Introduction: The Genetic Landscape of Early-Onset Alzheimer’s Disease
Alzheimer’s disease (AD) is a heterogeneous neurodegenerative disorder traditionally classified by the age of symptom onset. While late-onset Alzheimer’s disease (LOAD), occurring after age 65, is the most prevalent form, early-onset Alzheimer’s disease (EOAD) presents a unique clinical challenge. While rare autosomal dominant mutations in APP, PSEN1, and PSEN2 account for a small fraction of EOAD cases, the genetic architecture of sporadic EOAD—which accounts for the majority of cases—remains largely elusive.
Recent advances in genomic medicine have shifted focus toward polygenic risk scores (PGS), which aggregate the cumulative effects of thousands of common genetic variants. While the utility of PGS in predicting LOAD is well-documented, its relevance to the distinct clinical and biological profile of EOAD has been less clear. A landmark study recently published in Alzheimer’s & Dementia, titled Alzheimer’s disease polygenic risk in early- and late-onset Alzheimer’s disease, sought to bridge this gap by evaluating how genetic risk factors identified in LOAD populations translate to the EOAD phenotype.
