Year: 2019
Type: article
Abstract: The sequence of biomarker changes in the amyloid cascade and the subsequent onset of clinical symptoms has been hypothesized. A decades-long preclinical phase of Alzheimer's disease (AD) is thought to start with elevated levels of two key amyloids, b-amyloid (Ab) and tau, and end with severe cognitive and functional impairment. However, the time-course of the spread of Ab and tau and the onset of clinical symptoms is unknown. In 197 cognitively unimpaired individuals, 55 prodromal AD and 32 AD dementia patients from the Alzheimer's Disease Neuroimaging Initiative (ADNI), we estimated the time of initial changes in CSF Ab and tau, regional Ab PET, tau PET, and decreases in cognition with respect to the time of significant Ab deposition. Models were fit using mixed-effects regression and penalized regression splines. Significant changes in CSF Ab and tau, as well as regional Ab PET were estimated to occur 12–16 years before Ab-positivity, followed by increases in medial temporal lobe tau nine years before and medial parietal lobe tau eight years before Ab-positivity. The Preclinical Alzheimer's Cognitive Composite (PACC) declined significantly by the time of Ab-positivity, followed by the MMSE nine years after Ab-positivity. Explicit estimates of the time at which CSF Ab and tau levels start to change, regional Ab deposition occurs and tau pathology spreads beyond the temporal lobe and the proximity of these events to the onset of cognitive symptoms provide a clearer picture of the time course of the amyloid cascade. More than two decades elapse between the first biomarker changes and a significant reduction of MMSE scores. Precise estimates of the temporal changes of AD biomarkers will identify a potential window for early treatment.
Source: Alzheimer s & Dementia
Authors: Philip Insel, Oskar Hansson, Niklas Mattsson
Institution: Lund University
Language: English
Subfield: Psychiatry and Mental health
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W2980846676