Proteomic signatures of Alzheimer's disease and Lewy body dementias: A comparative analysis

Abstract INTRODUCTION We aimed to identify unique proteomic signatures of Alzheimer's disease (AD), dementia with Lewy bodies (DLB), and Parkinson's disease dementia (PDD). METHODS We conducted a comparative proteomic analysis of 33 post mortem brains from AD, DLB, and PDD individuals without dementia focusing on prefrontal, cingulate, and parietal cortices, using weighted gene co‐expression network analyses with differential enrichment analysis. RESULTS Network modules revealed hub proteins common to all dementias. Lewy body dementias differed from AD by reduced levels of the autophagy protein p62 ( SQSTM1 ), whereas DLB was distinguished from both AD and PDD by altered TRIM33 and cysteine/glutamate transporter (SLC7A11) across brain regions. An increase in mitochondrial and synaptic proteins was related to better cognition whereas enrichment in the extracellular matrix, complement system, and autophagy proteins was associated with greater cognitive impairment. DISCUSSION Our study offers valuable insights into the network‐based biomarker characterization of molecular signatures of AD, DLB, and PDD. Highlights Reduced levels of the autophagy protein p62 ( SQSTM1 ) differentiated Lewy body dementias from Alzheimer's disease (AD) across multiple brain regions. Dementia with Lewy bodies (DLB) was distinguished from both AD and Parkinson's disease dementia (PDD) by altered TRIM33 and cysteine/glutamate transporter (SLC7A11) levels across brain regions. Key mitochondrial oxidative phosphorylation proteins (e.g., COX7A2, TOMM40L, NDUFV1), and synaptic proteins (e.g., GABRB3, GABRB2, GLUA3, GLUA4, SNAP47, dynamin1) were more abundant in preserved cognitive states. Extracellular matrix proteins and members of the complement system (decorin, biglycan, C4A, C4B) showed a strong positive correlation with cognitive decline.