Rare and novel genetic variants in sporadic and familial Alzheimer’s disease: insights from the first Saudi cohort

Background Alzheimer’s disease (AD) is a complex brain disorder that is greatly affected by genetics. Next-generation sequencing (NGS) has facilitated the discovery of rare variants in new genes that may be linked to AD in different populations. However, we still know very little about the genetic makeup of AD in Saudi Arabia and other Arab populations. Objectives This study aims to explore rare variants that are predicted to be deleterious in a group of 64 Saudi patients diagnosed with sporadic and familial Alzheimer’s disease (AD). These patients previously tested negative for mutations in genes known to cause AD and were genotyped for APOE alleles. Methods We performed whole-exome sequencing (WES) on the Ion Proton platform. Then, we used our internal process for filtering, validating, and prioritizing variants. Results Using stringent selection criteria, we identified 107 rare candidate variants with potential functional relevance. Of these, 26 (24.3%) were novel, while the remaining variants had been previously reported in public databases. Among these candidates, 33 were connected to AD, 28 to both AD and other neurodegenerative disorders (OND), 34 to OND-related functions, and 11 to broader processes like aging, inflammation, and neuronal regulation. We found rare missense variants in genes involved in important processes related to Alzheimer’s disease. These processes include mainly Aβ and Tau pathology, kinase signaling, stress response, and neuroinflammation. Conclusion Our analysis reveals diverse genetic contributors to Alzheimer’s disease in a population that remains largely underrepresented in genomic studies. We identified candidate variants in 53% of the patients, highlighting the value of expanding AD genetics research to non-European populations.