Tau-related Atrophy is Independent of β-Amyloid & APOE ε4

Last Updated Date: February 28, 2025

Authors: Felix Carbonell, Ph.D., Carolann McNicoll, Alex P. Zijdenbos, Ph.D., Barry J. Bedell, M.D., Ph.D.

Key Takeaways

• Tau has a stronger association with structural atrophy measures than β-amyloid
• Cortical thinning, volume loss, and gray matter density reduction in Mild Cognitive Impairment (MCI) do not appear to be significantly associated with the APOE ε4 genotype
• The relationship between tau and brain atrophy measures remains spatially consistent even after adjusting for β-amyloid

Tau and Amyloid PET imaging have been shown to correlate with glucose metabolism in Mild Cognitive Impairment (MCI), but the relationship between tau, β-amyloid, and brain atrophy remains unclear. While glucose metabolism reflects functional impairment, cortical thickness, cortical volume, and gray matter (GM) density serve as key biomarkers of neurodegeneration. Understanding the spatial associations between these factors is essential for tracking disease progression in Alzheimer’s disease (AD).

To investigate these relationships, we conducted a whole-brain analysis of cortical thickness, cortical volume, GM density, tau, β-amyloid, and APOE ε4 genotype in individuals with MCI. We employed Singular Value Decomposition (SVD) to examine spatially distributed patterns of cross-correlation between tau and brain atrophy measures, while accounting for the effects of β-amyloid and APOE ε4 genotype.

Our findings reveal that cortical thinning, volume loss, and GM density reduction in MCI do not appear to be significantly associated with APOE ε4 genotype. Instead, tau shows a significantly stronger association with atrophy measures than β-amyloid, particularly in the entorhinal cortex and posterior cingulate cortex. The tau-related reduction in cortical thickness, volume, and GM density remains spatially consistent even after adjusting for β-amyloid effects.

In our analysis, the first SVD component accounted for 21.56% of the total co-variability between tau and cortical thickness, with the strongest correlations observed in the entorhinal cortex and fusiform gyri. Scatterplot analysis of SVD-based tau and thickness scores demonstrated a stronger association than that of tau and glucose metabolism, independent of APOE ε4 status. Additionally, voxelwise statistical analysis confirmed that tau, rather than β-amyloid, had a more substantial impact on cortical thinning in MCI, particularly in the precuneus, posterior cingulate cortex, and entorhinal cortex.

This study is the first to examine whole-brain atrophy patterns in relation to tau and β-amyloid using a network-based approach. Our results highlight that entorhinal cortex tau accumulation and cortical atrophy are key hallmarks of cognitive deterioration in MCI. Tau-related neurodegeneration appears to occur independently of β-amyloid and APOE ε4 status, underscoring tau’s critical role in disease progression.

Presentation Highlights

*Data used in preparation of this presentation were obtained from from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database. The investigators at ADNI contributed to the design and implementation of ADNI and/or provided data, but did not participate in analysis or writing of this report.