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. 2025 Jan 16;10(1):14.
doi: 10.3390/geriatrics10010014.

Genetic Predisposition to Hippocampal Atrophy and Risk of Amnestic Mild Cognitive Impairment and Alzheimer's Dementia

Ioannis Liampas  1 , Vasileios Siokas  1 , Niki Mourtzi  2 , Sokratis Charisis  2   3 , Stefanos N Sampatakakis  2 , Ioannis Foukarakis  2 , Alex Hatzimanolis  4 , Alfredo Ramirez  5   6   7   8   9 , Jean-Charles Lambert  10 , Mary Yannakoulia  11 , Mary H Kosmidis  12 , Efthimios Dardiotis  1 , Georgios M Hadjigeorgiou  13 , Paraskevi Sakka  14 , Konstantinos Rouskas  15 , Nikolaos Scarmeas  2   16
Affiliations

Genetic Predisposition to Hippocampal Atrophy and Risk of Amnestic Mild Cognitive Impairment and Alzheimer's Dementia

Ioannis Liampas et al. Geriatrics (Basel). .

Abstract

Background: There is a paucity of evidence on the association between genetic propensity for hippocampal atrophy with cognitive outcomes. Therefore, we examined the relationship of the polygenic risk score for hippocampal atrophy (PRShp) with the incidence of amnestic mild cognitive impairment (aMCI) and Alzheimer's disease (AD) as well as the rates of cognitive decline.

Methods: Participants were drawn from the population-based HELIAD cohort. Comprehensive neuropsychological assessments were performed at baseline and at follow-up. PRShp was derived from the summary statistics of a large genome-wide association study for hippocampal volume. Cox proportional hazards models as well as generalized estimating equations (GEEs) were used to evaluate the association of PRShp with the combined incidence of aMCI/AD and cognitive changes over time, respectively. All models were adjusted for age, sex, education, and apolipoprotein E (APOE) genotype.

Results: Our analysis included 618 older adults, among whom 73 developed aMCI/AD after an average follow-up of 2.96 ± 0.8 years. Each additional SD of PRShp elevated the relative hazard for incident aMCI/AD by 46%. Participants at the top quartile of PRShp had an almost three times higher risk of converting to aMCI/AD compared to the lowest quartile group. Higher PRShp scores were also linked to steeper global cognitive and memory decline. The impact of PRShp was greater among women and younger adults.

Conclusions: Our findings support the association of PRShp with aMCI/AD incidence and with global cognitive and memory decline over time. The PRS association was sex- and age-dependent, suggesting that these factors should be considered in genetic modelling for AD.

Keywords: Alzheimer’s disease; cognitive decline; hippocampal atrophy; polygenic risk score.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Cumulative survival curves depicting the combined aMCI–AD risk of participants with different levels of PRShp (p for trend = 0.021). The figure was derived from a model adjusted for age, sex, education, PC1, PC2, and APOE ε4 genotype.
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