Biomarkers of synaptic degeneration in Alzheimer’s disease

Abstract

Synapse has been considered a critical neuronal structure in the procession of Alzheimer’s disease (AD), attacked by two pathological molecule aggregates (amyloid-β and phosphorylated tau) in the brain, disturbing synaptic homeostasis before disease manifestation and subsequently causing synaptic degeneration. Recently, evidence has emerged indicating that soluble oligomeric amyloid-β (AβO) and tau exert direct toxicity on synapses, causing synaptic damage. Synaptic degeneration is closely linked to cognitive decline in AD, even in the asymptomatic stages of AD. Therefore, the identification of novel, specific, and sensitive biomarkers involved in synaptic degeneration holds significant promise for early diagnosis of AD, reducing synaptic degeneration and loss, and controlling the progression of AD. Currently, a range of biomarkers in cerebrospinal fluid (CSF), such as synaptosome-associated protein 25 (SNAP-25), synaptotagmin-1, growth-associated protein-43 (GAP-43), and neurogranin (Ng), along with functional brain imaging techniques, can detect variations in synaptic density, offering high sensitivity and specificity for AD diagnosis. However, these methods face challenges, including invasiveness, high cost, and limited accessibility. In contrast, biomarkers found in blood or urine provide a minimally invasive, cost-effective, and more accessible alternative to traditional diagnostic methods. Notably, neuron-derived exosomes in blood, which contain synaptic proteins, show variations in concentration that can serve as indicators of synaptic injury, providing an additional, less invasive approach to AD diagnosis and monitoring.