Descriptive Analysis of Genetic Variants in Individuals Without a Clinical Diagnosis of Alzheimer's Disease in a Population from Southwestern Colombia.

Abstract

Introduction: Alzheimer's Disease (AD) is the most common cause of dementia worldwide and a chronic neurodegenerative disorder with well-established pathophysiological mechanisms. In Colombia, its prevalence is increasing, but in the southwestern region, information on its clinical course is scarce, limiting adequate care and public health strategies. This study aimed to describe the frequency and characteristics of genetic variants in AD candidate genes in a population in southwestern Colombia without a clinical diagnosis of the disease.

Methods: A descriptive observational analysis was conducted on 320 whole exomes from patients without a clinical diagnosis of AD. Reported genomic variants in the APOE, ABCA7, APP, PSEN1, PSEN2, and CLU genes were examined for allele frequency, clinical significance, and interaction network predictions to assess their genetic impact on the population.

Results: We identified 294 genetic variants, including 267 previously unreported. Among the 27 variants reported in ClinVar, most lacked a definitive clinical interpretation and were classified as Variants of Uncertain Significance (VUS) or as variants without a defined clinical significance in accordance with the guidelines of the American College of Medical Genetics and Genomics (ACMG). ABCA7 gene had the highest frequency of variants (n=164), and the PSEN1 gene had the lowest (n=14). While most variants lacked clinical significance, the APOE c.487C>T (p.Arg163Cys) variant was identified as likely pathogenic.

Discussion: The genetics of AD are complex and contribute to a predisposition to developing the disease; hence, the importance of conducting studies in our Colombian population, which is characterized by great genetic variability. In our study, we identified 267 unreported variants associated with the genes APOE, ABCA7, APP, PSEN1, PSEN2, and CLU. The lack of updated data in our population underscores the need for further research to determine their clinical impact.

Conclusion: This research contributes to characterizing AD genetic variability in the Colombian population and identifies several previously unreported variants. According to our results, we recommend studying their potential functional and clinical impact to improve early diagnosis and support the development of targeted therapies, thereby contributing to a better understanding of the disease in southwestern Colombia.