Uncovering Ethnicity-Specific Recessive Loci for Alzheimer's Disease in 89 Dominican Families Using Family-Based WGS Analysis

In a sample of 89 Dominican families from the National Institute on Aging's Alzheimer's Disease Sequencing Project (ADSP), where at least one family member had a confirmed Alzheimer's disease (AD) diagnosis, we conducted an exploratory recessive whole-genome sequencing (WGS) analysis using family-based association testing (FBAT-GEE). This method tests jointly for affection status and age-at-onset under a recessive inheritance mode. Our analysis identified a genome-wide significant association for rs847697 in the PDK2 gene on chromosome 17, near the MAPT gene previously implicated in AD through linkage studies. Additionally, we detected four suggestive loci (p-value < 1 × 10⁻⁶). Given the unexpected strength of these associations in a modest sample size, we rigorously reviewed data quality, ruling out technical artifacts. The PDK2 association was driven by a small subset of families, aligning with recessive inheritance expectations. However, it could not be replicated in other AD datasets including Estudio Familiar de Influencia Genetica en Alzheimer (EFIGA), the National Institute of Mental Health (NIMH), and European Americans from NIA ADSP, suggesting a possible population-specific or ancestry-related effect. This study highlights the effectiveness of the FBAT approach in detecting unique genetic associations in smaller, isolated populations—findings that might be diluted in larger biobank studies where these populations are underrepresented.