Latest advances in cerebrospinal fluid and blood biomarkers of Alzheimer’s disease

Alzheimer’s disease (AD) is the most common neurodegenerative disease and its diagnosis has classically been based on clinical symptoms. Recently, a biological rather than a syndromic definition of the disease has been proposed that is based on biomarkers that reflect neuropathological changes. In AD, there are two main biomarker categories, namely neuroimaging and fluid biomarkers [cerebrospinal fluid (CSF) and blood]. As a complex and multifactorial disease, AD biomarkers are important for an accurate diagnosis and to stage the disease, assess the prognosis, test target engagement, and measure the response to treatment. In addition, biomarkers provide us with information that, even if it does not have a current clinical use, helps us to understand the mechanisms of the disease. In addition to the pathological hallmarks of AD, which include amyloid-β and tau deposition, there are multiple concomitant pathological events that play a key role in the disease. These include, but are not limited to, neurodegeneration, inflammation, vascular dysregulation or synaptic dysfunction. In addition, AD patients often have an accumulation of other proteins including α-synuclein and TDP-43, which may have a pathogenic effect on AD. In combination, there is a need to have biomarkers that reflect different aspects of AD pathogenesis and this will be important in the future to establish what are the most suitable applications for each of these AD-related biomarkers. It is unclear whether sex, gender, or both have an effect on the causes of AD. There may be differences in fluid biomarkers due to sex but this issue has often been neglected and warrants further research. In this review, we summarize the current state of the principal AD fluid biomarkers and discuss the effect of sex on these biomarkers.