Alzheimer’s disease (AD) poses a significant challenge, with adult aging being its primary risk factor. AD prevalence doubles every five years after the age of 65, leading to cognitive difficulties ranging from memory and executive function deficits to sensory and motor processing issues. The complexity of these cognitive challenges is thought to result from the failure of multiple distributed brain systems interconnected within a large-scale network.
Distinguishing between age-related and AD-specific brain network changes is crucial for understanding the disease’s etiology and developing effective diagnostic and staging approaches. The functional organization of the brain can be assessed at rest, revealing a modular organization in healthy young adults. This modular organization involves the segregation of large-scale brain systems, supporting functional specialization and influencing individual differences in brain function and cognitive abilities.
However, multiple studies have demonstrated alterations in resting-state brain system segregation in AD. Patients exhibit fewer modular networks than healthy controls, and higher brain system segregation mitigates the impact of AD severity on cognition. Longitudinal changes in brain system segregation among healthy adults are also indicative of dementia, independent of AD-related genetic risk and structural deterioration.Â
Notably, brain system segregation changes over the course of healthy adult aging, independent of AD. It tends to decline with increasing age and is associated with alterations in brain function, cognitive changes, and environmental exposures during adulthood. These age-related changes underscore the importance of distinguishing between normal aging processes and those specific to AD.Â
The current study, conducted through the Alzheimer’s Disease Neuroimaging Initiative (ADNI), aimed to unravel the relationships between AD dementia severity and aging on functional brain system segregation. The participants, totaling 783 individuals aged 55–96 years, underwent structural and functional magnetic resonance imaging (fMRI) processing.
Data were collected under various ADNI studies, and participants were diagnosed based on criteria such as the Wechsler Memory Scale, Mini-Mental State Exam, clinical dementia rating, and subjective memory concerns. The findings revealed that AD dementia severity and aging were independently associated with reductions in resting-state brain system segregation.
Importantly, these alterations were evident irrespective of the presence of amyloid burden or AD-related genetic risk. Closer examination revealed that greater dementia severity and older age were linked to alterations in distinct sets of resting-state correlations, suggesting unique patterns of network interactions.Â
The study corroborated early reports indicating AD-associated alterations in relationships among default system regions. However, it extended these findings by demonstrating that AD dementia severity affects functional relationships beyond default and association networks. These alterations involve systems related to higher-order cognitive operations (association systems) and those implicated in sensory and motor processing.
Even in mild cases of impairment (CDR = 0.5), these alterations were discernible and differed from aging-related functional network changes, which typically spare sensory-motor systems relative to association systems. Contrary to the “disconnection hypothesis” of AD, which suggests weakened functional relationships across brain systems, the study found an unexpected strengthening of resting-state functional relationships across distinct brain systems.
This strengthening, observed with increasing dementia severity, challenges conventional notions and may be a maladaptive consequence of white matter structural disconnection or damage to brain network hubs facilitating information integration. In contrast to dementia, age-associated alterations were more pronounced among within-system relationships. The weakening of within-system interactions observed with increased age likely reflects the progressive loss of brain area specialization.
Previous reports of increasing age being associated with both decreasing within-system relationships and increasing between-system correlations were not entirely replicated in this study. Possible explanations include unaccounted preclinical pathology in “healthy” individuals or variations in statistical control for cardiac and respiratory signals.Â
In summary, the study highlights the unique patterns of brain network alterations associated with AD dementia severity and aging. These findings provide valuable insights into the distinct relationships between large-scale resting-state network organization, cognitive dysfunction, and the aging process.
The observed alterations in sensory-motor network relationships in AD underscore the importance of considering a broader spectrum of cognitive functions affected by the disease. The results motivate the refinement of functional network-based biomarkers for AD diagnosis and staging, offering a promising avenue for advancing our understanding of this complex neurodegenerative condition.Â
Journal Reference Â
Ziwei Zhang, Micaela Y. Chan, Liang Han, Claudia A. Carreno, Ezra Winter-Nelson, Gagan S. Wig and for the Alzheimer’s Disease Neuroimaging Initiative (ADNI) Journal of Neuroscience 15 November 2023, 43 (46) 7879-7892; DOI: https://doi.org/10.1523/JNEUROSCI.0579-23.2023. Â
