Atrophy signature for alpha‐synuclein copathology in Alzheimer's disease

INTRODUCTION: Brain atrophy patterns in Alzheimer's disease (AD) are well established, however, the contribution of alpha-synuclein (α-syn) copathology to these patterns remains unclear. This study investigates magnetic resonance imaging (MRI) -based atrophy patterns in AD patients with α-syn copathology. METHODS: = 191). Participants were classified into AD-α-syn seed amplification assay positive (αSAA+), AD-αSAA-, and healthy controls (CTR). Group comparisons of MRI regions were conducted using permutation tests adjusting for age and sex. RESULTS: Compared to CTR, both AD-αSAA- and AD-αSAA+ showed widespread cortical thinning. Direct comparison of AD-αSAA+ versus AD-αSAA- revealed differential involvement of insular, entorhinal, lateral temporal, pre and postcentral gyrus, frontal cortices, and amygdala, although with minimum size effect. DISCUSSION: α-Syn copathology was associated with more extensive and pronounced atrophy, especially in frontal, lateral temporal, entorhinal, and amygdalar regions. This suggests that α-syn is associated with greater neurodegeneration beyond typical AD patterns.