Dissociable Effects of Alzheimer's Disease-Related Cognitive Dysfunction and Aging on Functional Brain Network Segregation

Alzheimer's disease (AD) is associated with changes in large-scale functional brain network organization. Individuals with AD exhibit less segregated resting-state brain networks compared with individuals without dementia. However, declines in brain network segregation are also evident as adult individuals grow older. Determining whether these observations reflect unique or overlapping alterations on the functional connectome of the brain is essential for understanding the impact of AD on network organization and incorporating measures of functional brain network or-ganization toward AD characterization. Relationships between AD dementia severity and participant's age on resting-state brain system segregation were examined in 326 cognitively healthy and 275 cognitively impaired human individ-ual s recruited through the Alzheimer's Disease Neuroimaging Initiative (ADNI) (N 5 601; age range, 55-96 years; 320 females). Greater dementia severity and increasing age were independently associated with lower brain system segre-gation. Further, dementia versus age relationships with brain network organization varied according to the processing roles of brain systems and types of network interactions. Aging was associated with alterations to association systems, primarily among within-system relationships. Conversely, dementia severity was associated with alterations that included both association systems and sensory-motor systems and was most prominent among cross-system interac-tions. Dementia-related network alterations were evident regardless of the presence of cortical amyloid burden, revealing that the measures of functional network organization are unique from this marker of AD-related pathology. Collectively, these observations demonstrate the specific and widespread alterations in the topological organization of large-scale brain networks that accompany AD and highlight functionally dissociable brain network vulnerabilities associated with AD-related cognitive dysfunction versus aging.