The causal association between resting state intrinsic functional networks and neurodegeneration

Alterations of resting state intrinsic functional networks have been associated with neurodegenerative diseases even before the onset of cognitive symptoms. Emerging hypotheses propose a role of resting state intrinsic functional networks alterations in the risk or vulnerability to neurodegeneration. It is unknown whether intrinsic functional network alterations can be causal for neurodegenerative diseases. We sought to answer this question using two-sample Mendelian randomization. Using the largest genome-wide association study of resting state intrinsic functional connectivity (n = 47 276), we generated genetic instruments (at the significance level 2.8 ×10^-11) to proxy resting state intrinsic functional network features. Based on the known brain regions implicated in different neurodegenerative diseases, we generated genetically proxied resting state intrinsic functional features and tested their association with their paired neurodegenerative outcomes: features in parieto-temporal regions and Alzheimer dementia (111 326 cases, 677 663 controls); frontal region and frontotemporal dementia (2154 cases, 4308 controls); temporal pole region and semantic dementia (308 cases, 616 controls), and occipital region with Lewy body dementia (LBD) (2591 cases, 4027 controls). Major depressive disorder outcome (170 756 cases, 329 443 controls) was included as a positive control and tested for its association with genetically proxied default mode network (DMN) exposure. Inverse-variance weighted analysis was used to estimate the association between the exposures (standard deviation units) and outcomes. Power and sensitivity analyses were completed to assess the robustness of the results. None of the genetically proxied functional network features were significantly associated with neurodegenerative outcomes (adjusted P value >0.05), despite sufficient calculated power. Two resting state features in the visual cortex showed a nominal level of association with LBD (P = 0.01), a finding that was replicated using a different instrument (P = 0.03). The genetically proxied DMN connectivity was associated with the risk of depression (P = 0.024), supporting the validity of the genetic instruments. Sensitivity analyses were supportive of the main results. This is the first study to comprehensively assess the potential causal effect of resting state intrinsic functional network features on the risk of neurodegeneration. Overall, the results do not support a causal role for the tested associations. However, we report a nominal association between visual network connectivity and Lewy body dementia that requires further evaluation.