Beyond Targeted Gene Panels: Whole-Exome Sequencing as a Strategic Platform for Precision Therapeutics in Alzheimer’s Disease

Alzheimer’s disease (AD) continues to be one of the greatest challenges in public health due to its multifactorial and heterogeneous nature, involving multiple physiological axes that encompass a large number of genetic, metabolic, vascular, and inflammatory interactions. In current clinical practice, medical specialties, mainly neurology and psychiatry, still rely on targeted gene panels for genetic evaluation. Although these panels remain effective for certain predefined hypotheses, their restricted and predefined nature limits the detection of the broader spectrum of genetic variation that may contribute to the complex biological interactions underlying neurodegeneration. Whole-exome sequencing (WES) is, from our clinic-based perspective, one of the most comprehensive genomic approaches currently available, since it allows the analysis of the ~19,500 protein-coding regions, and depending on the library approximately 5500 additional clinically relevant genomic loci, including splice sites, untranslated regions, long non-coding RNAs (lncRNAs), pseudogenes, regulatory elements and mitochondrial DNA (mtDNA). It enables the identification of pathogenic variants and variants of uncertain significance (VUS) under the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) classification frameworks. It also expands biological interpretation to variants conventionally classified as benign, which, when interpreted collectively, may contribute to pathway-level contextualization within the hypothesis-generating theoretical framework proposed in this review without implying pathogenicity, causal inference, or immediate clinical actionability. Additionally, WES enables the identification of secondary and incidental findings that may provide clinically relevant information beyond the primary phenotype, thereby supporting preventive surveillance and clinical risk management. This review analyzes the use of WES as a strategic platform for personalized decision-making in contemporary practice given the multifactorial and heterogeneous complexity of AD. It also addresses the complexities and limitations of the ACMG/AMP recommendations for filtering and classification of variants, the lack of standardization between reports and platforms, and the need for physician training, which constitute a great challenge for the translation of data to therapeutic decision-making. While the clinical utility of whole-exome sequencing (WES) in genetic diagnosis and precision medicine is well established, this review additionally proposes a hypothesis-generating theoretical framework whereby variants conventionally classified as benign or of uncertain significance may contribute to pathway-level biological contextualization in Alzheimer’s disease.