Genetic risk of late-onset Alzheimer’s disease is associated with longitudinal loss of functional brain network segregation in middle-aged cognitively healthy individuals: The PREVENT-Dementia Study

It is well acknowledged that the pathological processes of Alzheimer’s disease (AD) start decades before clinical manifestations, but early indicators of AD in midlife remain unclear. Functional segregation of brain networks has recently emerged as a key indicator of brain health. In this study, we investigated the vulnerability of intrinsic brain networks to loss of functional segregation during healthy adult lifespan and in cognitively healthy midlife individuals at risk of late-onset AD, and the association between segregation loss and cognition in midlife. Network segregation was measured using the participation coefficient metric within a graph-theoretic framework. In a healthy adult lifespan cohort (18-88 years, N=652), linear relationships of network segregation with age and cortical grey matter volume (GMV) were assessed using multiple regression models. In a cognitively healthy midlife cohort (40-59 years, N=210), associations between network segregation and established risk factors for AD were examined cross-sectionally and longitudinally (over 2 years). Across the healthy adult lifespan, global network segregation was positively associated with GMV and negatively associated with age, replicating previous findings. Three high-order networks [default mode (DMN), frontal-parietal control, and salience] and two sensorimotor networks (visual and motor) showed prominent age-related changes in functional segregation throughout adulthood. At midlife, cross-sectionally, cognitively healthy apolipoprotein ( APOE ) ε4 carriers had higher global segregation than non-carriers. The DMN was the only individual network to show such an effect of APOE genotype. Higher global and DMN segregation was associated with better episodic and relational memory. Critically, APOE ε4 carriers, but not non-carriers, showed a significant longitudinal loss of segregation in the DMN over 2 years. Overall, our findings suggest that functional network segregation constitutes a novel and early substrate for the impact of the genetic AD risk on the brain in midlife and thus have implications for the early detection and intervention in AD. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study was funded by the UK Alzheimers Society (grant numbers 178 and 264), the US Alzheimers Association (grant number TriBEKa-17-519007) and philanthropic donations. ### 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 NHS Research Ethics Committee of London Camberwell St Giles gave ethical approval for this work. 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 All data produced in the present study are available upon reasonable request to the authors