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

Babić Leko, Mirjana; Nikolac Perković, Matea; Španić, Ena; Švob Štrac, Dubravka; Pleić, Nikolina; Vogrinc, Željka; Gunjača, Ivana; Bežovan, Dora; Nedić Erjavec, Gordana; Klepac, Nataša; Borovečki, Fran; Zemunik, Tatijana; Pivac, Nela; Hof, Patrick R.; Šimić, Goran (2022) Serotonin Receptor Gene Polymorphisms Are Associated with Cerebrospinal Fluid, Genetic, and Neuropsychological Biomarkers of Alzheimer’s Disease. Biomedicines, 10 (12). p. 3118. ISSN 2227-9059

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Official URL: http://doi.org/10.3390/biomedicines10123118

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 β1–42 (Aβ1–42) and an increase in p-tau181/Aβ1–42 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.

Item Type:

Article

Uncontrolled Keywords:

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

Subjects:

BIOMEDICINE AND HEALTHCARE > Clinical Medical Sciences

Divisions:

Division of Molecular Medicine

Projects:

Project title	Project leader	Project code	Project type
Uloga krvno-moždane barijere, urođene imunosti i oligomerizacije tau proteina u patogenezi Alzheimerove bolesti	Goran Šimić	IP-2019-04-3584	Znanstveno-istraživački projekti
Hiperfosforilacija, agregacija i transsinaptički prijenos tau proteina u Alzheimerovoj bolesti: analiza likvora i ispitivanje potencijalnih neuroprotektivnih spojeva	Goran Šimić	IP-2014-09-9730	Znanstveno-istraživački projekti
Reguliranje funkcije štitne i doštitne žlijezde i homeostaze kalcija u krvi	Tatijana Zemunik	IP-2019-04-2593	Znanstveno-istraživački projekti