Amyloid-Associated Hyperconnectivity Drives Tau Spread in Alzheimer’s Disease

Academic Background

Alzheimer’s Disease (AD) is a common neurodegenerative disorder characterized by the accumulation of amyloid-beta (Aβ) plaques and the abnormal aggregation and spread of tau protein in the brain. The traditional “amyloid cascade hypothesis” posits that Aβ accumulation triggers tau pathology, leading to neuronal degeneration and cognitive decline. However, the mechanism by which Aβ influences tau spread remains unclear. Existing research suggests that Aβ may promote activity-dependent tau spread by inducing neuronal hyperactivity and hyperconnectivity. This mechanism has not been fully validated in human patients, and its implications for therapeutic strategies require further investigation. This study aims to explore whether Aβ accelerates tau spread across brain regions by enhancing neuronal connectivity and to uncover the potential role of this process in AD progression.

Source of the Paper

This paper was co-authored by Sebastian N. Roemer-Cassiano, Fabian Wagner, Lisa Evangelista, and others from institutions such as the University Hospital Munich, the Institute for Stroke and Dementia Research at LMU Munich, and the Max Planck School of Cognition. It was published on January 22, 2025, in the journal Science Translational Medicine.

Study Design and Process

Study Subjects and Data Sources

The study is based on data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) and the A4 study, including two cohorts:
1. ADNI Cohort: 209 participants, comprising 69 amyloid-negative (Aβ−) cognitively normal (CN) controls and 140 amyloid-positive (Aβ+) patients across the preclinical-to-dementia spectrum of AD. All participants underwent amyloid-PET, resting-state functional MRI (fMRI), and longitudinal tau-PET scans, with an average follow-up of 2.74 years.
2. A4 Cohort: 400 cognitively normal participants, including 55 Aβ− controls and 345 Aβ+ preclinical AD patients, used to validate the cross-sectional findings from the ADNI cohort.

Study Process

1. Data Acquisition and Preprocessing

   • Amyloid-PET, tau-PET, and fMRI data were collected using standardized imaging protocols.
     
   • Tau-PET data were regionally normalized using standard methods, and amyloid-PET data were converted to the international centiloid scale to harmonize results across different tracers.
     
   • fMRI data were denoised, motion-corrected, and bandpass-filtered to compute functional connectivity matrices.
     

2. Tau Epicenter Identification and Functional Connectivity Analysis

   • Tau Epicenter Definition: For each Aβ+ patient, the top 5% of brain regions with the highest tau deposition were identified as tau epicenters.
     
   • Functional Connectivity Calculation: Functional connectivity between the tau epicenters and other brain regions was computed.
     

3. Analysis of Aβ and Functional Connectivity
   Linear regression models were used to analyze the relationship between Aβ burden and the strength of functional connectivity of tau epicenters, controlling for covariates such as age, sex, and diagnosis.

4. Analysis of Functional Connectivity and Tau Spread
   Longitudinal tau-PET data were used to assess whether stronger functional connectivity between tau epicenters and other brain regions predicted faster tau accumulation in those regions.

5. Mediation Analysis
   Mediation models were employed to test whether the effect of Aβ on tau accumulation is mediated by increased functional connectivity.

Key Findings

1. Relationship Between Aβ and Functional Connectivity of Tau Epicenters

   • Patients with higher Aβ burden showed significantly stronger functional connectivity between tau epicenters and posterior temporal, parietal, and occipital brain regions.
     
   • This result was validated in both the ADNI and A4 cohorts, indicating that Aβ-associated hyperconnectivity is an early feature of AD.
     

2. Relationship Between Functional Connectivity and Tau Spread

   • Brain regions with stronger functional connectivity exhibited significantly faster tau accumulation, particularly in temporal, parietal, and occipital regions.
     
   • The findings suggest that increased functional connectivity is closely associated with transneuronal tau spread.
     

3. Mediating Role of Functional Connectivity in Aβ-Driven Tau Spread

   • Mediation analysis revealed that 5% to 25% of the effect of Aβ on tau accumulation was mediated by increased functional connectivity.
     
   • This finding highlights the mechanism by which Aβ accelerates tau spread across brain regions through the induction of neuronal hyperconnectivity.

Conclusions

This study is the first to validate in human patients the mechanism by which Aβ promotes tau spread across brain regions by inducing neuronal hyperconnectivity. This discovery not only provides new insights into the pathology of AD but also offers a theoretical basis for developing therapeutic strategies targeting Aβ-associated neuronal hyperconnectivity. Modulating neuronal connectivity may potentially delay tau spread, thereby slowing disease progression in AD.

Highlights of the Study

1. Key Finding: Revealed the mechanism by which Aβ accelerates tau spread through enhanced neuronal connectivity.
   
2. Methodological Innovation: Integrated multimodal imaging data and longitudinal analyses to comprehensively evaluate the role of functional connectivity in tau spread.
   
3. Clinical Significance: Identified a new potential therapeutic target for AD by modulating neuronal connectivity to slow disease progression.
   

Additional Valuable Information

The study also found that Aβ-associated hyperconnectivity is not only significant between tau epicenters and posterior brain regions but is also present throughout the entire brain. Additionally, higher Aβ burden was correlated with increased glucose metabolism, further supporting the hypothesis that Aβ induces neuronal hyperactivity. These findings provide important directions for future research, including the integration of electrophysiological measures to further validate the relationship between neuronal activity and connectivity.