The interplay between insomnia and Alzheimer’s Disease across three main brain networks

Background Insomnia is prevalent along the trajectory of Alzheimer’s disease (AD), but the neurobiological underpinning of their interaction is poorly understood. Here, we assessed structural and functional brain measures within and between the default mode network (DMN), salience network (SN), and central executive network (CEN). Methods We selected 320 subjects from the ADNI database and divided by their diagnosis: cognitively normal (CN), Mild Cognitive Impairment (MCI), and AD, with and without self-reported insomnia symptoms. We measured the gray matter volume (GMV), structural covariance (SC), degrees centrality (DC), and functional connectivity (FC). We tested the effect and interaction of insomnia symptoms and diagnosis on each index across groups. Subsequently, we performed a within-group linear regression for each network. Finally, we correlated brain abnormalities with cognitive scores. Results Insomnia symptoms were associated with FC alterations across all groups. The AD group also demonstrated an interaction between insomnia and diagnosis. In the CN and MCI groups, insomnia symptoms were characterized by patterns of within-network hyperconnectivity, while in the AD group, within- and between-network hypoconnectivity was observed. FC alterations within and between DMN and CEN hubs were associated with reduced MMSE scores in each of the groups. SC and GMV alterations were non-significant in the presence of insomnia symptoms, and DC indices only showed network-level alterations in the CEN for AD individuals. Conclusions Insomnia symptoms affect the intrinsic functional organization of the three networks along the AD trajectory. Patients with AD present with a unique pattern of insomnia-related functional alterations, highlighting the profound interaction between both conditions. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study did not receive any funding. J.D.E. is funded by the German Federal Ministry of Education and Research (BMBF) and the Max Planck Society. S.B.E received Helmholtz Imaging Platform grant (NimRLS, ZT-I-PF-4-010). Data collection and sharing for this project was funded by the Alzheimer's Disease Neuroimaging Initiative (ADNI) (National Institutes of Health Grant U01 AG024904) and DOD ADNI (Department of Defense award number W81XWH-12-2-0012). Other contributors and funding sources can be found on the ADNI website: ([https://adni.loni.usc.edu/wpcontent/uploads/how\_to\_apply/ADNI\_Acknowledgement\_List.pdf][1]). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study used openly available human data that were originally located at the Alzheimer Disease Neuroimaging Initiative (ADNI) website () I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as [ClinicalTrials.gov][2]. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes The Alzheimer Disease Neuroimaging Initiative (ADNI) is a multisite initiative for the prevention and treatment of AD. The MRI, CSF biomarker, and clinical data used in the present study are available under the ADNI data sharing policy. Modifications to the data were tracked by DataLad and are reported in a GitLab repository (). [1]: https://adni.loni.usc.edu/wpcontent/uploads/how_to_apply/ADNI_Acknowledgement_List.pdf [2]: http://ClinicalTrials.gov