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Amyloid-PET pipeline choice influences classification of preclinical Alzheimers disease
Coath, W.; Bollack, A.; Scott, C. J.; Keshavan, A.; Malone, I. B.; Murray-Smith, H.; Markiewicz, P. J.; Erlandsson et al.. medRxiv (preprint), 2026-08-19
Topic: Amyloid, tau and blood-test diagnosis
BACKGROUNDQuantitative amyloid-beta (A{beta})-PET is increasingly used in AD prevention trials. Although the Centiloid (CL) framework provides a common scale, variability persists across processing pipelines, including differences in template/native space, partial volume correction (PVC), and reference region. These choices may influence cut-points, and in turn positivity rates, as well as longitudinal accumulation rates. We examined cut-point estimates and inter-pipeline discordance in a community cohort where many are expected to have early A{beta} deposition. METHODSWe analysed [{superscript 1}F]florbetapir PET/MR data from predominantly cognitively unimpaired ([~]95%) individuals aged [~]71 years at baseline (n=433) and at follow-up (n=328; [~]2.4-year interval) in Insight 46 (1946 British birth cohort). Centiloids were derived using the standard pipeline and ten in-house pipelines employing alternative reference regions and PVC in native space. Gaussian mixture modelling estimated cut-points with bootstrapped uncertainty. We assessed A{beta}-discordance across pipelines as a function of standard CLs and examined follow-up CSF A{beta}42/A{beta}40 (n=120) and PET in individuals with discordant baseline classifications. RESULTSBaseline cut-points were 10-23 CL across pipelines, classifying 16-25% as A{beta}-positive. Reliable accumulation cut-points were 3.5-6 CL/year, identifying 16- 22% as accumulators. Uncertainty varied across pipelines. At baseline, 18% were discordant across PET measures, predominantly between 11-35 standard CLs. The discordant group showed higher A{beta}-PET accumulation and lower CSF A{beta}42/A{beta}40 than concordant negatives. CONCLUSIONSDisagreement between A{beta}-PET methods was highest between 11-35 standard Centiloids and was frequently associated with accumulating A{beta}. These findings highlight the importance of considering cut-point uncertainty and methodological influences when interpreting early-stage amyloidosis. HighlightsO_LIProcessing methods significantly influence amyloid PET Centiloid estimates C_LIO_LIAmyloid positivity thresholds and varied across commonly used PET methods C_LIO_LIPET discordance was greatest within an intermediate range between 11-35 Centiloids C_LIO_LIFuture CSF and longitudinal PET suggest PET discordance frequently reflects early amyloidosis C_LI
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APA 7th
Coath, W., Bollack, A., Scott, C. J., Keshavan, A., Malone, I. B., Murray-Smith, H., et al. (2026). Amyloid-PET pipeline choice influences classification of preclinical Alzheimers disease. medRxiv (preprint). https://doi.org/10.64898/2026.08.14.26360465
Vancouver
Coath W, Bollack A, Scott CJ, Keshavan A, Malone IB, Murray-Smith H, et al. Amyloid-PET pipeline choice influences classification of preclinical Alzheimers disease. medRxiv (preprint). 2026. doi:10.64898/2026.08.14.26360465.
BibTeX
@article{coath2026-82e86751,
author = {Coath, W. and Bollack, A. and Scott, C. J. and Keshavan, A. and Malone, I. B. and Murray-Smith, H. and Markiewicz, P. J. and Erlandsson and others},
title = {{Amyloid-PET pipeline choice influences classification of preclinical Alzheimers disease}},
journal = {medRxiv (preprint)},
year = {2026},
doi = {10.64898/2026.08.14.26360465},
url = {https://doi.org/10.64898/2026.08.14.26360465}
}
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Key findings
- CONCLUSIONSDisagreement between A{beta}-PET methods was highest between 11-35 standard Centiloids and was frequently associated with accumulating A{beta}.
- These findings highlight the importance of considering cut-point uncertainty and methodological influences when interpreting early-stage amyloidosis.
- HighlightsO_LIProcessing methods significantly influence amyloid PET Centiloid estimates C_LIO_LIAmyloid positivity thresholds and varied across commonly used PET methods C_LIO_LIPET discordance was greatest within an intermediate range between 11-35 Centiloids C_LIO_LIFuture CSF and longitudinal PE
Why it matters
Different amyloid-PET processing pipelines produced different positivity thresholds and disagreed most between 11 and 35 Centiloids, often in people who were accumulating amyloid. The authors stress that cut-point uncertainty and method choices matter when interpreting early-stage amyloidosis.
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Study details
- Study designlongitudinal study
- Participants433
- Evidence strengthModerate
How this study scored 16/100
Preprint — not yet peer-reviewed. It scored 39 on the same rubric, but non-peer-reviewed sources are capped at 16, so it shows as 16. Scored zero for effect reported and randomised / blinded because the record does not state it. We have no data on impact for its field and year, so that was left out: it earned 37 of the 94 points we could judge it on, which is 39 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 2 / 10 | Tier 4 — not a peer-reviewed journal (medRxiv (preprint)) |
| Journal's citation record | 0 / 4 | Not a journal article, so the journal's record does not count |
| Study design | 7 / 12 | A longitudinal study following the same people over time |
| Strength of evidence | 3 / 5 | Rated “moderate” in our summary |
| Peer-review validation | 4 / 10 | Preprint — not yet peer-reviewed. Hosted on a preprint server. |
| How recent | 5 / 5 | 2026 — within 1 year(s) of the newest study here |
| Sample size | 2 / 4 | 433 participants |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 3 / 3 | Studied in people (participant count stated) |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | 0 / 7 | Cited 0 times (OpenAlex, 2026-10-10) |
| Citations per year | 0 / 5 | 0.0 citations a year over 2 year(s) since 2026 |
| Impact for its field and year | — / 6 | No field-weighted citation impact (OpenAlex has none yet) — left out of this score |
| Cited by studies here | 0 / 6 | No other study in this library cites it |
| Still being cited | 0 / 4 | Cited 0 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 3 / 4 | Last-listed author David M. Cash: h-index 60 (OpenAlex, whole career) |
| Institution's track record | 2 / 3 | University College London: institution h-index 2,029 (OpenAlex) |
| Multi-centre collaboration | 3 / 3 | OpenAlex lists 12 institution(s) in 4 countries |
| Indexed in PubMed | 1 / 2 | Not in PubMed, but has a DOI |
| Free to read | 2 / 2 | Free to read |
| Points | 37 / 94 | Scored on 19 of 20 parts. We have no data for the rest, so they are left out: 37 of the 94 points we could judge it on is 39 out of 100. |
| Total | 39 / 100 | Capped to 16 because this is not a peer-reviewed article. |
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