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 to non-demented individuals. However, declines in brain network segregation are also evident as adult individuals grow older. Determining whether these observations reflect unique or overlapping impacts on the brain's functional connectome is essential for understanding the impact of AD on network organization and incorporating measures of functional brain network organization towards AD characterization. The effects of AD dementia severity and participant's age on resting-state brain system segregation were examined in 326 cognitively healthy and 275 cognitively impaired Alzheimer's Disease Neuroimaging Initiative (ADNI) human individuals (N = 601, age range 55 - 96 years, 320 females). Greater dementia severity and increasing age were independently associated with lower brain system segregation. 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 interactions. Dementia-related network alterations were evident irrespective of 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 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. Significance Statement Alzheimer's disease (AD) associated cognitive dysfunction is hypothesized to be a consequence of brain network damage. It is unclear exactly how brain network alterations vary with dementia severity and whether they are distinct from alterations associated with aging. We evaluated functional brain network organization measured at rest among individuals who varied in age and dementia status. AD and aging exerted dissociable impacts on the brain's functional connectome. AD-associated brain network alterations were widespread and involved systems that subserve both higher order cognitive, but also sensory and motor operations. Importantly, AD-related network alterations were independent of amyloid pathology. The research furthers our understanding of AD-related brain dysfunction and motivates refining existing frameworks of dementia characterization with measures of functional network organization.