Multiomics and proteomic insights into Alzheimer’s disease biology in down syndrome

INTRODUCTION: Down syndrome (DS) confers a high risk of Alzheimer's disease (AD) and is widely recognized as a genetically determined form of AD. As such, DS provides a uniquely informative biological context in which to investigate AD initiation and progression. Defining the molecular mechanisms that link trisomy 21 to neurodegeneration has broad implications for AD biology and neurotherapeutic development. AREAS COVERED: This review summarizes findings from brain, cerebrospinal fluid, and blood-based proteomic studies, integrated with transcriptomic and multiomics analyses, to characterize molecular pathways underlying AD in DS. The literature was identified through iterative PubMed/MEDLINE searches and manual review of reference lists, considering studies available through June 2026 with no limitation to publication dates. We discuss evidence for early disruption of proteostasis, mitochondrial and synaptic function, immune and vascular signaling, and the convergence of these alterations with sporadic and familial AD. Large cohort studies and lesion-specific proteomics are reviewed to highlight shared and subtype-specific molecular features, as well as current technical and data interpretation limitations. EXPERT OPINION: Brain, lesion-specific, cerebrospinal fluid, and blood-based proteomics, interpreted alongside transcriptomic and complementary omics data, position DSAD as a network-level disorder in which amyloid and tau pathology interact with immune, vascular, metabolic, synaptic, and proteostasis pathways. This integrated proteomic framework helps define shared and subtype-specific mechanisms across DSAD, sporadic AD, and autosomal dominant AD, while supporting biological staging, patient stratification, and therapeutic target discovery.