AD Gene Carriers Show Tau Changes Years Before Symptoms

Nancy A. Melville

October 29, 2018

ATLANTA — In people who are genetically predisposed to develop Alzheimer's disease (AD), notable changes occur in tau peptides decades before the estimated age of symptom onset — a fact that offers potentially important pieces of the complex puzzle of how AD progresses, new research suggests.

"For the first time, we demonstrate that the phosphorylation status of the tau protein measured in the CSF [cerebrospinal fluid] appears to track distinct stages of the Alzheimer's disease cascade in DIAD [dominantly inherited Alzheimer's disease], as measured by both estimated years to symptom onset as well as by neuroimaging biomarkers that sequentially change as dementia approaches," said first author Nicolas Barthélemy, PhD, Department of Neurology, Washington University, St. Louis, Missouri.

Tau peptides have a basic role in functions of the central nervous system, but in their hyperphosphorylated form, they are also key components of AD tangles, Barthélemy noted.

He presented the findings here at ANA 2018: 143rd Annual Meeting of the American Neurological Association.

Defining AD Status

The investigators used mass spectrometry imaging to better understand when increased phosphorylation begins to occur in tau peptides in individuals who carry the genetic mutation for AD. They evaluated normal and phosphorylated tau peptides in the CSF of 115 participants in the Dominantly Inherited Alzheimer Network (DIAN). All patients were still asymptomatic.

The researchers assessed 405 samples from DIAD mutation carriers, representing four tau sites, T181, S202, T205 and T217, and compared them with 639 CSF samples from 234 cross-sectional participants.

Among DIAD mutation carriers, phosphorylation occurred on peptides at the T217 site as much as 21 years prior to the estimated age of onset, as well as 2 years prior to β-amyloid deposition observed with Pittsburgh compound-B positron-emission tomography (PiB-PET).

Increases in total tau levels and in the phosphorylation rate at the T205 site were observed much closer to symptom onset among DIAD mutation carriers.

Levels of T217 hyperphosphorylation were strongly associated with mean cortical β-amyloid deposition on PiB-PET in the asymptomatic carriers of mutations (P < .0001), whereas rates of phosphorylation on the T205 area were inversely associated with numerous cortical areas of fluorodeoxyglucose metabolism (P < .05) and atrophy (P < .01).

"We found that CSF tau T217 hyperphosphorylation is strongly associated with amyloidosis," Barthélemy said.

"The findings indicate that tau phosphorylation can define Alzheimer's disease status...by using site-specific changes," he added.

Furthermore, there is "phosphorylation modification on T205 closer to symptom onset, brain atrophy, and hypometabolism," Barthélemy said.

"This work allows us to evaluate the association of PET tau imaging with new CSF tau biomarkers and improve method sensitivity to monitor more phosphorylated sites in CSF," he said.

"Staging the Disease"

Asked by Medscape Medical News to comment, ANA President David M. Holtzman, MD, professor and chair of neurology at Washington University, St. Louis, Missouri, said the findings add to the understanding of the mechanisms that may underlie the earliest stages of AD.

"What they showed was that one form of the tau protein that has a certain phosphorylation site starts to accumulate and increases. It's present all the time, but it goes higher about 20 years before symptoms start, and it's probably due to the fact that amyloid is leading to the release of that protein from nerve cells," Holtzman said.

"Interestingly, the study also showed different phosphorylation changes, but not until right about when the Alzheimer's symptoms are coming on. So there are these different molecular effects on tau that are useful at staging the disease," he said.

The insights of these patterns could have therapeutic implications, he added.

"We're seeing that one effect occurs very early, well before the start of symptoms, and the other occurs much later. So that could be very useful for monitoring the effects of therapy if you're targeting that molecule, for example," Holtzman explained.

"Or maybe if you're presymptomatic, the patterns could help tell you where you are along the time course. So that is really important if we want to test treatments that delay the disease," he added.

"We want to know when we're treating people, so some things might be more effective as a primary prevention really early, or some may be okay for later," said Holtzman. "That's why I think these are really important findings."

The authors and Dr Holtzman have disclosed no relevant financial relationships.

ANA 2018: 143rd Annual Meeting of the American Neurological Association. Abstract 425, presented October 21, 2018.

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