A protective role for the cerebellum in cognitive aging
Authors: d’Oleire Uquillas Federico , Sefik Esra , Seidlitz Jakob , Merriman Jewel , Zhang Veronica , Cohen Jonathan D. , Romero-Garcia Rafael , Warrier Varun , Bethlehem Richard A.I. , Alexander-Bloch Aaron F. , Sepulcre Jorge , Wang Samuel S.-H. , Vannini Patrizia , Gomez Jesse 
Published: October 2024

Background

Brain reserve — the brain’s resilience to age-related change or damage — provides protection against cognitive decline. The cerebellum is relatively unstudied as a contributor to brain reserve. This study investigates cerebellar brain reserve in the largest cohort to date.

Methods

We used data from the Human Connectome Project (n=708, 36-100yrs), UK Biobank (n=45,013, 44-81yrs), and ADNI (n=1,423, 56-95yrs). ADNI participants were cognitively normal or had a diagnosis of mild cognitive impairment or Alzheimer’s disease (AD) dementia. We examined associations between cerebellar tissue volume, age, Montreal Cognitive Assessment (MoCA) scores, global PET amyloid burden, and APOE genotype.

Findings

HCP-Aging data revealed heterogenous aging-associated changes in cerebellar volume, with the greatest effects in posterior hemispheric regions (crus I) (Bonferroni-corrected,p<0·05). MoCA scores were associated with higher tissue density in the cerebellum (p<0·0001) to the same extent as neocortex, and MoCA scores coupled most strongly with posterior cerebellar cortex. Strikingly, greater volume in MoCA visuospatial-related cerebellar cortex protected against aging-related cognitive decline (p=0·0001). We replicated tissue aging results in the UK Biobank with the greatest aging-related effects in posterior cerebellum (p<0·0001), and an association of greater cerebellar volumes with less cognitive decline (Trails Making-B:p<0·00001; Digit Symbol Substitution:p=0·034). AD patients with low amyloid-beta burden (Aβ−) exhibited the strongest cerebellar association with MoCA (volume x group, Aβ− AD:p=0·0001). In Aβ− individuals, APOE ε4/ε4 carriers showed the greatest effect with MoCA (volume x APOE, ε4/ε4:p=0·017).

Interpretation

Our large-scale study demonstrates a potentially strong role for the cerebellum in mitigating cognitive decline. The persistence of this protection in APOE ε4/ε4 carriers reshapes our understanding of reserve and AD risk. Our findings open the cerebellum as a novel target for future clinical research on brain reserve in aging populations.

Funding

National Science Foundation, National Academies of Sciences, Engineering and Medicine, National Institutes of Health.

Research in Context

Evidence before this study

We searched PubMed and GoogleScholar between August 12, 2023, and September 25, 2024 for articles irrespective of language or date of publication, relating to measures of cortical and cerebellar aging. Search terms included “cerebellum”, “cognitive aging”, “cerebellar reserve”, “Alzheimer’s disease”, “covariance”, “retrogenesis”, and “connectivity”. Prior research demonstrated that the cerebellum may play a role in cognitive function. Studies have shown that cerebellar development is spatially heterogenous, with posterior regions undergoing the most protracted change in structure and function. Brain reserve has been predominantly studied in the neocortex, with some studies suggesting the cerebellum may contribute to cognitive changes in diseases like Alzheimer’s disease (AD) dementia. Cerebellar volume differences between young and older adults have been noted, as well as between healthy adults and neurodegenerative conditions like Parkinson’s disease. However, the cerebellum’s contribution to cognitive reserve, particularly in healthy aging and individuals with a clinical diagnosis of mild cognitive impairment or AD dementia, had not been explored especially in large population-based datasets.

Added value of this study

To our knowledge, this study is the largest to date looking into how cerebellar structures contribute to cognitive outcomes in both healthy older adults, and those with mild cognitive impairment or AD dementia. We leverage three large neuroimaging datasets — HCP-Aging, UK Biobank, and ADNI — and demonstrate that cerebellar aging is spatially heterogeneous, with posterior regions showing the greatest age-related decline. We further establish a significant link between larger cerebellar volumes and better cognitive outcomes, suggesting that the cerebellum plays a role in cognitive resilience. Additionally, we identify how cerebellar structures predict cognitive performance and interact with amyloid-beta brain pathology and APOE genotype, particularly in those with low amyloid brain burden and those at greatest risk of AD such as in homozygous APOE e4 allele carriers.

Implications of all the available evidence

The aging of the global population raises the challenge of maintaining cognitive health in older age. Our research focuses on the cerebellum as a novel mediator of preserved cognitive function in old age and clinical dementia. Our findings have profound implications, given that individuals with robust cerebellar structures may be missed during cognitive and clinical screenings. Greater cerebellum volume seems to be most advantageous in those at higher risk for Alzheimer’s disease based on APOE4 status and those who have yet to accumulate substantial amyloid-beta brain pathology. Our study underscores the importance of the cerebellum as a novel brain reserve mechanism in aging populations.