Blood Proteomics in Relation to Alzheimer’s Disease and Dementia: Potential Biomarkers and Systemic Implications

Abstract

Dementia is a decline in cognitive abilities that impairs an individual’s ability to engage in everyday activities, commonly caused by Alzheimer’s disease (60-70% of cases). Current biomarkers are usually derived using neuroimaging or from cerebrospinal fluid (CSF) and include a decrease in amyloid beta 42 fragment (Aß42) and an increase in phosphorylated tau (p- tau). Blood-based biomarkers are an attractive alternative due to lower invasiveness and cost, yet accurate interpretation remains a significant challenge in reflecting AD pathology. This review aims to assess the plasma proteomic changes in AD and dementia by examining the replicability of blood plasma biomarkers and identifying shared pathways and distinctive AD-specific markers. After excluding 307 records from a total of 316, fourteen articles were included in the literature review, reporting 33 association studies with 7931, 8687, and 145 AD, dementia, and Mild Cognitive Impairment (MCI) subjects, respectively. We identified 1579 unique proteins associated with the conditions, with the majority (80.7%) originating from AD vs control studies.To ensure reliable results for subsequent analyses, we applied replicability filters based on the number of proteins that met the threshold. In the overlap of 215 proteins between AD and dementia, enriched biological functions implicated blood coagulation, hemostasis, cell secretion, organization, and adhesion. Specific genes, such as SERPINF2, associated with the plasmin cascade and neurodegeneration, emerged as potential indicators of AD-related vascular changes. AD-specific proteins revealed enriched biological functions related to magnesium ion response, neuromuscular junction development, and postsynapse organization. APP and LRRK2, associated with early onset AD and dementia, were replicated in our review. Comparisons with a recent proteomics study using brain cortex tissue underscored the need for a multi- tissue approach in biomarker discovery for AD. While overlaps in some genes (e.g., APP, GFAP) suggested shared molecular mechanisms across tissues, distinctive sets of genes indicated tissue-specific responses to AD. Despite challenges in consistency and heterogeneity, the findings encourage further exploration of blood-based biomarkers. Recognizing the complexity in identifying these markers and their interplay with central nervous system processes is crucial for advancing our understanding of the mechanisms associated with AD and dementia.