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Sex-specific effects of apolipoprotein E ε4 genotype on longitudinal hippocampal atrophy in amnestic mild cognitive impairment over a 2-year evaluation period
Chang-Hyun Park, Hyunji Lee, Young Min Lee, Byung Dae Lee, Eunsoo Moon, Hwagyu Suh, Kyungwon Kim, Hak Jin Kim et al.. Journal of Alzheimer s Disease, 2025-02-01
Topic: Brain proteins, microglia and lab models
Background Hippocampal atrophy is implicated in the early onset of Alzheimer's disease (AD). It is closely associated with rapid cognitive decline and serves as a critical predictor for conversion from mild cognitive impairment (MCI) to AD. Consequently, with growing interest in utilizing hippocampal volume (HV) as an outcome measure in clinical trials, elucidating the neurobiological mechanisms underlying hippocampal atrophy is essential for early diagnosing AD and predicting its progression. Objective The risk of AD associated with the apolipoprotein E ε4 ( APOE4 ) allele is higher in females than in males. However, the presence of sex-specific effects of the APOE4 genotype on longitudinal hippocampal atrophy (ΔHV) remains unclear. We aimed to examine the effects of the interaction between the APOE4 genotype and sex on ΔHV in amnestic mild cognitive impairment (aMCI). Methods This hospital-based prospective longitudinal study included 73 patients with aMCI. ΔHV, the major outcome measure, was assessed using magnetic resonance imaging performed at a baseline date and 2 years after the baseline evaluation. A two-way analysis of variance was conducted to examine the effects of the interaction between the APOE4 genotype and sex on ΔHV over the 2-year period. Results A significant interaction was observed between APOE4 and sex concerning ΔHV ( p = 0.036). In females, ΔHV significantly correlated with the APOE4 status. Female APOE4 carriers (ε3/ε4) exhibited 2.3 times higher ΔHV compared with female non-carriers (ε3/ε3) (−0.51 ± 0.28 versus −0.22 ± 0.26, p < 0.001). In contrast, ΔHV was not linked to the APOE4 status in males ( p = 0.599). Conclusions We identified that the APOE4 genotype affected ΔHV in females. Our findings suggest that female APOE4 carriers, unlike males, may be more susceptible than non-carriers to the underlying pathophysiological mechanisms of hippocampal atrophy in aMCI.
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APA 7th
Park, C.-H., Lee, H., Lee, Y. M., Lee, B. D., Moon, E., Suh, H., et al. (2025). Sex-specific effects of apolipoprotein E ε4 genotype on longitudinal hippocampal atrophy in amnestic mild cognitive impairment over a 2-year evaluation period. Journal of Alzheimer s Disease. https://doi.org/10.1177/13872877241313066
Vancouver
Park C.-H, Lee H, Lee YM, Lee BD, Moon E, Suh H, et al. Sex-specific effects of apolipoprotein E ε4 genotype on longitudinal hippocampal atrophy in amnestic mild cognitive impairment over a 2-year evaluation period. Journal of Alzheimer s Disease. 2025. doi:10.1177/13872877241313066. PMID: 39924830.
BibTeX
@article{park2025-39924830,
author = {Park, Chang-Hyun and Lee, Hyunji and Lee, Young Min and Lee, Byung Dae and Moon, Eunsoo and Suh, Hwagyu and Kim, Kyungwon and Kim, Hak Jin and others},
title = {{Sex-specific effects of apolipoprotein E ε4 genotype on longitudinal hippocampal atrophy in amnestic mild cognitive impairment over a 2-year evaluation period}},
journal = {Journal of Alzheimer s Disease},
year = {2025},
doi = {10.1177/13872877241313066},
pmid = {39924830},
url = {https://doi.org/10.1177/13872877241313066}
}
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Key findings
- It is closely associated with rapid cognitive decline and serves as a critical predictor for conversion from mild cognitive impairment (MCI) to AD.
- Objective The risk of AD associated with the apolipoprotein E ε4 ( APOE4 ) allele is higher in females than in males.
- Results A significant interaction was observed between APOE4 and sex concerning ΔHV ( p = 0.036).
- In females, ΔHV significantly correlated with the APOE4 status.
- Female APOE4 carriers (ε3/ε4) exhibited 2.3 times higher ΔHV compared with female non-carriers (ε3/ε3) (−0.51 ± 0.28 versus −0.22 ± 0.26, p < 0.001).
Why it matters
In this 2-year study of 73 people with amnestic mild cognitive impairment, a significant interaction was found between APOE4 genotype and sex on hippocampal atrophy, with female APOE4 carriers showing 2.3 times higher atrophy. It does not test a treatment or cure, but it suggests sex-specific effects may matter when using hippocampal volume in trials or for predicting progression.
Study details
- Study designlongitudinal study
- Participants73
- Evidence strengthModerate
How this study scored 44/100
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 (Journal of Alzheimer s Disease) |
| Journal's citation record | 2 / 4 | Journal of Alzheimer s Disease: journal h-index 218 (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 | 1 / 4 | 73 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 1 times (OpenAlex, 2026-10-10) |
| Citations per year | 0 / 5 | 0.3 citations a year over 3 year(s) since 2025 |
| Impact for its field and year | 1 / 6 | Cited 0.6× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 0 / 6 | No other study in this library cites it |
| Still being cited | 0 / 4 | Cited 1 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 2 / 4 | Last-listed author Chang‐Seok Kim: h-index 36 (OpenAlex, whole career) |
| Institution's track record | 0 / 3 | Pusan National University: institution h-index 456 (OpenAlex) |
| Multi-centre collaboration | 1 / 3 | OpenAlex lists 2 institution(s) in 1 country |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 39924830) |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Total | 44 / 100 | — |
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