HAI Book 2025 - Flipbook - Page 102
Qiu, Ting
3
Unraveling the impact of amyloid-β and tau pathology on brain
structure and cognitive function during preclinical and prodromal
Alzheimer9s disease
Ting Qiu1, Zhen-Qi Liu3, Jonathan Gallego-Rudolf1,3, Manon Edde4, Alex Valcourt Caron4,
Yuanchao Zhang5,6, Jean-Paul Soucy3, R. Nathan Spreng1,2,3, Maxime Descoteaux4, Sylvia
Villeneuve1,2
1
Douglas Mental Health University Institute, McGill University, Montreal, QC, CA
Department of Psychiatry, McGill University, Montreal, QC, CA
3
Montreal Neurological Institute, Montreal, QC, CA
4
Sherbrooke Connectivity Imaging Laboratory (SCIL), Université de Sherbrooke, Sherbrooke, QC, CA
5
The Clinical Hospital of Chengdu Brain Science Institute, MOE Key Lab for Neuroinformation, University of Electronic
Science and Technology of China, Chengdu, CN
6
School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, CN
2
Alzheimer9s disease (AD) is characterized by the pathological accumulation of amyloid-beta (A´) and tau proteins,
which progressively compromise brain function and structure, eventually leading to cognitive decline. We
investigated the cross-sectional and longitudinal relationship between A´ and tau deposition and structural
properties, specifically cortical thickness, cortical free-water-corrected mean diffusivity (MDT), and hippocampal
volume (HV), during the preclinical and prodromal stages of AD. We also examined which pathological and/or
structural properties are more strongly associated with memory deficits.
We first conducted partial least square analyses (PLS) to identify the pathological-structural associations
between AD pathology and structural properties across three groups: cognitively unimpaired A´ negative (CU
A´2), cognitively unimpaired A´ positive (CU A´+), and mild cognitive impairment A´ positive (MCI A´+). In the CU
A´2 group, increased A´ was associated with greater cortical thickness, larger HV, and lower MDT. In the CU A´+
and MCI A´+ groups, elevated A´ and tau were associated with reduced cortical thickness and increased MDT
(Figure 1). Similar associations were found between AD pathology and grey matter changes over time in PLSderived key brain regions (Figure 2A). Combining all individuals, we observed inverse U-shaped associations
between A´ and both cortical thickness and HV, and a U-shaped association between A´ and MDT (Figure 2B).
Longitudinal analyses also revealed inverse U-shaped associations between A´ and cortical thickness/HV slopes,
and a U-shaped relationship between A´ and MDT slope (Figure 2C). Lastly, we found that all pathological and
structural biomarker tested were independently associated with memory in A´+ individuals, but only tau remained
significant when including all brain markers in the same model (Figure 3).
This study demonstrates a biphasic trajectory of structural changes in response to A´ pathology and emphasizes
the central role of tau in neurodegeneration leading to clinical onset.
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