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Advanced structural brain aging in preclinical autosomal dominant Alzheimer disease
Millar PR, Gordon BA, Wisch JK, Schultz SA, Benzinger TL, Cruchaga C, Hassenstab JJ, Ibanez L et al.. Molecular neurodegeneration, 2023-12-19
Topic: Amyloid, tau and blood-test diagnosis
Background "Brain-predicted age" estimates biological age from complex, nonlinear features in neuroimaging scans. The brain age gap (BAG) between predicted and chronological age is elevated in sporadic Alzheimer disease (AD), but is underexplored in autosomal dominant AD (ADAD), in which AD progression is highly predictable with minimal confounding age-related co-pathology. Methods We modeled BAG in 257 deeply-phenotyped ADAD mutation-carriers and 179 non-carriers from the Dominantly Inherited Alzheimer Network using minimally-processed structural MRI scans. We then tested whether BAG differed as a function of mutation and cognitive status, or estimated years until symptom onset, and whether it was associated with established markers of amyloid (PiB PET, CSF amyloid-β-42/40), phosphorylated tau (CSF and plasma pTau-181), neurodegeneration (CSF and plasma neurofilament-light-chain [NfL]), and cognition (global neuropsychological composite and CDR-sum of boxes). We compared BAG to other MRI measures, and examined heterogeneity in BAG as a function of ADAD mutation variants, APOE ε4 carrier status, sex, and education. Results Advanced brain aging was observed in mutation-carriers approximately 7 years before expected symptom onset, in line with other established structural indicators of atrophy. BAG was moderately associated with amyloid PET and strongly associated with pTau-181, NfL, and cognition in mutation-carriers. Mutation variants, sex, and years of education contributed to variability in BAG. Conclusions We extend prior work using BAG from sporadic AD to ADAD, noting consistent results. BAG associates well with markers of pTau, neurodegeneration, and cognition, but to a lesser extent, amyloid, in ADAD. BAG may capture similar signal to established MRI measures. However, BAG offers unique benefits in simplicity of data processing and interpretation. Thus, results in this unique ADAD cohort with few age-related confounds suggest that brain aging attributable to AD neuropathology can be accurately quantified from minimally-processed MRI.
Key findings
- We then tested whether BAG differed as a function of mutation and cognitive status, or estimated years until symptom onset, and whether it was associated with established markers of amyloid (PiB PET, CSF amyloid-β-42/40), phosphorylated tau (CSF and plasma pTau-181), neurodegeneration (CSF and plasma neurofilament-light-chain [NfL]), and cognition (global neuropsychological composite and CDR-sum of boxes).
- Results Advanced brain aging was observed in mutation-carriers approximately 7 years before expected symptom onset, in line with other established structural indicators of atrophy.
- BAG was moderately associated with amyloid PET and strongly associated with pTau-181, NfL, and cognition in mutation-carriers.
- Conclusions We extend prior work using BAG from sporadic AD to ADAD, noting consistent results.
- Thus, results in this unique ADAD cohort with few age-related confounds suggest that brain aging attributable to AD neuropathology can be accurately quantified from minimally-processed MRI.
Why it matters
In people with autosomal dominant Alzheimer's disease mutations, brain-predicted age was advanced about 7 years before expected symptom onset and was strongly associated with pTau-181. This supports brain age as a marker of early disease progression, not a treatment or cure.
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Study details
- Evidence strengthModerate
How this study scored 45/100
Published in a peer-reviewed journal. Scored zero for study design, sample size, effect reported, studied in people and randomised / blinded because the record does not state it.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (Molecular neurodegeneration) |
| Journal's citation record | 2 / 4 | Molecular Neurodegeneration: journal h-index 164 (OpenAlex, 2026-10-29) |
| Study design | 0 / 12 | No study design recorded — scores zero, not guessed (not stated in the record — scored 0) |
| 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 12 times (OpenAlex, 2026-10-10) |
| Citations per year | 1 / 5 | 2.4 citations a year over 5 year(s) since 2023 |
| Impact for its field and year | 2 / 6 | Cited 2.2× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 1 / 6 | Cited by 1 other studies in this library |
| Still being cited | 1 / 4 | Cited 12 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 3 / 4 | Last-listed author Eric McDade: h-index 65 (OpenAlex, whole career) |
| Institution's track record | 3 / 3 | Harvard University: institution h-index 3,235 (OpenAlex) |
| Multi-centre collaboration | 3 / 3 | OpenAlex lists 21 institution(s) in 8 countries |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 38111006) |
| Free to read | 2 / 2 | Free to read |
| Total | 45 / 100 | — |
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Read the original
- DOI: 10.1186/s13024-023-00688-3
- PubMed: 38111006
- Original source →
- Free full text: Molecular Neurodegeneration →
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
Millar, P. R., Gordon, B. A., Wisch, J. K., Schultz, S. A., Benzinger, T. L., Cruchaga, C., et al. (2023). Advanced structural brain aging in preclinical autosomal dominant Alzheimer disease. Molecular neurodegeneration. https://doi.org/10.1186/s13024-023-00688-3
Vancouver
Millar PR, Gordon BA, Wisch JK, Schultz SA, Benzinger TL, Cruchaga C, et al. Advanced structural brain aging in preclinical autosomal dominant Alzheimer disease. Molecular neurodegeneration. 2023. doi:10.1186/s13024-023-00688-3. PMID: 38111006.
BibTeX
@article{millar2023-38111006,
author = {Millar, P. R. and Gordon, B. A. and Wisch, J. K. and Schultz, S. A. and Benzinger, T. L. and Cruchaga, C. and Hassenstab, J. J. and Ibanez, L. and others},
title = {{Advanced structural brain aging in preclinical autosomal dominant Alzheimer disease}},
journal = {Molecular neurodegeneration},
year = {2023},
doi = {10.1186/s13024-023-00688-3},
pmid = {38111006},
url = {https://doi.org/10.1186/s13024-023-00688-3}
}
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