Exploring the Complex Interplay between Alzheimer’s Disease and Aging: Insights from Functional Brain System Segregation


Adult aging is recognized as the primary risk factor for Alzheimer’s disease (AD), a neurodegenerative disorder characterized by a progressive decline in cognitive function. The prevalence of AD doubles every 5 years after the age of 65, underscoring the intimate connection between aging and the onset of this devastating condition (Hebert et al., 2013).

The clinical manifestations of AD encompass a spectrum of cognitive difficulties, ranging from deficits in memory and executive function to sensory and motor processing impairments (Salmon and Bondi, 2009; Albers et al., 2015; Murphy, 2019). These challenges are thought to arise from the failure of multiple distributed brain systems interconnected within a large-scale brain network (Delbeuck et al., 2003; Stam, 2014; Yu et al., 2021).

To unravel the complexities of AD-related brain dysfunction, it is crucial to discern how the alterations in brain network organization associated with AD differ from those occurring in typical aging.

Resting-State Functional Connectome: A Window into Brain Organization

The functional organization of the brain can be elucidated through the examination of the resting-state functional connectome, particularly in healthy young adults. This connectome reveals a modular organization characterized by the segregation of large-scale brain systems, facilitating functional specialization and supporting individual differences in cognitive abilities (Tononi et al., 1994; Sporns and Betzel, 2016; Wig, 2017).

Altered Brain System Segregation in Alzheimer’s Disease

Evidence indicates that resting-state brain system segregation is disrupted in AD. Compared to healthy controls, AD patients exhibit fewer modular networks, suggesting a breakdown in the normal modular organization (Brier et al., 2014a). Moreover, higher brain system segregation appears to mitigate the impact of AD severity on cognition in both autosomal-dominant and sporadic AD cases (Ewers et al., 2021).

Longitudinal changes in brain system segregation among healthy individuals are predictive of dementia, independent of AD-related genetic risk, pathological markers (cortical amyloid and CSF tau burden), and structural deterioration (Chan et al., 2021). This implies that AD’s effects on brain function extend beyond isolated regions or specific brain systems, emphasizing the importance of assessing the broader network interactions through measures of system segregation.

Dynamic Changes in Brain System Segregation during Healthy Aging

However, it is essential to recognize that alterations in brain system segregation are not exclusive to AD. In the absence of AD, healthy aging is associated with a decline in brain system segregation with increasing age (Betzel et al., 2014; Chan et al., 2014; Sala-Llonch et al., 2015; Geerligs et al., 2015b; Han et al. 2018). These age-related changes are linked to alterations in brain function, cognitive decline, and are influenced by environmental exposures during adulthood (Chan et al., 2017, 2018, 2021; Chong et al., 2019; Pedersen et al., 2021).

Navigating the Complexity: Comparing AD-Related and Aging-Related Network Changes

While it is evident that both AD and aging are associated with reductions in resting-state brain system segregation, the critical question arises: Do the observed functional network changes in AD mirror common or unique patterns compared to those occurring in normal aging?

Merely comparing summary network measures might obscure meaningful differences in network topology (Wig, 2017). To disentangle the intricate correlation patterns associated with AD from those associated with aging, we embarked on an investigation to determine whether distinct relationships exist between AD dementia severity and aging concerning functional brain system segregation and the specific network interactions that constitute this measure.


The discussion surrounding Alzheimer’s disease (AD) and aging has been further illuminated by an exploration into resting-state brain system segregation. This intricate analysis reveals that AD dementia severity and aging independently contribute to reductions in brain system segregation, offering valuable insights into the functional changes associated with these processes.

Associations with Dementia Severity and Aging:

The study presents compelling evidence that dementia severity and aging are distinct contributors to alterations in resting-state brain system segregation. Notably, these alterations persist irrespective of amyloid burden or the presence of the APOE4 genetic risk factor. The study emphasizes the importance of scrutinizing large-scale resting-state network organization to disentangle the intricate relationships between AD-related and aging-related brain dysfunction.

Dissociation of Alterations in Resting-State Correlations:

The investigation discerns that increasing dementia severity and older age are linked to alterations in different sets of resting-state correlations. These alterations are characterized by their functional roles and the nature of network interactions, suggesting a nuanced relationship between AD and aging in terms of their impact on brain network organization.

Alzheimer’s Disease and Functional Network Interactions:

The study aligns with prior research pinpointing AD-associated alterations in default system regions. However, it extends beyond previous findings by demonstrating that AD dementia severity affects a broader spectrum of functional relationships, involving both higher-order cognitive operations and sensory-motor processing. Even in mild cases of impairment, alterations are detectable, challenging preconceived notions about the nature and extent of cognitive deficits in early-stage AD.

Sensory-Motor Network Alterations in Alzheimer’s Disease:

Unexpectedly, alterations in sensory-motor network relationships are observed in AD, challenging conventional views of cognitive deficits primarily involving long-term memory and executive function. The findings underscore the need to consider sensory and motor function as early indicators of AD, aligning with existing evidence of impairments in visual, auditory, and olfactory processing among AD patients.

Functional Systems Interaction in Dementia:

Contrary to the “disconnection hypothesis,” which posits weakened structural connections in AD, the study unveils strengthened resting-state functional relationships across distinct brain systems. This counterintuitive observation may be a maladaptive consequence of white matter structural disconnection or damage to brain network hubs. The concept of information integration emerges as a central deficit in AD, aligning with behavioral impairments observed in patients.

Aging-Related Alterations:

In contrast to dementia, aging-related alterations predominantly affect within-system relationships. The weakening of these interactions reflects the progressive loss of brain area specialization, a common aspect of aging. The study cautions against potential confounding factors, such as cardiac and respiratory signals, highlighting the need for meticulous control in addressing age-related differences in functional correlations.

Independence from Amyloid Pathology:

Crucially, the study demonstrates that greater dementia severity is associated with lower brain system segregation independently of amyloid pathology. This challenges prevailing views linking AD-related brain dysfunction solely to amyloid burden and suggests that functional alterations provide a distinct measure of cognitive resilience in AD.

Implications for AD Biomarker Frameworks:

The study calls for a reevaluation of current AD biomarker frameworks, proposing the incorporation of functional measures, such as resting-state system segregation, into existing models. This recommendation stems from the observed dissociation between alterations in brain system segregation and AD-related pathology, emphasizing the unique contribution of functional measures to understanding cognitive dysfunction in AD.


In conclusion, the intricate interplay between Alzheimer’s disease and aging is unraveled through a meticulous examination of resting-state brain system segregation. This study not only advances our understanding of the distinct contributions of AD dementia severity and aging to functional network alterations but also calls for a paradigm shift in how we conceptualize and measure cognitive resilience in the context of AD.


Alzheimer’s and Lower Brain System Segregation

Alzheimer’s disease is a neurodegenerative disorder that affects the brain. It is characterized by the buildup of amyloid plaques and tau tangles in the brain, which leads to the loss of brain cells and cognitive decline.

One of the early changes that occurs in Alzheimer’s disease is a decrease in brain system segregation. Brain system segregation is the organization of the brain into distinct functional networks. These networks are responsible for different cognitive functions, such as memory, attention, and language.

How Does Lower Brain System Segregation Affect Alzheimer’s?

Examining individual changes in resting-state brain system segregation across years a, For each participant, resting-state brain network graphs were created using functional nodes (Chan et al.³³) labeled by their corresponding functional systems (Power et al.³⁹). b, While the exact topology of networks differs between individuals, examples of brain graphs are depicted here for two individuals of equivalent age at their first scan but with differing degrees of longitudinal change in brain system segregation. Relative to their baseline networks, greater reductions in brain system segregation are observable in the participant on the right than in the participant on the left over a comparable time span (white dashed circle, reduced separation of brain systems). – https://www.researchgate.net/figure/Examining-individual-changes-in-resting-state-brain-system-segregation-across-years-a_fig2_356154965

A decrease in brain system segregation can lead to a number of cognitive problems in Alzheimer’s disease. For example, it can make it difficult to remember recently learned information, to pay attention, and to communicate effectively.

What Causes Lower Brain System Segregation in Alzheimer’s?

The exact cause of lower brain system segregation in Alzheimer’s disease is not fully understood. However, it is thought to be related to the buildup of amyloid plaques and tau tangles in the brain. These plaques and tangles can disrupt the connections between different brain regions, leading to a decrease in brain system segregation.

What are the Implications of Lower Brain System Segregation in Alzheimer’s?

The decrease in brain system segregation that occurs in Alzheimer’s disease is a significant factor in the cognitive decline that is associated with the disorder. It is also a potential target for new Alzheimer’s treatments.

Potential Treatments for Lower Brain System Segregation in Alzheimer’s

Several potential treatments for lower brain system segregation in Alzheimer’s disease are currently being investigated. These treatments include:

  • Medications that target amyloid plaques and tau tangles. These medications aim to slow or stop the progression of Alzheimer’s disease by removing or preventing the buildup of amyloid plaques and tau tangles.
  • Non-pharmaceutical interventions. These interventions include cognitive training, physical exercise, and social interaction. These interventions may help to improve cognitive function in people with Alzheimer’s disease, even if they do not stop the progression of the disease.

Future Directions for Research

Researchers are continuing to investigate the causes and consequences of lower brain system segregation in Alzheimer’s disease. This research is important for developing new treatments for the disorder.


Lower brain system segregation is a significant factor in the cognitive decline that is associated with Alzheimer’s disease. It is a potential target for new Alzheimer’s treatments. Researchers are continuing to investigate the causes and consequences of lower brain system segregation in Alzheimer’s disease. This research is important for developing new treatments for the disorder.

reference link: https://www.jneurosci.org/content/43/46/7879#sec-22


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