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Clinical expression beyond measured Alzheimer disease molecular pathology: a discovery and external evaluation study
Zhang S, Bao R, He H, Initiative ftADN, Team tHaABS(S, Zhang T, Cheng W, Ding W.. Research Square, 2026-08-31
Topic: Plasma and spinal-fluid biomarkers
Background Cognitive expression varies substantially among people with comparable Alzheimer disease molecular pathology. We evaluated whether a prespecified profile integrating hippocampal structure, education, and plasma glial fibrillary acidic protein (GFAP) captured cognition beyond measured phosphorylated tau 217 (pTau217), amyloid PET, and tau PET burden. Methods We used the Alzheimer’s Disease Neuroimaging Initiative (ADNI; n = 436) for discovery and the Health and Aging Brain Study: Health Disparities (HABS-HD; n = 491) for external evaluation. The profile was the equal-weight mean of intracranial-volume-normalised hippocampal volume, education, and inverse log-transformed plasma GFAP. The primary outcome was cohort-standardised four-item Preclinical Alzheimer Cognitive Composite (PACC4). Linear models adjusted for pTau217, amyloid PET, tau PET, age, and sex. Prespecified analyses examined pathology-balanced residual cognition, selection weighting, longitudinal cognition, and clinical progression. Results Higher profile values were associated with higher PACC4 in ADNI (β = 0.703, 95% CI 0.573–0.834; ΔR²=12.1%; P < 0.001) and HABS-HD (β = 0.818, 95% CI 0.657–0.979; ΔR²=15.5%; P < 0.001), with no evidence of between-cohort heterogeneity (P = 0.274; I²=16.3%). In pathology-balanced samples, residual cognition differed by 0.695 SD in ADNI (53 pairs) and 0.823 SD in HABS-HD (79 pairs). The HABS-HD association was similar after inverse selection-probability weighting (β = 0.837, 95% CI 0.656–1.017; P < 0.001). Associations with progression attenuated after additional adjustment for baseline cognition and clinical status. Conclusions A prespecified structure–reserve–glial profile captured reproducible cognitive variation beyond measured Alzheimer disease molecular pathology across two cohorts. It provides an explanatory clinical-expression framework, not evidence of a causal resilience mechanism or a validated individual-level prognostic tool. Trial registration Not applicable.
Key findings
- Results Higher profile values were associated with higher PACC4 in ADNI (β = 0.703, 95% CI 0.573–0.834; ΔR²=12.1%; P < 0.001) and HABS-HD (β = 0.818, 95% CI 0.657–0.979; ΔR²=15.5%; P < 0.001), with no evidence of between-cohort heterogeneity (P = 0.274; I²=16.3%).
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Study details
- Study designlongitudinal study
- Participants436
- Effect size12.1%; 15.5%; 16.3%
- Evidence strengthModerate
How this study scored 16/100
Preprint — not yet peer-reviewed. It scored 47 on the same rubric, but non-peer-reviewed sources are capped at 16, so it shows as 16. Scored zero for randomised / blinded because the record does not state it. We have no data on times cited, citations per year, impact for its field and year, cited by studies here, still being cited, senior author's track record, institution's track record and multi-centre collaboration, so those were left out: it earned 29 of the 62 points we could judge it on, which is 47 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 2 / 10 | Tier 4 — not a peer-reviewed journal (Research Square) |
| 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 | 436 participants |
| Effect reported | 2 / 3 | Effect reported as a number, without an interval or test |
| 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 | — / 7 | No citation count (not found in OpenAlex) — left out of this score |
| Citations per year | — / 5 | No citation count or no year — left out of this score |
| 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 | — / 6 | Not yet checked against this library's citation graph — left out of this score |
| Still being cited | — / 4 | No yearly citation counts — left out of this score |
| Senior author's track record | — / 4 | Senior author's record not available — left out of this score |
| Institution's track record | — / 3 | No institution listed in OpenAlex — left out of this score |
| Multi-centre collaboration | — / 3 | Institutions not listed — left out of this score |
| Indexed in PubMed | 1 / 2 | Not in PubMed, but has a DOI |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Points | 29 / 62 | Scored on 12 of 20 parts. We have no data for the rest, so they are left out: 29 of the 62 points we could judge it on is 47 out of 100. |
| Total | 47 / 100 | Capped to 16 because this is not a peer-reviewed article. |
What each of these 20 components measures, and what this score is not →
Read the original
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Cite this study APA, Vancouver, BibTeX · download .bib or .ris
Built from the record alzhub holds for this paper, not looked up. Volume, issue and page numbers are not held in the record. The record names 7 authors; APA and Vancouver show the first six, BibTeX and the downloads carry all of them. Check the citation against the original before you use it.
APA 7th
Zhang, S., Bao, R., He, H., Initiative ftADN, Zhang, T., Cheng, W., et al. (2026). Clinical expression beyond measured Alzheimer disease molecular pathology: a discovery and external evaluation study. Research Square. https://doi.org/10.21203/rs.3.rs-10847343/v1
Vancouver
Zhang S, Bao R, He H, Initiative ftADN, Zhang T, Cheng W, et al. Clinical expression beyond measured Alzheimer disease molecular pathology: a discovery and external evaluation study. Research Square. 2026. doi:10.21203/rs.3.rs-10847343/v1.
BibTeX
@article{zhang2026-f99a3bc7,
author = {Zhang, S. and Bao, R. and He, H. and {Initiative ftADN} and Zhang, T. and Cheng, W. and Ding, W.},
title = {{Clinical expression beyond measured Alzheimer disease molecular pathology: a discovery and external evaluation study}},
journal = {Research Square},
year = {2026},
doi = {10.21203/rs.3.rs-10847343/v1},
url = {https://doi.org/10.21203/rs.3.rs-10847343/v1}
}
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