Genetic drivers of hippocampal atrophy highlight the role of APOE functional variants and AD polygenicity in Mild Cognitive Impairment
Vilor-Tejedor, Natalia ; Rodrigo, Albert ; Genius, Patricia ; Rodríguez-Fernández, Blanca ; Anastasi, Federica ; Pelkmans, Wiesje LU ; Navarro, Arcadi ; Adams, Hieab H. ; Wisse, Laura LU
and Gispert, Juan D.
, et al.
(2025)
In NeuroImage: Clinical
48.
- Abstract
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... (More)
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.
(Less)
- author
- Vilor-Tejedor, Natalia
; Rodrigo, Albert
; Genius, Patricia
; Rodríguez-Fernández, Blanca
; Anastasi, Federica
; Pelkmans, Wiesje
LU
; Navarro, Arcadi
; Adams, Hieab H.
; Wisse, Laura
LU
and Gispert, Juan D.
, et al. (More)
- Vilor-Tejedor, Natalia
; Rodrigo, Albert
; Genius, Patricia
; Rodríguez-Fernández, Blanca
; Anastasi, Federica
; Pelkmans, Wiesje
LU
; Navarro, Arcadi
; Adams, Hieab H.
; Wisse, Laura
LU
; Gispert, Juan D.
and Evans, Tavia E.
(Less)
- organization
- publishing date
- 2025
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- APOE, Genetic risk, Hippocampal atrophy, Mild cognitive impairment, Protein quantitative trait loci
- in
- NeuroImage: Clinical
- volume
- 48
- article number
- 103889
- publisher
- Elsevier
- external identifiers
-
- scopus:105019321208
- pmid:41092763
- ISSN
- 2213-1582
- DOI
- 10.1016/j.nicl.2025.103889
- language
- English
- LU publication?
- yes
- additional info
- Publisher Copyright: © 2025 The Author(s).
- id
- fc66f6ba-ce63-43ad-84c4-e1970c5c6df0
- date added to LUP
- 2026-01-19 14:24:56
- date last changed
- 2026-01-19 14:25:50
@article{fc66f6ba-ce63-43ad-84c4-e1970c5c6df0,
abstract = {{<p>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.</p>}},
author = {{Vilor-Tejedor, Natalia and Rodrigo, Albert and Genius, Patricia and Rodríguez-Fernández, Blanca and Anastasi, Federica and Pelkmans, Wiesje and Navarro, Arcadi and Adams, Hieab H. and Wisse, Laura and Gispert, Juan D. and Evans, Tavia E.}},
issn = {{2213-1582}},
keywords = {{APOE; Genetic risk; Hippocampal atrophy; Mild cognitive impairment; Protein quantitative trait loci}},
language = {{eng}},
publisher = {{Elsevier}},
series = {{NeuroImage: Clinical}},
title = {{Genetic drivers of hippocampal atrophy highlight the role of APOE functional variants and AD polygenicity in Mild Cognitive Impairment}},
url = {{http://dx.doi.org/10.1016/j.nicl.2025.103889}},
doi = {{10.1016/j.nicl.2025.103889}},
volume = {{48}},
year = {{2025}},
}