CSF PrP-amyloid seeding predicts clinical onset in inherited prion disease

T. H. Mok; A. Nihat; S. M. Vallabh; B. Noa; N. Omer; M. Geschwind; S. E. Arnold; E. V. Minikel; J. Collinge; S. Mead

doi:10.64898/2026.11.03.26367164

AI summary · DOI: 10.64898/2026.11.03.26367164 · medRxiv: Neurology

CSF PrP-amyloid seeding predicts clinical onset in inherited prion disease

T. H. Mok, A. Nihat, S. M. Vallabh, B. Noa, N. Omer, M. Geschwind, S. E. Arnold, E. V. Minikel,

and 2 more authors

J. Collinge, S. Mead

Original paper Published on 04 Nov. 2026 medRxiv preprint License: CC BY 4.0 Also in: fr

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The essentials

In PRNP E200K carriers, CSF RT-QuIC positivity preceded clinical onset and marked substantially elevated near-term conversion risk.

Question

Does CSF PrP-amyloid seeding detected by RT-QuIC predict clinical conversion in people carrying the PRNP E200K mutation? The study examines whether positivity identifies a clinically meaningful pre-symptomatic state.

Method

The authors analysed longitudinal CSF RT-QuIC results from 94 E200K carriers in natural-history cohorts in the US, UK, and Israel: 212 samples, with median follow-up of 1.1 years and maximum follow-up of 7.6 years. They used repeated sample-level and subject-level landmark analyses to relate RT-QuIC status to subsequent clinical onset.

Findings

Result All 11 carriers who developed CJD had at least one positive RT-QuIC result before clinical onset.
See the passage in the paper
All converters had at least one positive RT-QuIC result before clinical onset.
Result First RT-QuIC positivity appeared a median of 2.0 years before symptoms.
See the passage in the paper
First positivity appeared a median of 2.0 years prior to symptoms (IQR 1.3–3.3; range 0.2–4.8).
Result In the repeated-landmark analysis, estimated 3-year conversion-free survival was 19% after positive samples and 97% after negative samples.
Authors’ interpretation Within observed follow-up, RT-QuIC positivity is interpreted as marking entry into a clinically silent prodromal phase with elevated short-term onset risk.
See the passage in the paper
Transition to RT-QuIC positivity appears to mark unidirectional entry into a clinically silent prodromal phase with sharply elevated short-term risk of onset.

Limitations

The evidence is based on a modest number of converters, limiting the strength and generalizability of subgroup conclusions.
See the passage in the paper
Finally, although based on a modest number of converters, these E200K RT-QuIC data provide unusually strong evidence that a binary seeding biomarker can mark a clinically meaningful state transition preceding onset in human neurodegeneration.
The findings concern E200K carriers, so their applicability to other inherited prion mutations remains to be established.
RT-QuIC-positive asymptomatic carriers were uncommon, which may constrain recruitment into biomarker-enriched preventive trials.
See the passage in the paper
However, enrichment alone may not solve the practical problem of trial feasibility, because asymptomatic RT-QuIC-positive carriers are uncommon and may be slow to identify and recruit.

Why it matters

The authors argue that CSF RT-QuIC positivity can support near-term risk stratification and preventive-trial enrichment in E200K carriers. They propose that the findings motivate prospective use of RT-QuIC in trials and evaluation of related approaches in other proteinopathies.

Written by AI from the paper. Passages are checked word for word against the text we analysed; the rest may contain errors.

AI-generated keywords: PRNP E200K RT-QuIC prion disease preclinical detection Creutzfeldt-Jakob disease

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Comprehensive Summary
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Original abstract

This preprint examines whether cerebrospinal fluid (CSF) evidence of prion-protein amyloid seeding can identify people with the inherited PRNP E200K mutation who are approaching clinical disease onset. The question is important because preventive treatments targeting prion protein may be most effective before substantial brain damage occurs, while the timing of onset in mutation carriers is difficult to predict. The authors assessed real-time quaking-induced conversion (RT-QuIC), an assay that detects prion-seeding activity, as a potential marker of this preclinical transition. The study combined longitudinal data from natural-history cohorts in the United States, the United Kingdom, and Israel. It included 94 E200K carriers—55 women and 39 men—with 212 CSF samples. Participants had a median age of 57.5 years at sampling. Follow-up lasted a median of 1.1 years, with a maximum of 7.6 years. Israeli samples were tested using first-generation RT-QuIC, while samples from the UK and US were tested using a faster, second-generation version. During follow-up, 11 participants developed Creutzfeldt-Jakob disease (CJD), while 83 remained asymptomatic. All 11 participants who developed CJD had at least one RT-QuIC-positive sample before symptom onset. In four, an initial negative result was followed by a positive result, observed 1.0 to 3.42 years before onset. The other seven were already positive at their first available sampling, a median of 2.51 years before onset. Across all participants who developed CJD, the median interval from first observed positivity to symptoms was 2.0 years (interquartile range, 1.3–3.3; range, 0.2–4.8). All participants who remained asymptomatic tested negative at every observed time point. Among the 44 people with repeat lumbar punctures, 23 had at least three years of follow-up and eight had at least five years; none developed CJD or became RT-QuIC-positive during their observed follow-up. The authors assessed risk after each sample and conducted a separate analysis using each person’s first positive or last classifiable negative sample. In the sample-level analysis, the estimated proportions still asymptomatic one, two, three, and five years after a positive result were 57%, 33%, 19%, and 0%, respectively. After a negative result, the corresponding proportions were 100%, 97%, 97%, and 89%. In the subject-level analysis, the proportions remaining asymptomatic one, two, and three years after first positivity were 73%, 45%, and 36%. After a last negative result, they were 100%, 96%, and 96%. For predicting onset within three years of a sample, the reported sensitivity was 89.5%, specificity 92.0%, positive predictive value 81.0%, and negative predictive value 95.8%, based on 69 classifiable samples. The authors interpret RT-QuIC positivity as a marker of a clinically silent phase associated with substantially elevated near-term risk. They suggest it may help with risk stratification and the recruitment of participants for preventive trials or the selection of trial endpoints. Annual sampling might be practical, but the results should not yet guide clinical care. Important limitations include the small number of participants who developed CJD, relatively short follow-up for many participants, and the restriction to E200K carriers, which means the findings may not apply to other inherited prion mutations. The analyses also combined two generations of the assay and treated samples from the same people as repeated landmarks.

A Possible Early Warning Signal for Inherited Prion Disease

For people who carry a genetic risk for Creutzfeldt-Jakob disease (CJD), one of the hardest questions is when symptoms might begin. The inherited PRNP E200K mutation raises the risk of disease, but the timing of onset is difficult to predict. That uncertainty also complicates efforts to test preventive treatments: therapies aimed at prion protein may have the best chance of helping before serious brain damage occurs.

The preprint “CSF PrP-amyloid seeding predicts clinical onset in inherited prion disease,” by T. H. Mok, A. Nihat, S. M. Vallabh, B. Noa, N. Omer, M. Geschwind et al., explores whether a laboratory test could help identify this preclinical period. The researchers studied real-time quaking-induced conversion, or RT-QuIC, an assay that detects prion-seeding activity in cerebrospinal fluid (CSF).

Tracking carriers over time

The study brought together natural-history data from cohorts in the United States, the United Kingdom, and Israel. In total, it included 94 people with the E200K mutation: 55 women and 39 men. They provided 212 CSF samples, and their median age at sampling was 57.5 years. Follow-up lasted a median of 1.1 years, with some participants followed for as long as 7.6 years.

Samples from Israel were tested with a first-generation RT-QuIC assay, while those from the United States and the United Kingdom were tested with a faster, second-generation version. During follow-up, 11 participants developed CJD. The other 83 remained asymptomatic during the observed period.

Positive results preceded symptoms

Every participant who developed CJD had at least one positive RT-QuIC result before symptoms began. For four people, an initial negative result was followed by a positive one; the positive result came 1.0 to 3.42 years before onset. The other seven were already positive at their first available sampling, a median of 2.51 years before symptoms.

Across the 11 participants, the median time from the first observed positive result to clinical onset was 2.0 years. The range was broad, from 0.2 to 4.8 years, which is an important reminder that a positive result does not pinpoint an exact onset date.

By contrast, all 83 participants who remained asymptomatic tested negative at every observed time point. Among the 44 people who had repeat lumbar punctures, 23 were followed for at least three years and eight for at least five years. None developed CJD or became RT-QuIC-positive during their observed follow-up. These findings are reassuring for the periods studied, but they cannot establish that a person will never develop disease.

How well did the test distinguish near-term risk?

The researchers estimated how often participants remained asymptomatic after positive or negative samples. In an analysis treating each sample as a separate landmark, 57% of people were still asymptomatic one year after a positive result, 33% at two years, 19% at three years, and none at five years. After a negative result, the corresponding estimates were 100%, 97%, 97%, and 89%.

A separate analysis based on each participant’s first positive or last classifiable negative result showed a similar pattern. After first positivity, 73% remained asymptomatic at one year, 45% at two years, and 36% at three years. After a last negative result, the estimates were 100%, 96%, and 96% at those same intervals.

For predicting disease onset within three years of a sample, the study reported 89.5% sensitivity and 92.0% specificity. The positive predictive value was 81.0%, while the negative predictive value was 95.8%. These estimates were based on 69 samples that could be classified for the analysis. In practical terms, the results suggest that RT-QuIC positivity was strongly associated with elevated near-term risk in this group, while a negative result was associated with a lower risk over the period assessed.

Promise for research, not yet clinical guidance

The authors see RT-QuIC as a possible tool for identifying a clinically silent phase of inherited prion disease. If confirmed, it could help researchers select participants for preventive-treatment trials, focus enrollment on people at higher near-term risk, or plan when to assess trial outcomes. The findings also suggest that annual sampling may be practical, though the study does not establish an ideal testing schedule.

Several limitations call for caution. Only 11 participants developed CJD, and follow-up was relatively short for many of the people who remained asymptomatic. The study included only E200K carriers, so its findings may not apply to other inherited prion mutations. It also combined two generations of the assay, and some analyses treated multiple samples from the same person as separate landmarks. These factors mean the reported performance estimates need validation in larger, longer studies.

For now, the results are most relevant to research—not to individual medical decisions. RT-QuIC positivity may offer a useful warning signal for studying the approach to symptoms, but it cannot say precisely when disease will begin or determine what care a person should receive. Further work will be needed before the test can be used confidently outside research settings.

Created on 09 Nov. 2026

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Weekly letter Presented in "Brain and behaviour this week" of 9 November 2026. Brain and behaviour this week: What persists when the brain changes

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CSF PrP-amyloid seeding predicts clinical onset in inherited prion disease

The essentials

Question

Method

Findings

Limitations

Why it matters

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Definitions

A Possible Early Warning Signal for Inherited Prion Disease

Tracking carriers over time

Positive results preceded symptoms

How well did the test distinguish near-term risk?

Promise for research, not yet clinical guidance

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