The functional minisatellite at the 3'-UTR of SLC6A3/DAT1 and dementia spectrum disorders: an association study in a population of Central Italy

Background: Dementia comprises a spectrum of neurodegenerative disorders marked by progressive cognitive and behavioural decline, with Alzheimer’s disease (AD) being the most prevalent form. While several genetic factors have been implicated in AD pathogenesis, a significant portion of heritability remains unexplained. One potential contributor to this “missing heritability” is structural variation within non-coding regions, such as variable-number tandem repeats (VNTRs). This study investigated the 40-bp VNTR located in the 3’ untranslated region of the SLC6A3/DAT1 (henceforth referred to as DAT1) gene, a polymorphism previously associated with dopamine regulation and psychiatric conditions, for potential associations with dementia spectrum disorders and related neuropsychiatric phenotypes. Methods: A cohort of 799 elderly individuals from Central Italy, including AD, mild cognitive impairment (MCI), mixed dementia, and control subjects, was genotyped for the DAT1 VNTR and the APOE alleles. Neuropsychiatric evaluation was performed using the Neuropsychiatric Inventory (NPI). Results: No significant association was observed between DAT1-VNTR genotypes and any dementia diagnosis. However, neuropsychiatric analysis revealed significant associations between DAT1-VNTR genotypes and behavioural symptoms. Carriers of the short (*S) allele showed association with apathy (especially in the presence of APOE*4), irritability, and disinhibition. The *S/*S genotype was notably linked to elevated NPI scores for irritability and disinhibition. Conclusions: These findings suggest that while the DAT1 VNTR is not directly associated with dementia diagnoses, it may contribute to modulating neuropsychiatric symptoms across dementia types. The results emphasize the importance of investigating non-coding genetic variants and their interactions with established risk alleles, such as APOE*4. Larger studies are needed to validate these findings and explore the functional consequences of DAT1 variation in neurodegeneration. This work contributes to our understanding of the dopaminergic system’s influence on behavioural phenotypes in dementia. It warrants the VNTR as a candidate contributing to neuropsychiatric symptom variability in aging populations.