Alzheimer's disease: genetic background in the era of next-generation sequencing technologies

While rare, highly penetrant variants in APP, PSEN1 and PSEN2 are associated with early-onset Alzheimer's disease, especially its familial form, the disease in general is shaped by a complex interplay of various genetic factors. Both common and rare variants across numerous loci, which were identified mainly during large genome-wide association studies, contribute to disease risk, phenotypic heterogeneity and progression in both early- and late-onset forms. This review synthesizes current understanding of the genetic architecture of Alzheimer's disease in the era of next-generation sequencing, with particular emphasis on variant classes beyond single nucleotide polymorphisms. Structural variants, including copy number variations, tandem repeat expansions and transposable element insertions, are considered as potential contributors to the 'missing heritability' in Alzheimer's disease. In addition, we discuss somatic mosaicism that represents another layer of its complexity. We highlight how whole-genome sequencing, combined with advanced bioinformatic pipelines and reference resources, enables systematic detection of different variant types. We also outline the translational potential of genetic discoveries, including polygenic risk and hazard score models for patient stratification, and underscore the importance of integrative genomic and multi-omic approaches in advancing precision medicine in Alzheimer's disease.