Differential default-mode network effective connectivity in young-onset Alzheimer's disease variants

Young-onset Alzheimer's Disease(AD) is a rare form of AD characterized by early symptom onset (< 65 years) and heterogeneous clinical phenotypes. Previous studies have consistently shown that patients with late-onset AD exhibit alterations in the default mode network-a large-scale brain network associated with self-related processing and autobiographical memory. However, the functional organization of the default-mode network is far less clear in young-onset AD. Here, we assessed default-mode network effective connectivity in two common young-onset AD variants (i.e., typical amnestic variant and posterior cortical atrophy) and healthy participants to identify disease- and variant-specific differences in the default-mode network. This case-control study was conducted with thirty-nine young-onset AD patients, including typical amnestic (n = 26, 15 females, mean age = 61) and posterior cortical atrophy (n = 13; 8 females, mean age = 61.8), and 24 age-matched healthy participants (13 females, mean age=60.1). All participants underwent resting-state functional MRI and extensive neuropsychological testing. Spectral dynamic causal modelling was performed to quantify resting-state effective connectivity between default-mode network regions. Parametric empirical Bayes analysis was then performed to characterise group differences in effective connectivity. Our results showed that patients with typical AD variant showed increased connectivity from medial prefrontal cortex to posterior default-mode network nodes as well as reduced inhibitory connectivity from hippocampus to other default-mode network nodes, relative to healthy controls. Patients with posterior cortical atrophy exhibited decreased connectivity from posterior cingulate cortex to medial prefrontal cortex and bilateral angular gyrus and reduced inhibitory connectivity from left hippocampus to other default-mode network nodes compared to healthy controls. Right hippocampus connectivity differentiated the two patient groups. Patients with typical AD variant had lower inhibitory connectivity from right hippocampus to other default-mode network nodes than the patients with posterior cortical atrophy. Our findings suggest that resting-state default-mode network connectivity is a physiological phenotype of young-onset AD that could contribute to a new understanding offunctional integration in this condition. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement The YOAD study was funded by Alzheimer's Research UK through a generous donation from Iceland Foods. AR and KJF are affiliated with The Wellcome Centre for Human Neuroimaging, supported by core funding from Wellcome [203147/Z/16/Z]. AR is a CIFAR Azrieli Global Scholar in the Brain, Mind & Consciousness Program. JMS acknowledges the support ofthe National Institute for Health Research University College London Hospitals Biomedical Research Centre, Wolfson Foundation, Alzheimer's Research UK, Brain Research UK, Weston Brain Institute, Medical Research Council, British Heart Foundation, UK Dementia Research Institute and Alzheimer's Association. A.R. is funded by the Australian Research Council (Ref: DP200100757) and the Australian National Health and Medical Research Council (Investigator Grant 1194910). RWP acknowledges support from the National Institute for Health Research University College London Hospitals Biomedical Research Centre, the Alzheimer's Association. SC acknowledges the support of the Economic and Social Research Council and National Institute for Health Research (ESRC/NIHR ES/L001810/1). K. Y. is an Etherington PCA Senior Research Fellow and is funded by the Alzheimer's Society, grant number 453 (ASJF/18/003). ### 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 was approved by the National Hospital for Neurology and Neurosurgery Research Ethics Committee. All participants provided written informed consent. 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. 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 data that support the findings of this study are available from the corresponding author, upon reasonable request.