Brain network connectivity and dementia risk: a bidirectional Mendelian randomisation perspective

Disruptions in resting-state functional brain networks are consistently observed in dementia, yet their underlying relationships remain incompletely understood. This study aimed to investigate potential associations between resting-state functional MRI (rs-fMRI) phenotypes and various dementia subtypes.

We performed bidirectional two-sample Mendelian randomization (MR) analyses using summary statistics from 191 rs-fMRI phenotypes (n = 34,691) and five types of dementia (n = 6,618 to 373,159). Forward MR assessed the effects of rs-fMRI phenotypes on dementia risk, while reverse MR evaluated the impact of dementia on rs-fMRI phenotypes.

Forward MR analysis identified seven rs-fMRI phenotypes significantly associated with dementia risk. Enhanced dorsolateral superior frontal gyrus connectivity, part of the default mode network, was linked to reduced Alzheimer's disease risk (odds ratio (OR) = 0.52, 95 % confidence interval (CI): 0.41-0.66, P = 1.10 × 10^-7). Increased connectivity within the default mode and central executive networks correlated with lower vascular dementia risk (OR = 0.60, 95 % CI: 0.48-0.75, P = 9.44 × 10^-6). Reverse MR revealed significant associations between dementia subtypes and rs-fMRI phenotypes, including Alzheimer's disease-related increases in limbic connectivity and decreases in default mode and central executive networks. For Lewy body dementia, heightened connectivity in salience and sensorimotor networks and reduced default mode connectivity were observed.

Our findings identify functional networks whose connectivity patterns may be associated with dementia risk and could provide potential insights for biomarker discovery or preventive research. However, these results are based on statistical inference and require further validation in longitudinal and experimental studies to confirm their clinical relevance and potential translational implications.