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Genetic drivers of hippocampal atrophy highlight the role of APOE functional variants and AD polygenicity in Mild Cognitive Impairment
Natàlia Vilor‐Tejedor, Albert Rodrigo, Patricia Genius, Blanca Rodríguez‐Fernández, Federica Anastasi, Wiesje Pelkmans, Arcadi Navarro, Hieab H.H. Adams et al.. NeuroImage Clinical, 2025-01-01
Topic: Brain proteins, microglia and lab models
• Longitudinal imaging-genetics study of hippocampal atrophy trajectories over 5 years in ADNI. • APOE -ε4 carriership and ApoE CSF proteomic quantitative trait loci are key genetic drivers of accelerated hippocampal atrophy in amyloid-positive MCI. • Genetic effects are stage-specific, with strongest associations during the prodromal phase of AD. • Sex differences in atrophy rates are observed, but do not significantly alter genetic influences. • Findings support the utility of APOE and functional genetic markers as stratification tools for early neurodegeneration in AD. The hippocampus, crucial in cognitive aging and Alzheimer’s disease (AD), shows early atrophy during disease progression. This study investigated 5-year trajectories of hippocampal volumes across AD stages, focusing on genetic predisposition to AD, captured through the polygenic risk score for AD (PRS-AD) and APOE, and their impact on hippocampal atrophy. Analyzing data from 1,051 participants in the ADNI, we found that AD genetic risk accelerates a reduction in hippocampal volume, particularly in individuals with mild cognitive impairment (MCI). Effects were primarily driven by cerebrospinal fluid protein quantitative trait loci of APOE. Excluding the APOE region from analyses negated these effects, underscoring its critical role. This stage-specific effect suggested that AD genetic factors, particularly the APOE region, exert their influence primarily before or during the transition to MCI, highlighting the hippocampus’s increased vulnerability during this period. These findings underscored the importance of targeting the MCI stage for early detection and intervention in AD. Further research is warranted to elucidate these dynamics and their potential clinical applications.
Key findings
- • Longitudinal imaging-genetics study of hippocampal atrophy trajectories over 5 years in ADNI. • APOE -ε4 carriership and ApoE CSF proteomic quantitative trait loci are key genetic drivers of accelerated hippocampal atrophy in amyloid-positive MCI. • Genetic effects are stage-specific, with strongest associations during the prodromal phase of AD. • Sex differences in atrophy rates are observed, but do not significantly alter genetic influences. • Findings support the utility of APOE and functional genetic markers as stratification tools for early neurodegeneration in AD.
- Analyzing data from 1,051 participants in the ADNI, we found that AD genetic risk accelerates a reduction in hippocampal volume, particularly in individuals with mild cognitive impairment (MCI).
- This stage-specific effect suggested that AD genetic factors, particularly the APOE region, exert their influence primarily before or during the transition to MCI, highlighting the hippocampus’s increased vulnerability during this period.
- These findings underscored the importance of targeting the MCI stage for early detection and intervention in AD.
Why it matters
In over 1,000 ADNI participants, APOE-ε4 carriership and ApoE cerebrospinal fluid protein quantitative trait loci were key genetic drivers of accelerated hippocampal atrophy in amyloid-positive mild cognitive impairment, with effects strongest during the prodromal phase. The findings support using APOE and functional genetic markers as stratification tools for early neurodegeneration.
Study details
- Study designlongitudinal study
- Participants1,051
- Evidence strengthModerate
How this study scored 51/100
Published in a peer-reviewed journal, and it is a longitudinal study following the same people over time. Scored zero for effect reported and randomised / blinded because the record does not state it.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (NeuroImage Clinical) |
| Journal's citation record | 1 / 4 | NeuroImage Clinical: journal h-index 133 (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 | 4 / 5 | 2025 — within 3 year(s) of the newest study here |
| Sample size | 3 / 4 | 1,051 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 | 1 / 7 | Cited 2 times (OpenAlex, 2026-10-10) |
| Citations per year | 0 / 5 | 0.7 citations a year over 3 year(s) since 2025 |
| 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 1 other studies in this library |
| Still being cited | 0 / 4 | Cited 2 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 1 / 4 | Last-listed author Tavia E. Evans: h-index 14 (OpenAlex, whole career) |
| Institution's track record | 1 / 3 | Radboud University Nijmegen: institution h-index 1,143 (OpenAlex) |
| Multi-centre collaboration | 3 / 3 | OpenAlex lists 17 institution(s) in 5 countries |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 41092763) |
| Free to read | 2 / 2 | Free to read |
| Total | 51 / 100 | — |
What each of these 20 components measures, and what this score is not →
Read the original
- DOI: 10.1016/j.nicl.2025.103889
- PubMed: 41092763
- Original source →
- Free full text: NeuroImage Clinical →
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
Vilor‐Tejedor, N., Rodrigo, A., Genius, P., Rodríguez‐Fernández, B., Anastasi, F., Pelkmans, W., et al. (2025). Genetic drivers of hippocampal atrophy highlight the role of APOE functional variants and AD polygenicity in Mild Cognitive Impairment. NeuroImage Clinical. https://doi.org/10.1016/j.nicl.2025.103889
Vancouver
Vilor‐Tejedor N, Rodrigo A, Genius P, Rodríguez‐Fernández B, Anastasi F, Pelkmans W, et al. Genetic drivers of hippocampal atrophy highlight the role of APOE functional variants and AD polygenicity in Mild Cognitive Impairment. NeuroImage Clinical. 2025. doi:10.1016/j.nicl.2025.103889. PMID: 41092763.
BibTeX
@article{vilortejedor2025-41092763,
author = {Vilor‐Tejedor, Natàlia and Rodrigo, Albert and Genius, Patricia and Rodríguez‐Fernández, Blanca and Anastasi, Federica and Pelkmans, Wiesje and Navarro, Arcadi and Adams, Hieab H.H. and others},
title = {{Genetic drivers of hippocampal atrophy highlight the role of APOE functional variants and AD polygenicity in Mild Cognitive Impairment}},
journal = {NeuroImage Clinical},
year = {2025},
doi = {10.1016/j.nicl.2025.103889},
pmid = {41092763},
url = {https://doi.org/10.1016/j.nicl.2025.103889}
}
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