Tracking structural changes in preclinical and prodromal Alzheimer’s disease: insights from amyloid‐beta pathology

Abstract Background Amyloid‐beta (Aβ) and tau pathology in Alzheimer’s disease (AD) is commonly associated with disruptions in grey matter integrity, including reduced cortical thickness (CT) and increased cortical mean diffusivity (MD). However, some cross‐sectional studies have also reported an increase in CT during the preclinical stage of the disease. Using over 10 years of longitudinal neuroimaging data from the PREVENT‐AD cohort, we examined the association between AD pathology (Aβ and tau) and brain structure, measured by CT, free‐water corrected MD (MD T ), and hippocampal volume. We also estimated the longitudinal trajectories of structural changes along the Aβ positivity timeline across the preclinical and prodromal stages of AD. Method We performed partial least square analyses (PLS) separately for Aβ negative (Aβ−) and Aβ positive (Aβ+) groups to identify key brain regions that contributed to pathological‐structural associations. We then assessed the cross‐sectional and longitudinal associations between AD pathology and structural measures within the PLS‐identified regions across all participants. Using the sampled iterative local approximation algorithm, we estimated the time from Aβ+ onset and calculated years from Aβ+ for each MRI scan. These estimates allowed us to track the structural changes relative to Aβ positivity (Figure 1). Result We found that higher Aβ deposition was associated with decreased MD T and increased CT in the Aβ− group, whereas the Aβ+ group showed opposite associations. Across all participants, associations for MD T followed a U‐shaped pattern, while CT exhibited an inverse U‐shaped relationship with Aβ pathology (Figure 2). These associations were observed in several key AD‐related regions, including the entorhinal cortex, fusiform gyrus, and inferior parietal lobule, and middle temporal regions. Longitudinal analyses revealed similar trajectory patterns along the Aβ+ timeline, with these changes emerging several years before Aβ positivity onset (Figure 3). Conclusion Our study suggests that brain structural changes in response to Aβ pathology start decades before symptoms and may follow highly nonlinear trajectories. The initial increases in CT and decreases in MD T might be related to the space taken by Aβ and/or several other biological processes occurring during the preclinical stage of the disease, such as neuroinflammation, astrocytic and microglia activation, or brain swelling.

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