A new generation of AD biomarkers: 2019 to 2021

Alzheimer’s disease (AD) is the most common form of dementia and cases are rising worldwide. The effort to fight this disease is hampered by a lack of disease-modifying treatments and the absence of an early, accurate diagnostic tool. Neuropathology begins years or decades before symptoms occur and, upon onset of symptoms, diagnosis can take a year or more. Such delays postpone treatment and make research into the early stages of the disease difficult. Ideally, clinicians require a minimally invasive test that can detect AD in its early stages, before cognitive symptoms occur. Advances in proteomic technologies have facilitated the study of promising biomarkers of AD. Over the last two years (2019–2021) studies have identified and validated many species which can be measured in cerebrospinal fluid (CSF), plasma, or in both fluids, and which have a high predictive value for AD. We herein discuss proteins which have been highlighted as promising biomarkers of AD in the last two years, and consider implications for future research within the research framework of the amyloid (A), tau (T), neurodegeneration (N) scoring system. We review recently identified species of amyloid and tau which may improve diagnosis when used in combination with current measures such as amyloid-beta-42 (Aβ42), total tau (t-tau) and phosphorylated tau (p-tau). In addition, several proteins have been identified as likely proxies for neurodegeneration, including neurofilament light (NfL), synaptosomal-associated protein 25 (SNAP-25) and neurogranin (NRGN). Finally, proteins originating from diverse processes such as neuroinflammation, lipid transport and mitochondrial dysfunction could aid in both AD diagnosis and patient stratification.