Familial Risk for Dementia, Cognitive Performance, and the Human Cerebello-Hippocampal Circuit: A Study in the European Prevention of Alzheimer’s Disease cohort

Abstract The cerebello-hippocampal (CB-HP) circuit is increasingly implicated in episodic and spatial memory, yet its role in normal aging, dementia risk, and sex differences remains unclear. Structure and function in both the hippocampus and cerebellum have been linked to mild cognitive impairment, Alzheimer’s Disease, and cognitive decline in healthy older adults. Literature on the CB-HP circuit is largely limited to animal studies and small samples of young adults in the context of visuospatial abilities, underscoring the need for large, diverse aging cohorts to establish CB-HP connectivity as an early, translatable marker of neurodegeneration. Here, we investigate the CB-HP circuit in the context of aging, dementia risk, behavior, and sex differences in healthy older adults to advance understanding of cognitive decline in the aging population. We explored this relationship in 857 healthy adults with and without a family history of dementia (aged 50-88, 59% female, 71% family history positive) using resting-state functional connectivity MRI (rsMRI) and behavioral assessments. We hypothesized that CB-HP functional connectivity (FC) would be lower with increased age, relate positively to cognitive performance, be lower in females positive for family history of dementia, and be lower in mild cognitive impairment (MCI)-risk than cognitively normal (CN) participants with sex differences therein. We observed selective links between CB-HP FC, cognition, and sex. MCI risk participants performed worse on spatial memory performances than CN, whereas CB-HP FC showed opposite performance slopes by risk status, suggesting the CB-HP circuit may function as a compensatory network for short-term recall. Sex differences were seen on cognitive tasks (delayed episodic memory and spatial tasks) and in CB-HP a better visuospatial index was linked to greater FC in females, while males displayed an inverse relationship. Behavioral differences by familial dementia history were shown, although CB-HP FC did not show effects here. Overall, CB-HP networks appear behaviorally silent in the aggregate but reveal risk- and sex-dependent relationships when memory demands and circuit nodes are considered. Competing Interest Statement The authors have declared no competing interest.