Serotonin Receptor Gene Polymorphisms Are Associated with Cerebrospinal Fluid, Genetic, and Neuropsychological Biomarkers of Alzheimer's Disease

Mirjana Babić Leko; Matea Nikolac Perković; Ena Španić; Dubravka Švob Štrac; Nikolina Pleić; Željka Vogrinc; Ivana Gunjača; Dora Bežovan; Gordana Nedić Erjavec; Nataša Klepac; Fran Borovečki; Tatijana Zemunik; Nela Pivac; Patrick R Hof; Goran Šimić

doi:10.3390/biomedicines10123118

Serotonin Receptor Gene Polymorphisms Are Associated with Cerebrospinal Fluid, Genetic, and Neuropsychological Biomarkers of Alzheimer's Disease

Biomedicines. 2022 Dec 2;10(12):3118. doi: 10.3390/biomedicines10123118.

Authors

Mirjana Babić Leko^{1

2}, Matea Nikolac Perković³, Ena Španić¹, Dubravka Švob Štrac³, Nikolina Pleić², Željka Vogrinc⁴, Ivana Gunjača², Dora Bežovan⁵, Gordana Nedić Erjavec³, Nataša Klepac⁶, Fran Borovečki⁶, Tatijana Zemunik², Nela Pivac³, Patrick R Hof⁷, Goran Šimić¹

Affiliations

¹ Department of Neuroscience, Croatian Institute for Brain Research, University of Zagreb Medical School, 10000 Zagreb, Croatia.
² Department of Medical Biology, School of Medicine, University of Split, 21000 Split, Croatia.
³ Department of Molecular Medicine, Institute Ruđer Bošković, 10000 Zagreb, Croatia.
⁴ Laboratory for Neurobiochemistry, Department of Laboratory Diagnostics, University Hospital Centre Zagreb, 10000 Zagreb, Croatia.
⁵ General Hospital Zabok, 49210 Zabok, Croatia.
⁶ Department of Neurology, University Hospital Centre Zagreb, 10000 Zagreb, Croatia.
⁷ Nash Family Department of Neuroscience, Friedman Brain Institute, Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.

Abstract

A decrease in serotonergic transmission throughout the brain is among the earliest pathological changes in Alzheimer's disease (AD). Serotonergic receptors are also affected in AD. Polymorphisms in genes of serotonin (5HT) receptors have been mostly associated with behavioral and psychological symptoms of dementia (BPSD). In this study, we examined if AD patients carrying different genotypes in 5HTR1B rs13212041, 5HTR2A rs6313 (T102C), 5HTR2C rs3813929 (-759C/T), and 5HTR6 rs1805054 (C267T) polymorphisms have a higher risk of faster disease progression (assessed by neuropsychological testing), are more prone to develop AD-related pathology (reflected by levels of cerebrospinal fluid [CSF] AD biomarkers), or have an association with an apolipoprotein E (APOE) haplotype. This study included 115 patients with AD, 53 patients with mild cognitive impairment (MCI), and 2701 healthy controls. AD biomarkers were determined in the CSF of AD and MCI patients using enzyme-linked immunosorbent assays (ELISA), while polymorphisms were determined using either TaqMan SNP Genotyping Assays or Illumina genotyping platforms. We detected a significant decrease in the CSF amyloid β_1-42 (Aβ_1-42) and an increase in p-tau₁₈₁/Aβ_1-42 ratio in carriers of the T allele in the 5HTR2C rs3813929 (-759C/T) polymorphism. A significantly higher number of APOE ε4 allele carriers was observed among individuals carrying a TT genotype within the 5HTR2A T102C polymorphism, a C allele within the 5HTR1B rs13212041 polymorphism, and a T allele within the 5HTR6 rs1805054 (C267T) polymorphism. Additionally, individuals carrying the C allele within the 5HTR1B rs13212041 polymorphism were significantly more represented among AD patients and had poorer performances on the Rey-Osterrieth test. Carriers of the T allele within the 5HTR6 rs1805054 had poorer performances on the MMSE and ADAS-Cog. As all four analyzed polymorphisms of serotonin receptor genes showed an association with either genetic, CSF, or neuropsychological biomarkers of AD, they deserve further investigation as potential early genetic biomarkers of AD.

Keywords: 5-hydroxytryptamine (serotonin); 5HT receptors; Alzheimer’s disease; Mini-Mental State Examination; apolipoprotein E; biomarkers; cerebrospinal fluid.

Abstract

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