Association Of Apolipoprotein E Genotype And Blood-based Biomarkers In The Cog-aging Cohort Study:

Author Block:Maurício Lemos Bueno Fontes^1,2, Joice Coutinho Alvarenga^2,3, Rafaela D'Angelo Machado^2,4, Giovanna Correia Pereira Moro^1,2, João Arthur Rodrigues Barbosa⁵, Gabriela Tomé Oliveira Engelmann^2,3, Jonas Jardim de Paula^3,6, Marco Aurélio Fagundes Angelo⁷, Anja Schneider⁸, Pamela Martino Adami⁹, Maria Carolina DALMASSO, PhD¹⁰, Débora Marques de Miranda^11,3, Marco Aurélio Romano-Silva^3,11, Luiz Armando Cunha de Marco^3,11, Bernardo de Mattos Viana^3,6, Alfredo Ramírez Zuniga^9,8, MARIA APARECIDA BICALHO, PhD^3,12.
¹Undergraduate Medicine, Federal University of Minas Gerais, Belo Horizonte, Brazil, ²Cog-Aging Research Group, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil, ³Molecular Medicine Postgraduate Program, School of Medicine, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, Brazil, ⁴Undergraduate Psychology, Faculty of Health Sciences of Minas Gerais, Belo Horizonte, Brazil, ⁵Older Adult’s Psychiatry and Psychology Extension Program (PROEPSI), School of Medicine, Universade Federal de Minas Gerais (UFMG), Belo Horizonte, Brazil, ⁶Department of Psychiatry, School of Medicine, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, Brazil, ⁷Federal University of Minas Gerais, Belo Horizonte, Brazil, ⁸German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany, ⁹Division of Neurogenetics and Molecular Psychiatry, Department of Psychiatry and Psychotherapy, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany, ¹⁰Neuroscience and Complex Systems Unit - CONICET, Florencio Varela, Argentina, ¹¹Neurotec R National Institute of Science and Technology (INCT-Neurotec R), Faculty of Medicine, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, Brazil, ¹²Department of Internal Medicine, School of Medicine, Federal University of Minas gerais, Belo Horizonte, Brazil.

Abstract:
Background: Variations in blood-based biomarkers (BBM) have been reported across different apolipoprotein E (APOE) genotypes along the Alzheimer’s disease (AD) continuum. These alterations remain understudied in populations with low educational attainment. Objectives: To investigate the association between BBM and APOE genotype across the clinical continuum of AD.
Methods: A total of 316 participants, from Brazilian Cog-Aging cohort, were stratified into cognitively unimpaired (CU=29.8%), mild cognitive impairment (MCI=43.7%), dementia of the Alzheimer’s type (DAT=23.9%) and other dementias (2.5%). APOE genotyping was performed using real-time PCR. Participants were classified by the presence of at least one ε4 allele (ε4+ and ε4-). BBM (pTau-217, Aβ42, Aβ40, GFAP, and NfL) were quantified using single-molecule array technology (Simoa®). The Mann-Whitney U test was employed for hypothesis testing (JASP software). Clustermaps and hierarchical clustering were performed using Python (Seaborn package). Individual values were grouped by genotype using the median, standardized by z-score. Genotypes ε2/ε2 and ε2/ε4 were excluded due to small sample size.
Results: Mean age 76.77 years (SD=6.562); median 4 years of schooling (IQR=3); Women (76%); ε4+ (37.1%). In CU groups, no significant differences were found between ε4+ and ε4- groups. In MCI groups, pTau-217 levels (p<0.001), pTau-217/Aβ42 ratio (p<0.001), and GFAP levels (p=0.030) were higher in ε4+ and the Aβ42/Aβ40 ratio (p=0.006) was lower. In DAT groups, NfL (p=0.026) and Aβ42 (p=0.048) levels in ε4+ were lower. (table 1) (figure 1). Cluster analysis showed that ε4 carriers across genotypes exhibited higher pTau-217, pTau-217/Aβ42 and GFAP, with lower Aβ42 and Aβ42/Aβ40 ratio, whereas NfL exhibits a distinct pattern (figure 2).
Conclusion: In this cohort from a low- and middle-income country, characterized by low educational attainment, ε4 allele was associated with a distinct BBM expression pattern that is consistent with findings previously reported in high-income populations. In the MCI group, these differences suggest that ε4 carriers exhibit a higher reactive astrogliosis, amyloid and Tau disease burden. The NfL results may reflect the limited specificity of this BBM, highlighting the need for further investigation.