important to acknowledge several limitations that should be considered when interpreting the present findings. First, the cross-sectional nature of the study design precludes any inferences about how cerebellar functional connectivity dynamically changes over time as cognitive impairment progresses along the AD trajectory. Longitudinal studies tracking these cerebellar functional connectivity measures in conjunction with clinical outcomes will be crucial for elucidating the temporal dynamics and directionality of effects. Additionally, participants were recruited based on clinical diagnoses; therefore, the study lacked comprehensive biomarker data, such as amyloid positron emission tomography or cerebrospinal fluid analysis, ¹⁴ to determine the presence and extent of AD neuropathology in each individual. Integration of these biomarkers would significantly strengthen the mechanistic interpretability of the observed cerebello-cerebral functional connectivity alterations in relation to the underlying pathology. Furthermore, the relatively small sample size may limit statistical power to reliably detect subtle changes. Future larger-scale, multi-site studies with more ethnically and demographically heterogeneous samples are warranted. Despite these limitations, the present work provides a foundation for continued investigation into the cerebellum's role across the AD spectrum.

AD now is increasingly recognized as a network disorder. Instead of focusing solely on amyloid-beta plaques and neurofibrillary tangles, research now emphasizes how interconnected brain regions become dysfunctional, collectively leading to cognitive decline. We just began to understand the contribution of the cerebellum to the AD brain network and the knowledge gained has the potential to develop neuromodulation strategies for aMCI and/or AD by enhancing the network compensatory mechanism. ¹⁵