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Proteomic clusters underlie heterogeneity in preclinical Alzheimer's disease progression
Wisch JK, Butt OH, Gordon BA, Schindler SE, Fagan AM, Henson RL, Yang C, Boerwinkle AH et al.. Brain : a journal of neurology, 2023-07-01
Topic: Amyloid, tau and blood-test diagnosis
Heterogeneity in progression to Alzheimer's disease (AD) poses challenges for both clinical prognosis and clinical trial implementation. Multiple AD-related subtypes have previously been identified, suggesting differences in receptivity to drug interventions. We identified early differences in preclinical AD biomarkers, assessed patterns for developing preclinical AD across the amyloid-tau-(neurodegeneration) [AT(N)] framework, and considered potential sources of difference by analysing the CSF proteome. Participants (n = 10) enrolled in longitudinal studies at the Knight Alzheimer Disease Research Center completed four or more lumbar punctures. These individuals were cognitively normal at baseline. Cerebrospinal fluid measures of amyloid-β (Aβ)42, phosphorylated tau (pTau181), and neurofilament light chain (NfL) as well as proteomics values were evaluated. Imaging biomarkers, including PET amyloid and tau, and structural MRI, were repeatedly obtained when available. Individuals were staged according to the amyloid-tau-(neurodegeneration) framework. Growth mixture modelling, an unsupervised clustering technique, identified three patterns of biomarker progression as measured by CSF pTau181 and Aβ42. Two groups (AD Biomarker Positive and Intermediate AD Biomarker) showed distinct progression from normal biomarker status to having biomarkers consistent with preclinical AD. A third group (AD Biomarker Negative) did not develop abnormal AD biomarkers over time. Participants grouped by CSF trajectories were re-classified using only proteomic profiles (AUCAD Biomarker Positive versus AD Biomarker Negative = 0.857, AUCAD Biomarker Positive versus Intermediate AD Biomarkers = 0.525, AUCIntermediate AD Biomarkers versus AD Biomarker Negative = 0.952). We highlight heterogeneity in the development of AD biomarkers in cognitively normal individuals. We identified some individuals who became amyloid positive before the age of 50 years. A second group, Intermediate AD Biomarkers, developed elevated CSF ptau181 significantly before becoming amyloid positive. A third group were AD Biomarker Negative over repeated testing. Our results could influence the selection of participants for specific treatments (e.g. amyloid-reducing versus other agents) in clinical trials. CSF proteome analysis highlighted additional non-AT(N) biomarkers for potential therapies, including blood-brain barrier-, vascular-, immune-, and neuroinflammatory-related targets.
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APA 7th
Wisch, J. K., Butt, O. H., Gordon, B. A., Schindler, S. E., Fagan, A. M., Henson, R. L., et al. (2023). Proteomic clusters underlie heterogeneity in preclinical Alzheimer's disease progression. Brain : a journal of neurology. https://doi.org/10.1093/brain/awac484
Vancouver
Wisch JK, Butt OH, Gordon BA, Schindler SE, Fagan AM, Henson RL, et al. Proteomic clusters underlie heterogeneity in preclinical Alzheimer's disease progression. Brain : a journal of neurology. 2023. doi:10.1093/brain/awac484. PMID: 36542469.
BibTeX
@article{wisch2023-36542469,
author = {Wisch, J. K. and Butt, O. H. and Gordon, B. A. and Schindler, S. E. and Fagan, A. M. and Henson, R. L. and Yang, C. and Boerwinkle, A. H. and others},
title = {{Proteomic clusters underlie heterogeneity in preclinical Alzheimer's disease progression}},
journal = {Brain : a journal of neurology},
year = {2023},
doi = {10.1093/brain/awac484},
pmid = {36542469},
url = {https://doi.org/10.1093/brain/awac484}
}
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Key findings
- Participants grouped by CSF trajectories were re-classified using only proteomic profiles (AUCAD Biomarker Positive versus AD Biomarker Negative = 0.857, AUCAD Biomarker Positive versus Intermediate AD Biomarkers = 0.525, AUCIntermediate AD Biomarkers versus AD Biomarker Negative = 0.952).
- A second group, Intermediate AD Biomarkers, developed elevated CSF ptau181 significantly before becoming amyloid positive.
- Our results could influence the selection of participants for specific treatments (e.g. amyloid-reducing versus other agents) in clinical trials.
Why it matters
In only 10 people, cerebrospinal fluid proteomic patterns grouped participants into different trajectories of preclinical Alzheimer's biomarker progression. This very small longitudinal study suggests possible subtypes that could affect trial selection, but it does not treat, cure, or prevent Alzheimer's disease.
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Study details
- Study designlongitudinal study
- Evidence strengthModerate
How this study scored 50/100
Published in a leading specialty journal, and it is a longitudinal study following the same people over time. Scored zero for sample size, effect reported, studied in people and randomised / blinded because the record does not state it.
| Component | Points | Why |
|---|---|---|
| Journal tier | 9 / 10 | Tier 2 — leading specialty journal (Brain : a journal of neurology) |
| Journal's citation record | 4 / 4 | Brain: journal h-index 503 (OpenAlex, 2026-10-29) |
| 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 | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 3 / 5 | 2023 — within 6 year(s) of the newest study here |
| Sample size | 0 / 4 | Participant count not stated — scores zero (not stated in the record — scored 0) |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 0 / 3 | Not stated whether this was studied in people — scores zero (not stated in the record — scored 0) |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | 2 / 7 | Cited 11 times (OpenAlex, 2026-10-10) |
| Citations per year | 1 / 5 | 2.2 citations a year over 5 year(s) since 2023 |
| Impact for its field and year | 2 / 6 | Cited 1.3× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 1 / 6 | Cited by 2 other studies in this library |
| Still being cited | 1 / 4 | Cited 8 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 3 / 4 | Last-listed author Beau M. Ances: h-index 81 (OpenAlex, whole career) |
| Institution's track record | 2 / 3 | Washington University in St. Louis: institution h-index 1,962 (OpenAlex) |
| Multi-centre collaboration | 0 / 3 | OpenAlex lists 1 institution(s) in 1 country — scores zero (affiliation lists can be incomplete) |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 36542469) |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Total | 50 / 100 | — |
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