| Summary: | 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 <i>5HTR1B</i> rs13212041, <i>5HTR2A</i> rs6313 (T102C), <i>5HTR2C</i> rs3813929 (−759C/T), and <i>5HTR6</i> 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 (<i>APOE</i>) 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<sub>1–42</sub> (Aβ<sub>1–42</sub>) and an increase in p-tau<sub>181</sub>/Aβ<sub>1–42</sub> ratio in carriers of the T allele in the <i>5HTR2C</i> rs3813929 (−759C/T) polymorphism. A significantly higher number of <i>APOE</i> ε4 allele carriers was observed among individuals carrying a TT genotype within the <i>5HTR2A</i> T102C polymorphism, a C allele within the <i>5HTR1B</i> rs13212041 polymorphism, and a T allele within the <i>5HTR6</i> rs1805054 (C267T) polymorphism. Additionally, individuals carrying the C allele within the <i>5HTR1B</i> 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 <i>5HTR6</i> 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.
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