ORIGINAL RESEARCH article
Front. Aging
Sec. Genetics, Genomics and Epigenomics of Aging
This article is part of the Research TopicInsights in Genetics, Genomics and Epigenomics of Aging: 2025View all articles
Exploring Cognitive and Genetic Profiles in Healthy Adults: An Agglomerative Clustering Approach to APOE and PICALM Variants in Relation to Alzheimer's Disease
Provisionally accepted
- 1Humanitas University in Sosnowiec, Sosnowiec, Poland
- 2Uniwersytet Slaski w Katowicach, Katowice, Poland
- 3Karolinska Institutet, Stockholm, Sweden
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Introduction: The APOE ε4 and PICALM GG genotypes are strong genetic risk factors for Alzheimer's disease. This study aimed to identify cognitive subgroups using unsupervised machine learning and to investigate the influence of APOE and PICALM genotypes on cognitive performance. Material and methods: Cognitive, genetic and demographic data from 192 healthy middle-aged adults (50–63 years) from the PEARL-Neuro Database were analyzed using agglomerative hierarchical clustering. Neuropsychological tests included the California Verbal Learning Test, Raven's Progressive Matrices, and the Edinburgh Handedness Inventory. Subsequent analyses used linear regression models to assess the effects of APOE, PICALM, and their interaction on cognitive outcomes. Results: Two cognitive subgroups (better vs. worse performance) were identified for both females (n = 60/43) and males (n = 38/51). In women with lower cognitive performance, the presence of the APOE ε3ε4 allele was significantly associated with a higher number of perseverations (CVLT9: pFDR = 0.02, R2 = 0.18) and lower recognition accuracy (CVLT12: pFDR = 0.04, R2 = 0.12). A significant PICALM GG × education interaction was observed for fluid intelligence (pFDR = 0.03, R2 = 0.34). In men with lower cognitive performance, the APOE ε3ε4 genotype was associated with lower fluid intelligence scores (RPM: pFDR = 0.04, R2 = 0.09). Furthermore, significant APOE × PICALM interactions were found for verbal learning (CVLT1: pFDR = 0.03, R2 = 0.16) as well as delayed cued recall (CVLT6: pFDR = 0.03, R2 = 0.12; CVLT8: pFDR = 0.03, R2 = 0.13). Conclusions: This study revealed significant sex differences in gene–cognition interactions. In females with lower cognitive performance, the genotype APOE ε3ε4 was associated with poorer recognition, while the combined effects of APOE × PICALM in males were associated with weaker episodic memory. Although performance remained within normative ranges, these subtle differences may indicate early risk and warrant longitudinal monitoring.
Keywords: Alzheimer's disease, APOE genotype, PICALM genotype, Neuropsychological assessments, machine learning
Received: 28 Aug 2025; Accepted: 12 Dec 2025.
Copyright: © 2025 Bednorz, Trybek, Hoang and Religa. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Dorota Religa
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