br Applications of ATN in clinical trials In pivotal trials
Applications of ATN in clinical trials In pivotal trials, the use of biomarkers will also have to be considered in the context of regulatory risk and scrutiny. Although an important intended application of the framework is in research studies, its use will undoubtedly impact clinical development paradigms more broadly and ultimately affect labeling. This is because regulatory authorities generally look to the scientific or medical dna-pk inhibitor to define diseases for which treatments are being developed and establish appropriate diagnostic procedures for such disorders. The qualification opinions of the European Medicines Agency for novel methodologies in the predementia stage of AD include CSF Aβ 1–42 and t-tau levels , PET measures of amyloid burden , and volumetric MRI measures  (i.e., A, T, and N biomarkers) for drugs targeting Aβ or amyloid burden. While clinical measures are required as primary outcome measures in neuroscience, nusinersen was approved for the treatment of spinal muscular atrophy in 2016 based on a single pivotal trial. A variety of biomarkers were used in the development plan, which may have provided some support for regulatory approvals with only a single study. When trials use a biomarker result as an inclusion criterion, there is also the possibility that the label will require performing that test to support use of the treatment. However, if the diagnostic criteria become part of medical practice for diagnosis, regulators could also consider labeling that allows treatment of patients diagnosed based on usual medical practices (as is the case with many other diseases), rather than requiring specific tests in labeling. Importantly and increasingly across the globe, regulatory approval does not necessarily translate into payer coverage, and each country manages drug coverage decisions in a different way . In the United States, while the Food and Drug Administration focuses on safety and efficacy, the Centers for Medicare and Medicaid Services focuses on what is reasonable and necessary use criteria for patients. Centers for Medicare and Medicaid Services relies on published research and Food and Drug Administration to provide information related to drug efficacy, which Centers for Medicare and Medicaid Services uses to determine the appropriateness of coverage. In Canada, the Intergovernmental Common Drug Review, a separate organization from the Regulatory Authority (Health Canada), assesses cost effectiveness. There have been recent efforts to harmonize advice from regulators across different countries and between regulators and payers. How these differing approaches will manage biomarker issues in the context of drug approval adds uncertainty to the process.
Reconsidering clinical syndromes in the AD spectrum
Challenges and opportunities of the framework
Future directions The authors of the framework described it as a descriptive document that provides a common language and a basis for speaking about biomarkers but does not make hypotheses about causality and outcomes. The clinical syndrome remains the most important aspect of the disease for patients and caregivers. However, physicians and scientists should also be concerned about why (i.e., etiology) patients develop impairment. This can only be accomplished by defining etiology, which clinical syndromal categorization cannot do. Deep phenotyping with biomarkers, however, enables more precise and accurate characterization of pathophysiology than which is possible through clinical measures and thus should accelerate efforts to develop new treatments. Other potential areas of future research that could be advanced by adoption of the framework include the following:
Neuropathology of Alzheimer’s Disease Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by progressive impairments in cognitive functions . Histopathological hallmarks of AD are amyloid deposits and neurofibrillary tangles formed by hyperphosphorylated tau protein. Formation of oligomeric aggregates of β-amyloid (Aβ)1-42 peptide is the main culprit of AD. These aggregates interact with membrane receptors causing a neuropathological cascade that ultimately results into synaptic dysfunction and neuronal death . Both amyloid plaques and neurofibrillary tangle are mainly found in the hippocampus and other limbic brain regions that are involved in learning and memory processes and in emotional regulation , , . In particular, the hippocampus is particularly vulnerable to amyloid toxicity , . Early-onset familial AD (eFAD), is caused by mutations in the amyloid-ß precursor protein (APP) , or presenilin 1 (PSEN1)  and presenilin 2 (PSEN2), two components of the γ-secretase protein complex , . These mutations are inherited as an autosomal dominant trait . PSEN1 mutations (>180 described to date) account for most cases of eFAD, while APP and PSEN2 mutations are more rare. In subjects carrying these mutations the onset of AD can be predicted with certainty, and these subjects are now recruited for the study of early treatments with putative disease-modifying drugs, particularly monoclonal antibodies directed against Aβ1-24. Unfortunately, most of the AD cases are sporadic, and, to date, these cases can only be treated after the clinical onset of AD or, at best, in the in the phase of incipient AD, i.e., in patients with amnestic mild cognitive impairment (MCI) with demonstration of cerebral amyloidosis by PET staining, and reductions in Aβ1-42 and increases in tau protein in the cerebrospinal fluid. This seriously limits the value of clinical studies with potential disease-modifying drugs because AD neuropathology begins several years prior to the clinical onset (Fig. 1).