Charting the Next Road Map for CSF Biomarkers in Alzheimer's Disease and Related Dementias

Clinical prediction of underlying pathologic substrates in people with Alzheimer's disease (AD) dementia or related dementia syndromes (ADRD) has limited accuracy. Etiologic biomarkers - including cerebrospinal fluid (CSF) levels of AD proteins and cerebral amyloid PET imaging - have greatly modernized disease-modifying clinical trials in AD, but their integration into medical practice has been slow. Beyond core CSF AD biomarkers (including beta-amyloid 1-42, total tau, and tau phosphorylated at threonine 181), novel biomarkers have been interrogated in single- and multi-centered studies with uneven rigor. Here, we review early expectations for ideal AD/ADRD biomarkers, assess these goals' future applicability, and propose study designs and performance thresholds for meeting these ideals with a focus on CSF biomarkers. We further propose three new characteristics: equity (oversampling of diverse populations in the design and testing of biomarkers), access (reasonable availability to 80% of people at risk for disease, along with pre- and post-biomarker processes), and reliability (thorough evaluation of pre-analytical and analytical factors influencing measurements and performance). Finally, we urge biomarker scientists to balance the desire and evidence for a biomarker to reflect its namesake function, indulge data- as well as theory-driven associations, re-visit the subset of rigorously measured CSF biomarkers in large datasets (such as Alzheimer's disease neuroimaging initiative), and resist the temptation to favor ease over fail-safe in the development phase. This shift from discovery to application, and from suspended disbelief to cogent ingenuity, should allow the AD/ADRD biomarker field to live up to its billing during the next phase of neurodegenerative disease research.