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MRI-derived brain aging trajectories across the Alzheimer's continuum: links to cognition, pathology and lifestyle risk factors
Kuhn, E.; Antopoulos, G.; Kleineidam, L.; Stark, M.; Roeske, S.; Hoffstaedter, F.; Waite, L.; Peters et al.. medRxiv (preprint), 2026-08-22
Topic: Amyloid, tau and blood-test diagnosis
BackgroundThe brain age gap (BAG), the difference between neuroimaging-predicted and chronological age, captures inter-individual variation in brain aging. Although sensitive to Alzheimers disease (AD) pathology, its longitudinal patterns across the clinical AD continuum and prognostic relevance remain unclear. Methods577 participants from the DELCODE cohort (>2,100 MRI scans) were analysed: healthy controls individuals (HC, N=202), and patients with subjective cognitive decline (SCD, N=248), mild cognitive impairment (N=93), and AD dementia (N=34). All underwent structural MRI, amyloid (A{beta}42/40) and phosphorylated tau181 assessment, and lifestyle-related dementia risk profiling (LIBRA). BAG was derived using brainageR. Associations with baseline cognition, cognitive decline, and clinical progression (up to eight years) were examined using mixed-effects and Cox models. Mediation analyses tested whether BAG accounted for LIBRA-cognition associations. Biomarker-related and clinical findings were replicated in ADNI (N=461). FindingsBAG showed excellent short-term reliability, increased stepwise across the clinical spectrum and was elevated in amyloid-positive SCD, but not in asymptomatic amyloid-positive HC. Longitudinal BAG increases were strongest in amyloid- and tau-positive participants (A{beta}+T+). Higher BAG was associated with poorer baseline cognition and predicted cognitive decline, with strongest effects in A{beta}+T+. All main findings replicated in ADNI. BAG was associated with LIBRA only in biomarker-negative participants and partly mediated associations with cognitive outcomes in DELCODE. InterpretationBAG is a reliable non-invasive marker of structural brain health sensitive to AD pathology and to modifiable AD risk. Detectable divergence prior to objective cognitive impairment supports its relevance for early risk stratification and prevention-oriented research. FundingHelmholtz AI Cooperation Unit (ZT-I-PF-5-163).
Key findings
- Higher BAG was associated with poorer baseline cognition and predicted cognitive decline, with strongest effects in A{beta}+T+.
- BAG was associated with LIBRA only in biomarker-negative participants and partly mediated associations with cognitive outcomes in DELCODE.
Why it matters
In this longitudinal cohort, a higher brain age gap was linked to poorer baseline cognition and predicted cognitive decline, with the strongest effects in people positive for both amyloid and tau. This is observational, so it shows an association that may help identify who is at risk, not a treatment or cure.
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Study details
- Study designlongitudinal study
- Participants202
- Evidence strengthModerate
How this study scored 16/100
Preprint — not yet peer-reviewed. It scored 38 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 and senior author's track record, so those were left out: it earned 34 of the 90 points we could judge it on, which is 38 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 | 202 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 | — / 4 | OpenAlex's profile for last-listed author the DELCODE Study Group holds only 5 work(s), too few to judge a track record — left out of this score |
| Institution's track record | 2 / 3 | Imperial College London: institution h-index 1,744 (OpenAlex) |
| Multi-centre collaboration | 3 / 3 | OpenAlex lists 28 institution(s) in 3 countries |
| Indexed in PubMed | 1 / 2 | Not in PubMed, but has a DOI |
| Free to read | 2 / 2 | Free to read |
| Points | 34 / 90 | Scored on 18 of 20 parts. We have no data for the rest, so they are left out: 34 of the 90 points we could judge it on is 38 out of 100. |
| Total | 38 / 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
Full text: free to read — OpenAlex lists this copy as free to read: the link above (checked 6 Feb 1020).
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's author list ends in “et al.”, so not every author is named. Check the citation against the original before you use it.
APA 7th
Kuhn, E., Antopoulos, G., Kleineidam, L., Stark, M., Roeske, S., Hoffstaedter, F., et al. (2026). MRI-derived brain aging trajectories across the Alzheimer's continuum: links to cognition, pathology and lifestyle risk factors. medRxiv (preprint). https://doi.org/10.64898/2026.08.19.26360525
Vancouver
Kuhn E, Antopoulos G, Kleineidam L, Stark M, Roeske S, Hoffstaedter F, et al. MRI-derived brain aging trajectories across the Alzheimer's continuum: links to cognition, pathology and lifestyle risk factors. medRxiv (preprint). 2026. doi:10.64898/2026.08.19.26360525.
BibTeX
@article{kuhn2026-ad82dff0,
author = {Kuhn, E. and Antopoulos, G. and Kleineidam, L. and Stark, M. and Roeske, S. and Hoffstaedter, F. and Waite, L. and Peters and others},
title = {{MRI-derived brain aging trajectories across the Alzheimer's continuum: links to cognition, pathology and lifestyle risk factors}},
journal = {medRxiv (preprint)},
year = {2026},
doi = {10.64898/2026.08.19.26360525},
url = {https://doi.org/10.64898/2026.08.19.26360525}
}
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