Changes in brain connectivity revealed in people with preclinical Alzheimer’s disease

Summary: Accumulation of beta-amyloid and tau proteins disrupts connections between brain regions associated with memory years before the onset of Alzheimer’s disease symptoms.

Source: Mass General

A new study by researchers at Massachusetts General Hospital (MGH) shows the impact of early accumulation of amyloid-β and tau proteins on disrupting connections between brain structures important for memory.

These disrupted connections were present even before signs of cognitive impairment were observed. The findings may lead to strategies that can help detect the condition early.

For years, researchers have known that the amyloid-β and tau pathologies, hallmarks of Alzheimer’s disease, can lead to the death of neurons – the most abundant cells in the brain – which eventually leads to impairment and dementia.

“But we didn’t know how the brain’s connections react to the accumulation of these proteins very early in the disease process, even before the symptoms,” says Yakeel Quiroz, PhD, lead author of the paper published in the Proceedings of the National Academy of Sciences. Quiroz is a researcher in the Departments of Psychiatry and Neurology and Director of the MGH’s Familial Dementia Neuroimaging Laboratory and Multicultural Alzheimer’s Disease Prevention Program.

To learn more about this phenomenon, Quiroz and his colleagues used positron emission tomography (PET) for tau and amyloid-β, and functional magnetic resonance imaging (fMRI) to study how the pathologies of the disease d were linked to connectivity of brain regions and networks in individuals of a large family of more than 6,000 living members with prevalence of AD from Antioquia, Colombia, South America. Those with the mutation known as Presenilin-1 E280A) are almost certain to develop AD dementia, typically showing signs of mild cognitive impairment (MCI) at age 44 and dementia at age 49.

None of the individuals studied had yet exhibited cognitive symptoms. Quiroz and his colleagues forged a unique relationship with this Colombian family over the years, eventually creating the COLBOS Study (Colombia: Boston) in 2015 to learn about disease progression before the emergence of cognitive impairment and to find sensitive biomarkers to predict who is at high risk for dementia.

Previously, this research team showed that these people had elevated levels of amyloid-β almost two decades before the onset of MCI, and tau pathology almost six years before the onset. “Studying this unique population can really help us understand how amyloid-β and tau pathologies might affect how the brain communicates years before individuals develop dementia,” says Edmarie Guzmán-Vélez, co- first author of the article.

The team used fMRI to examine brain regions at the voxel level, like pixels that represent 3D units encompassing millions of brain cells, to examine connectivity within and between different brain networks. They learned that mutation carriers exhibited connection disruptions in the brain’s main memory network years before the onset of cognitive impairment in the family.

The researchers also developed a new mathematical approach combining both fMRI and molecular imaging to see more clearly when brain regions begin to disconnect during the disease process.

“This mathematical approach showed how the functional dysconnectivity of a memory network was explained by the early stages of tau pathology,” explains Ibai Diaz, co-first author of the paper.

These results suggest that functional disconnects are evident once tau begins to accumulate in the brain and before brain atrophy, a sign of neurodegeneration, is detected.

“This discovery improves our understanding of how AD-related pathology alters the functional organization of the brain years before the onset of cognitive impairment,” says Quiroz.

This shows a drawing of a brain with a hand underneath
For years, researchers have known that the amyloid-β and tau pathologies, hallmarks of Alzheimer’s disease, can lead to the death of neurons – the most abundant cells in the brain – which eventually leads to impairment and dementia. Image is in public domain

“These results are exciting because they also suggest that fMRI could be used in the future to identify people who may already have Alzheimer’s disease pathology in their brains and may develop dementia in the future, although further research is still needed.”

The researchers hope this idea will inject a level of urgency and importance into preclinical and clinical trials for AD, especially those targeting disease prevention.

Quiroz adds, “We now know that a lot is going on in the brains of people at risk for Alzheimer’s disease, even before signs of memory impairment. We therefore hope that such findings can improve our understanding of preclinical Alzheimer’s disease and help improve the selection of these people. who would benefit the most from participating in clinical trials.

Jorge Sepulcre is co-lead author. Funding for this research was provided by fellowships from the National Institutes of Health, a grant from the Alzheimer’s Association, the Massachusetts General Hospital ECOR Research Executive Committee, and an MGH Research Scholar Award.

About this Alzheimer’s disease research news

Author: Michael Morrison
Source: mass general
Contact: Michael Morrison – mass general
Picture: Image is in public domain

Original research: Access closed.
Amyloid-β and tau pathologies are linked to distinctive brain dysconnectomics in preclinical autosomal dominant Alzheimer’s disease” by Yakeel Quiroz et al. PNAS


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Amyloid-β and tau pathologies are linked to distinctive brain dysconnectomics in preclinical autosomal dominant Alzheimer’s disease

The human brain is composed of functional networks that have a modular topology, where brain regions are organized into communities that form dense internal (segregated) and external sparse (integrated) subnetworks that underlie higher-order cognitive functioning. .

Amyloid-β and tau pathology in preclinical Alzheimer’s disease (AD) is hypothesized to spread through functional networks, disrupting neural communication that leads to cognitive dysfunction.

We used network analyzes based on high-resolution graphs (at the voxel level) to test whether amyloid-β and tau load in vivo were associated with the segregation and integration of brain functional connections and memory. episodic in presenilin-1 E280A carriers without cognitive impairment. who are expected to develop early-onset AD dementia in an average of ∼13 years.

Compared to noncarriers, mutation carriers showed less functional segregation and integration in the posterior regions of the Default Mode Network (DMN), particularly the precuneus, and in the retrospenial cortex, which linked the temporal regions medial and cortical regions of the DMN. Mutation carriers also showed greater functional segregation and integration in regions connected to the salience network, including the striatum and thalamus.

Greater tau loading was associated with lower separate and integrated functional connectivity of DMN regions, particularly the precuneus and medial prefrontal cortex. In turn, greater tau pathology was linked to higher segregated and integrated functional connectivity in the retrospenial cortex and the anterior cingulate cortex, a hub of the salience network.

These findings inform our understanding of how AD-related pathology distinctly alters the functional architecture of the brain at the preclinical stage, eventually contributing to the spread of pathology and ultimately resulting in dementia.

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