APOEɛ4-TOMM40L Haplotype Increases the Risk of Mild Cognitive Impairment Conversion to Alzheimer’s Disease

Article type: Research Article

Authors: Cardoso, Remy^{a; *} | Lemos, Carolina^{b; c; d} | Oliveiros, Bárbara^{e; f; g} | Almeida, Maria Rosário^a | Baldeiras, Inês^{a; e; h} | Pereira, Cláudia Fragão^{a; e} | Santos, Ana^a | Duro, Dianaⁱ | Vieira, Danielaⁱ | Santana, Isabel^{a; e; i} | Oliveira, Catarina Resende^{a; e; j}

Affiliations: [a] Center for Neuroscience and Cell Biology, CNC-CIBB, University of Coimbra, Coimbra, Portugal | [b] UnIGENe, IBMC –Institute for Molecular and Cell Biology, Porto, Portugal | [c] i3S –Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal | [d] ICBAS - Instituto Ciências Biomédicas Abel Salazar, Universidade do Porto, Porto, Portugal | [e] Faculty of Medicine, University of Coimbra, Coimbra, Portugal | [f] Laboratory of Biostatistics and Medical Informatics, Faculty of Medicine, University of Coimbra, Coimbra, Portugal | [g] Coimbra Institute for Clinical and Biomedical Research, Faculty of Medicine, University of Coimbra, Coimbra, Portugal | [h] Neurochemistry Laboratory, Neurology Department, Coimbra University Hospital (CHUC), Coimbra, Portugal | [i] Neurology Department, Coimbra University Hospital (CHUC), Coimbra, Portugal | [j] Clinical Academic Center of Coimbra, Coimbra, Portugal

Correspondence: [*] Correspondence to: Remy Cardoso, MSc, Center for Neuroscience and Cell Biology, University of Coimbra, Rua Larga, Faculty of Medicine, Pólo I, 1^st floor, 3004-504 Coimbra, Portugal. Tel.: +351 912914558; E-mail: remycardoso@gmail.com.

Abstract: Background:Mild cognitive impairment (MCI) has been considered as a pre-dementia stage, although the factors leading to Alzheimer’s disease (AD) conversion remain controversial. Objective:Evaluate whether TOMM40 poly-T (TOMM40′ 523) polymorphism is associated with the risk and conversion time from MCI to AD and secondly with AD cerebrospinal fluid (CSF) biomarkers, disentangling the APOE genotype. Methods:147 AD patients, 102 MCI patients, and 105 cognitively normal controls were genotyped for poly-T polymorphism. MCI patients were subdivided into two groups, the group of patients that converted to AD (MCI-AD) and the group of those that remained stable (MCI-S). Results:TOMM40′ 523 L allele was significantly more frequent in the MCI-AD group and having at least one L allele significantly increased the risk of conversion from MCI to AD (OR = 8.346, p < 0.001, 95% CI: 2.830 to 24.617). However, when adjusted for the presence of APOE ɛ4 allele, both the L allele and ɛ4 allele lost significance in the model (p > 0.05). We then analyzed the APOE ɛ4-TOMM40′ 523 L haplotype and observed that patients carrying this haplotype had significantly higher risk (OR = 5.83; 95% CI = 2.30–14.83) and mean lower times of conversion to AD (p = 0.003). This haplotype was also significantly associated with a biomarker profile compatible with AD (p = 0.007). Conclusion:This study shows that the APOE ɛ4-TOMM40′ 523 L haplotype is associated with a higher risk and shorter times of conversion from MCI to AD, possibly driven by CSF biomarkers and mitochondrial dysfunction.

Keywords: Age of onset, Alzheimer’s disease, APOE , biomarker, cerebrospinal fluid, haplotype, mild cognitive impairment, poly T, progression, TOMM40

DOI: 10.3233/JAD-200556

Journal: Journal of Alzheimer's Disease, vol. 78, no. 2, pp. 587-601, 2020