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.
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