Lessons Learned in Time—Is Neurodegeneration Still Something Unpredictable?

Excerpt

It has been 25 years since the US National Institutes of Health Biomarkers Definitions Working Group proposed aspirational characteristics for disease-associated biomarkers to expedite and inform therapeutics research [1]. Among neurodegenerative disorders, quantitation or visualization of peptides and aggregates involved in disease pathogenesis has been—and remains—the central tenet for biomarker development. There has been unparalleled success in the maturation and application of etiologic biomarkers for Alzheimer’s disease (AD). Whereas researchers a decade ago celebrated the consistent association between AD neuropathology with positron emission tomography (PET) or cerebrospinal fluid (CSF) biomarkers [2], we have now witnessed approval by the US Food and Drug Administration (FDA) of insoluble AD protein PET imaging, soluble CSF AD proteins, and anti-amyloid disease-modifying therapies (DMTs). These advances have not come without pitfalls or caveats, many of which are judged more through the lens of societal values than scientific impact. However, even modest triumphs in its etiologic diagnosis and treatment augment AD’s transformation from a shifty clinical syndrome to a bona fide molecular disorder. Deliberate haste in identifying and targeting amyloid appears to have yielded reasonable return on investment compared to blithe discovery efforts which often fall short on accuracy, precision, or both. …