Association of genetic variants in cyclin-dependent kinase 5 with Alzheimer's disease in a Saudi cohort

Abstract

BackgroundCyclin-dependent kinase 5 (CDK5) plays a critical role in neuronal development, synaptic plasticity, and cytoskeletal regulation. Its dysregulation has been implicated in Alzheimer's disease (AD); however, supporting genetic evidence remains limited in Middle Eastern populations.ObjectiveThis study aimed to identify CDK5 genetic variants in a Saudi cohort with AD and evaluate their association with disease susceptibility, without addressing downstream functional mechanisms.MethodsPeripheral blood samples were obtained from 52 Saudi patients with AD and 60 age- and sex-matched healthy controls. Genomic DNA was extracted and quantified using a NanoDrop One spectrophotometer. CDK5 exons 1, 2, 6, 7, and 12 were amplified and sequenced by Sanger methodology on an ABI 3500 Genetic Analyzer. Variant screening and frequency comparisons were performed between dementia and control groups.ResultsEight CDK5 variants were identified in exonic (2, 12) and intronic (1-2, 7-8, 11-12) regions, including three novel variants (c.105delG, c.858C > T, and one intronic variant). No variants were detected in exons 1, 6, or 7. Frameshift variants c.103del and c.105delG were significantly more frequent in AD cases (38%) than controls (5%) (p < 0.001). Conversely, the synonymous c.855C > T variant (Exon 12) was more common in controls (23%) than cases (5%) (p < 0.01), indicating a significant association between specific CDK5 variants and AD.ConclusionsIdentification of novel CDK5 variants associated with AD in a Saudi cohort highlights population-specific genetic susceptibility. Further functional and biomarker studies are needed to clarify their biological relevance.