title: Hypothetical model of dynamic biomarkers of the Alzheimer's pathological cascade.
abstract: Currently available evidence strongly supports the position that the initiating event in Alzheimer's disease (AD) is related to abnormal processing of beta-amyloid (Abeta) peptide, ultimately leading to formation of Abeta plaques in the brain. This process occurs while individuals are still cognitively normal. Biomarkers of brain beta-amyloidosis are reductions in CSF Abeta(42) and increased amyloid PET tracer retention. After a lag period, which varies from patient to patient, neuronal dysfunction and neurodegeneration become the dominant pathological processes. Biomarkers of neuronal injury and neurodegeneration are increased CSF tau and structural MRI measures of cerebral atrophy. Neurodegeneration is accompanied by synaptic dysfunction, which is indicated by decreased fluorodeoxyglucose uptake on PET. We propose a model that relates disease stage to AD biomarkers in which Abeta biomarkers become abnormal first, before neurodegenerative biomarkers and cognitive symptoms, and neurodegenerative biomarkers become abnormal later, and correlate with clinical symptom severity.
authors.affiliation: Department of Radiology, Mayo Clinic, Rochester, MN 55905, USA. jack.cliff ord@mayo.edu
authors.forename: Clifford R
authors.initials: CR
authors.lastname: Jack
authors.forename: David S
authors.initials: DS
authors.lastname: Knopman
authors.forename: William J
authors.initials: WJ
authors.lastname: Jagust
authors.forename: Leslie M
authors.initials: LM
authors.lastname: Shaw
authors.forename: Paul S
authors.initials: PS
authors.lastname: Aisen
authors.forename: Michael W
authors.initials: MW
authors.lastname: Weiner
authors.forename: Ronald C
authors.initials: RC
authors.lastname: Petersen
authors.forename: John Q
authors.initials: JQ
authors.lastname: Trojanowski
mesh_terms: D000375:Aging / Q000235:genetics / Q000473:pathology / Q000502:physiology; D000544:Alzheimer Disease / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology*; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid / Q000378:metabolism; D053327:Apolipoprotein E4 / Q000235:genetics; D015415:Biomarkers / Q000134:cerebrospinal fluid / Q000378:metabolism*; D001921:Brain / Q000000981:diagnostic imaging / Q000473:pathology* / Q000503:physiopathology*; D003072:Cognition Disorders / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D018450:Disease Progression; D006801:Humans; D008279:Magnetic Resonance Imaging; D008959:Models, Neurological; D058225:Plaque, Amyloid / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D049268:Positron-Emission Tomography; D015398:Signal Transduction; D013997:Time Factors; D016875:tau Proteins / Q000134:cerebrospinal fluid / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D053327:Apolipoprotein E4; D015415:Biomarkers; C054369:MAPT protein, human; D016875:tau Proteins