Staging of Alzheimer’s disease: past, present, and future perspectives

Disease staging uses important points in the disease course to measure disease severity, evaluate clinical outcomes, and guide patient management. Staging of Alzheimer's disease (AD) has evolved from clinically defined stages based on symptomatic severity to integrated information on several biomarkers. Currently, staging of AD involves the identification of AD using biomarkers, with clinical outcomes designating disease severity. Staging of preclinical AD is possible using imaging biomarkers optimized to detect stage-specific pathological changes. Furthermore, phosphorylated tau (pTau) panels in which multiple pTau epitopes are evaluated from a single sample (plasma or CSF) may be useful for determining the extent of pathological tau hyperphosphorylation. Staging of AD using biomarkers will allow the identification of the optimal time-window in which specific therapeutic interventions will be most effective. For many years Alzheimer’s disease (AD) was associated with the dementia stage of the disease, the tail end of a pathophysiological process that lasts approximately two decades. Whereas early disease staging assessments focused on progressive deterioration of clinical functioning, brain imaging with positron emission tomography (PET) and cerebrospinal fluid (CSF) biomarker studies highlighted the long preclinical phase of AD in which a cascade of detectable biological abnormalities precede cognitive decline. The recent proliferation of imaging and fluid biomarkers of AD pathophysiology provide an opportunity for the identification of several biological stages in the preclinical phase of AD. We discuss the use of clinical and biomarker information in past, present, and future staging of AD. We highlight potential applications of PET, CSF, and plasma biomarkers for staging AD severity in vivo. For many years Alzheimer’s disease (AD) was associated with the dementia stage of the disease, the tail end of a pathophysiological process that lasts approximately two decades. Whereas early disease staging assessments focused on progressive deterioration of clinical functioning, brain imaging with positron emission tomography (PET) and cerebrospinal fluid (CSF) biomarker studies highlighted the long preclinical phase of AD in which a cascade of detectable biological abnormalities precede cognitive decline. The recent proliferation of imaging and fluid biomarkers of AD pathophysiology provide an opportunity for the identification of several biological stages in the preclinical phase of AD. We discuss the use of clinical and biomarker information in past, present, and future staging of AD. We highlight potential applications of PET, CSF, and plasma biomarkers for staging AD severity in vivo. clinical syndrome associated with AD pathophysiology. Typically conceptualized as amnestic predominant multidomain cognitive impairment resulting in dementia. a progressive neurodegenerative disease defined biologically by the accumulation of cerebral amyloid-β plaques and tau neurofibrillary tangles. a peptide produced by proteolytic processing of amyloid precursor protein (APP) by β- and γ-secretases. Amyloid-β peptides are the main component of extracellular plaques. Amyloid-β accumulation is considered to be an early central event in the pathogenic cascade of AD. a six-stage hierarchical AD staging system based on the anatomical distribution of tau neurofibrillary tangles. Early stages document abnormalities in medial temporal regions, whereas later stages include abnormalities extending to primary sensory cortices. CSF assays permit the investigation of protein production and clearance in the brain. a clinical syndrome characterized by major deficits in two or more cognitive domains, resulting in major inference with the ability to carry out the activities of daily life. framework for ranking progressive levels of disease severity based on the reliable identification of specific points in the disease course. Later stages are associated with worse prognosis. clinical syndrome characterized by cognitive decline greater than expected for an individual’s age and education level, but that does not cause interference in activities of daily living. the process of neuronal injury or neuronal death. Biomarkers include fluorodeoxyglucose (FDG)-PET, magnetic resonance imaging (MRI), and plasma neurofilament light (NfL). abnormal aggregates of intraneuronal hyperphosphorylated tau. One of the defining features of AD. Tau may become phosphorylated at one of several sites. a molecular imaging technique to quantify physiological functions using imaging agents radiolabeled with positron-emitting isotopes. the presence of abnormal concentrations of both amyloid-β and tau biomarkers in individuals without objective cognitive impairment. MCI with the presence of AD markers (abnormal amyloid-β and tau) that is considered to precede AD dementia. a microtubule-associated protein (MAP) that is involved in neuronal microtubule stabilization and intraneuronal transport. Becomes misfolded in AD.