<p>The differential mechanisms between proteinopathies and neurodegeneration in Alzheimer’s disease (AD) and dementia with Lewy bodies (DLB) remain unclear. To address this issue, we conducted a voxel-based morphometry and cerebrospinal fluid biomarker (α-synuclein, Aβ42, t-Tau and p-Tau₁₈₁) level correlation study in patients with DLB, AD and mixed cases (AD + DLB). Cerebrospinal fluid samples obtained by lumbar puncture and whole-brain T1-weighted images were collected in the AlphaLewyMA cohort. Within the cohort, 65 DLB patients, 18 AD patients, 24 AD + DLB patients and 16 neurological control subjects (NC) were clinically diagnosed. Correlation analyses were performed between cerebrospinal fluid biomarker levels and gray matter volumes using a voxel-based morphometry approach. A mediation analysis was performed to explore the role of gray matter volumes in the relationship between Aβ42 levels and clinical severity (MMSE scores). We observed a significant positive correlation between gray matter volumes and cerebrospinal fluid Aβ42 levels in the insula, the striatal regions, the right thalamus, and the claustrum in DLB patients (p_FDR &lt; 0.05). Mediation analysis revealed that gray matter volumes significantly mediated the relationship between Aβ42 levels and MMSE scores in DLB patients. We found no significant correlation with gray matter volumes for α-synuclein, p-Tau₁₈₁ or t-Tau in DLB patients (p_FDR &lt; 0.05). We found no significant correlations in the AD, AD + DLB and NC groups for any of the biomarkers (p_FDR &lt; 0.05). The specific correlation between a reduced cerebrospinal fluid Aβ42 level and lower gray matter volumes in insula, striatum, thalamus, and claustrum in DLB patients suggests a prominent role for amyloidopathy in promoting brain atrophy in key regions of the disease.</p>