ATLANTA -- Phosphorylation of one particular tau protein residue measured in cerebrospinal fluid (CSF) correlated with the distinct biological stages of Alzheimer's disease, researchers reported here.
Among people in the (DIAN) -- a group in which Alzheimer's disease progression is relatively predictable -- phosphorylated tau started increasing in CSF as early as 2 decades before the estimated age of symptom onset and 2 years before signs of Alzheimer's disease were seen on brain imaging, Nicolas Barthelemy, PhD, of Washington University at St. Louis, and colleagues reported at the annual meeting.
Action Points
- Note that this study was published as an abstract and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.
"Our study demonstrates unambiguously the hyperphosphorylation of CSF tau in familial Alzheimer's disease," Barthelemy told ľֱ.
"Surprisingly, one of the phosphorylated tau sites -- T217 -- has a nearly total association with brain amyloid," he added. "The modification of this site can be detected more than 20 years before the symptom onset at a time when amyloid plaques become detectable, when no tau aggregates are expected in the brain, and when CSF tau levels are normal. This suggests amyloid plaque deposition impacts tau metabolism at an early stage of the disease."
The study sought to develop a longitudinal profile of multiple CSF phosphorylated tau sites in relation to cortical amyloid and estimated age of symptom onset in familial Alzheimer's. Misfolded tau protein is a hallmark of Alzheimer disease, but the steps leading to soluble tau release and insoluble aggregation represent complex biological processes with uncertain relationships to other Alzheimer's pathologies, Barthelemy noted.
In this analysis, researchers assessed longitudinal beta-amyloid plaques with Pittsburgh Compound B (PiB) PET and CSF with mass spectrometry and immunoassays in 115 longitudinal and 234 cross-sectional DIAN participants who were at 50% risk of carrying a dominantly inherited Alzheimer's disease mutation.
Besides the T217-brain amyloid relationship, the researchers saw sequential changes at other phosphorylated sites. "T181 follows the T217 phosphorylation changes," Barthelemy said. "T205 phosphorylation increases closer to symptom onset and looks more associated to brain atrophy and brain hypometabolism. S202 remains normal and even decreases slightly when amyloid goes up." These distinct changes could be used to define Alzheimer's stages, he noted.
While phosphorylated tau has been shown to be predictive of Alzheimer's disease in other studies, the combination of the unusual DIAN cohort and the length of time to disease onset makes this research unique, said Li Gan, PhD, of Weill Cornell Medicine in New York City, who was not involved in the study.
"What's interesting is that some alterations of the same protein were more informative than others," Gan told ľֱ. "Some changes occurred very early, well before the predicted onset of Alzheimer's disease, while others were less predictable markers. This is important information that could be used for the early diagnosis of Alzheimer's disease."
The next steps will be to look at associations between these new CSF tau markers and tau aggregation measured by PET, Barthelemy noted. "Also, improvements in mass spectrometry sensitivity would allow us to increase the number of phosphorylated tau sites monitored in the future," he added.
Primary Source
American Neurological Association
Barthelemy N, et al "Profiling Alzheimer disease stages in dominantly inherited Alzheimer disease using CSF tau phosphorylation isoforms: Position matters" ANA 2018; Abstract M300.