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

Ioannis Liampas¹, Vasileios Siokas¹, Niki Mourtzi², Sokratis Charisis^{2

3}, Stefanos N Sampatakakis², Ioannis Foukarakis², Alex Hatzimanolis⁴, Alfredo Ramirez^{5

6

7

8

9}, Jean-Charles Lambert¹⁰, Mary Yannakoulia¹¹, Mary H Kosmidis¹², Efthimios Dardiotis¹, Georgios M Hadjigeorgiou¹³, Paraskevi Sakka¹⁴, Konstantinos Rouskas¹⁵, Nikolaos Scarmeas^{2

16}

Affiliations

¹ Department of Neurology, University Hospital of Larissa, School of Medicine, University of Thessaly, 41100 Larissa, Greece.
² 1st Department of Neurology, Aiginition Hospital, National and Kapodistrian University of Athens Medical School, 11528 Athens, Greece.
³ Department of Neurology, UT Health San Antonio, San Antonio, TX 78229, USA.
⁴ Department of Psychiatry, Aiginition Hospital, National and Kapodistrian University of Athens Medical School, 11528 Athens, Greece.
⁵ Division of Neurogenetics and Molecular Psychiatry, Department of Psychiatry and Psychotherapy, Medical Faculty, University of Cologne, 50923 Cologne, Germany.
⁶ Department of Neurodegenerative Diseases and Geriatric Psychiatry, University Hospital Bonn, 53127 Bonn, Germany.
⁷ German Center for Neurodegenerative Diseases (DZNE Bonn), 53175 Bonn, Germany.
⁸ Department of Psychiatry, Glenn Biggs Institute for Alzheimer's and Neurodegenerative Diseases, San Antonio, TX 78229, USA.
⁹ Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany.
¹⁰ U1167-RID-AGE Facteurs de Risque et Déterminants Moléculaires des Maladies Liés au Vieillissement, CHU Lille, Inserm, Institut Pasteur de Lille, Université de Lille, 59000 Lille, France.
¹¹ Department of Nutrition and Dietetics, Harokopio University, 17671 Athens, Greece.
¹² Lab of Cognitive Neuroscience, School of Psychology, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece.
¹³ Department of Neurology, Medical School, University of Cyprus, Nicosia 2414, Cyprus.
¹⁴ Athens Association of Alzheimer's Disease and Related Disorders, 11636 Maroussi, Greece.
¹⁵ Institute of Applied Biosciences, Centre for Research & Technology Hellas, 54124 Thessaloniki, Greece.
¹⁶ Department of Neurology, The Gertrude H. Sergievsky Center, Taub Institute for Research in Alzheimer's Disease and the Aging Brain, Columbia University, New York, NY 10032, USA.

PMID: 39846584
PMCID: PMC11755629
DOI: 10.3390/geriatrics10010014

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

Ioannis Liampas et al. Geriatrics (Basel). 2025.

. 2025 Jan 16;10(1):14.

doi: 10.3390/geriatrics10010014.

Authors

Affiliations

¹ Department of Neurology, University Hospital of Larissa, School of Medicine, University of Thessaly, 41100 Larissa, Greece.
² 1st Department of Neurology, Aiginition Hospital, National and Kapodistrian University of Athens Medical School, 11528 Athens, Greece.
³ Department of Neurology, UT Health San Antonio, San Antonio, TX 78229, USA.
⁴ Department of Psychiatry, Aiginition Hospital, National and Kapodistrian University of Athens Medical School, 11528 Athens, Greece.
⁵ Division of Neurogenetics and Molecular Psychiatry, Department of Psychiatry and Psychotherapy, Medical Faculty, University of Cologne, 50923 Cologne, Germany.
⁶ Department of Neurodegenerative Diseases and Geriatric Psychiatry, University Hospital Bonn, 53127 Bonn, Germany.
⁷ German Center for Neurodegenerative Diseases (DZNE Bonn), 53175 Bonn, Germany.
⁸ Department of Psychiatry, Glenn Biggs Institute for Alzheimer's and Neurodegenerative Diseases, San Antonio, TX 78229, USA.
⁹ Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany.
¹⁰ U1167-RID-AGE Facteurs de Risque et Déterminants Moléculaires des Maladies Liés au Vieillissement, CHU Lille, Inserm, Institut Pasteur de Lille, Université de Lille, 59000 Lille, France.
¹¹ Department of Nutrition and Dietetics, Harokopio University, 17671 Athens, Greece.
¹² Lab of Cognitive Neuroscience, School of Psychology, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece.
¹³ Department of Neurology, Medical School, University of Cyprus, Nicosia 2414, Cyprus.
¹⁴ Athens Association of Alzheimer's Disease and Related Disorders, 11636 Maroussi, Greece.
¹⁵ Institute of Applied Biosciences, Centre for Research & Technology Hellas, 54124 Thessaloniki, Greece.
¹⁶ Department of Neurology, The Gertrude H. Sergievsky Center, Taub Institute for Research in Alzheimer's Disease and the Aging Brain, Columbia University, New York, NY 10032, USA.

PMID: 39846584
PMCID: PMC11755629
DOI: 10.3390/geriatrics10010014

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**
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.

See this image and copyright information in PMC

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

Affiliations

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

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Grants and funding

LinkOut - more resources

Full Text Sources

Miscellaneous