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. 2025 Aug 1;26(15):7410.
doi: 10.3390/ijms26157410.

APOE Genotyping in Cognitive Disorders: Preliminary Observations from the Greek Population

Athanasia Athanasaki  1 , Ioanna Tsantzali  1 , Christos Kroupis  2 , Aikaterini Theodorou  1 , Fotini Boufidou  3 , Vasilios C Constantinides  3 , John S Tzartos  1 , Socrates J Tzartos  4 , Georgios Velonakis  5 , Christina Zompola  1 , Amalia Michalopoulou  1 , Panagiotis G Paraskevas  1 , Anastasios Bonakis  1 , Sotirios Giannopoulos  1 , Paraskevi Moutsatsou  2 , Georgios Tsivgoulis  1   6 , Elisabeth Kapaki  3 , George P Paraskevas  1   3
Affiliations

APOE Genotyping in Cognitive Disorders: Preliminary Observations from the Greek Population

Athanasia Athanasaki et al. Int J Mol Sci. .

Abstract

Alzheimer's disease (AD) is the most common cause of cognitive decline. Among the various susceptibility genes, the gene of apolipoprotein E (APOE) is probably the most important. It may be present in three allelic forms, termed ε2, ε3 and ε4, and the most common genotype is the ε3/ε3. Recently, it has been observed that subjects with the ε4/ε4 genotype may show near-full penetrance of AD biology (pathology and biomarkers), leading to the suggestion that ε4 homozygosity may represent a distinct genetic type of AD. The aim of the present study was to investigate the role of ε4 homozygosity or heterozygosity in the presence or absence of the AD biomarker profile in patients with cognitive disorders in the Greek population. A total of 274 patients were included in the study. They underwent APOE genotyping and cerebrospinal fluid (CSF) biomarker profiling. The presence of ε4 was associated with a lower age of symptom onset and decreased amyloid biomarkers (irrespective to AD or non-AD profiles), and predicted the presence of an AD profile by a positive predictive value approaching 100%. In conclusion, the ε4 allele has a significant effect on the risk and clinical parameters of cognitive impairment and AD in the Greek population, while the ε4/ε4 genotype may be highly indicative of the (co)existence of AD in cognitively impaired patients.

Keywords: Alzheimer’s disease; amyloid beta; apolipoprotein E; cognitive impairment; dementia; phospho-tau protein; tau protein.

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Conflict of interest statement

G.T., G.P.P., I.T, A.A., C.Z. and A.B. are clinical investigators in the “EVOKE” and “EVOKE plus” trials of semaglutide for early Alzheimer’s disease (NovoNordisk, NCT04777396 and NCT04777409, respectively). G.P.P received fees from Biogen International and from ITF Hellas, as a consultant of advisory boards. C.K. declares fees from Roche, Abbott and Snibe. S.J.T has shares in the research and diagnosis laboratory Tzartos NeuroDiagnostics. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.

Figures

Figure 1
Figure 1
The cumulative frequency distribution of age at disease onset according to the APOE genotype in patients with AD (a) and non-AD (b) biomarker profiles. Although shifted to the left (earlier age of onset compared to ε4 absence), there is no clear-cut difference between ε4 homozygotes and ε4 heterozygotes with AD. (c) The peak incidence of age of onset of AD becomes progressively earlier with an increasing ε4 load in individuals with AD. (d) Interestingly, the peak incidence of age of onset occurs earlier with an increasing ε4 load in non-AD patients as well.
Figure 2
Figure 2
Adjusted levels of CSF Aβ42 (a) and Aβ42/Aβ40 (b) in individuals with ε4 presence vs. ε4 absence.
Figure 3
Figure 3
(a) Increasing frequency of AD profile from ε4 absence to ε4 presence. Note that all ε4 homozygotes had AD biomarker profiles. (b) Increased frequency of ε4 presence in patients with AD biomarkers (the terms A+T− AD and A+T− Non-AD indicate A+T− patients with an increased or normal τP181/Aβ42 ratio, respectively). Note that ε4/ε4 was found only in patients with AD profile. (c,d) show pie charts of relative frequencies of various APOE genotypes in AD and non-AD biomarker profiles, respectively.
Figure 4
Figure 4
Clinical phenotypes/presentations in AD with at least 1 (a) or no ε4 allele (b) and in non-AD with at least 1 (c) or no ε4 allele (d).
Figure 5
Figure 5
A flow chart of the participants in the present study.
See this image and copyright information in PMC

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